WO2014106800A2 - Substituted 2-amino pyrimidine derivatives as kinase inhibitors - Google Patents

Substituted 2-amino pyrimidine derivatives as kinase inhibitors Download PDF

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WO2014106800A2
WO2014106800A2 PCT/IB2013/061358 IB2013061358W WO2014106800A2 WO 2014106800 A2 WO2014106800 A2 WO 2014106800A2 IB 2013061358 W IB2013061358 W IB 2013061358W WO 2014106800 A2 WO2014106800 A2 WO 2014106800A2
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amino
methyl
propyl
pyrimidin
oxo
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PCT/IB2013/061358
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French (fr)
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WO2014106800A3 (en
WO2014106800A8 (en
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Anima BORUAH
Subramanya Hosahalli
Sunil Kumar Panigrahi
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Aurigene Discovery Technologies Limited
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Publication of WO2014106800A8 publication Critical patent/WO2014106800A8/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/91—Oxygen atoms with aryl or aralkyl radicals attached in position 2 or 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to substituted 2-amino pyrimidine derivatives of formula (1) which are useful as kinase inhibitors.
  • the present invention relates also to the process for preparation of compounds of present invention and pharmaceutical composition thereof and their use 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 PI3K or at least one of such target.
  • Protein kinases play crucial role in regulating the different cell processes which include, but are not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation, signaling process and various regulatory mechanisms, by adding phosphate groups to the target protein residues (Hardie, G. and Hanks, S., The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA: 1995).
  • This phosphorylation event acts as molecular on/off switches that can modulate or regulate the target position biological function. Phosphorylation of targeted proteins occurs in response to a variety of extracellular signals.
  • the appropriate protein kinase functions in signaling pathways to activate or deactivate. Uncontrolled signaling due to defective control of protein phosphorylation is known to contribute to various diseases.
  • kinases are known to regulate many aspects of the cell growth, invasion that intrudes upon and destroys adjacent tissues and sometimes metastasis, or spreading to other locations in the body via lymph or blood.
  • Phosphatidylinositol (PI) 3-kinases are ubiquitous lipid kinases that function both as signal transducers down stream of cell surface receptors and in constitutive intracellular membrane and protein trafficking pathways. PI is known to play an important role in intracellular signal transduction. Cell signaling via 3'-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g. malignant transformation, growth factor signaling, inflammation, and immunity (Rameh et al (1999) J. Biol Chem, 274:8347-8350).
  • phosphatidylinositol 3-kinase also referred to as PI3-kinase or PI3K
  • PI3-kinase The enzyme responsible for generating these phosphorylated signaling products, phosphatidylinositol 3-kinase (also referred to as PI3-kinase or PI3K)
  • PI3-kinase also referred to as PI3-kinase or PI3K
  • All PI3Ks are dual-specificity enzymes with a lipid kinase activity that phosphorylates phosphoinositides at the 3-hydroxy position, and a less well characterized protein kinase activity (such as AKT, PDK1 and PKB).
  • the lipid products of PI3K catalysed reactions comprising phosphatidylinositol(3,4,5)-trisphosphate [PI(3,4,5)P3], [PI(3,4)P2] and [PI(3)P] act as second messengers apparently by recruiting kinases with lipid binding domains (including plekstrin homology (PH) regions), such as Akt and phosphoinositide-dependent kinase-1 (PDK1).
  • PH plekstrin homology
  • Akt and PDK1 Binding of Akt to membrane PIP3s causes the translocation of Akt to the plasma membrane, binding Akt into contact with PDK1, which is responsible for activating Akt.
  • the tumor-suppressor phosphatase i.e. Phosphatase and tensin homolog (PTEN) dephosphorylates PIP3 and therefore acts as a negative regulator of Akt activation.
  • the PI3-kinases Akt and PDK1 are important in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation (Vivanco et al ; Nature Rev.
  • mTOR also known as mammalian target of rapamycin or mechanistic target of rapamycin is a protein which in humans is encoded by the FRAP1 gene also belongs to the phosphatidylinositol 3-kinase-related kinase protein family.
  • Class I PI3Ks can phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-biphosphate (PIP2) to produce phosphatidylinositol-3-phosphate (PIP), phosphatidylinositol-3,4-biphosphate, and phosphatidylinositol-3,4,5-triphosphate, respectively.
  • Class II PI3Ks phosphorylate PI and phosphatidylinositol-4-phosphate
  • Class III PI3Ks can only phosphorylate PI.
  • PI3-kinase The initial purification and molecular cloning of PI3-kinase revealed that it was a heterodimer consisting of p85 and pi 10 subunits (Otsu et al., Cell , 65:91-104 (1991); Hiles et al., Cell , 70:419-29 (1992)). Since then, four distinct Class I PI3Ks have been identified, designated PI3K ⁇ , ⁇ , ⁇ , and ⁇ , each consisting of a distinct 110 kDa catalytic subunit and a regulatory subunit.
  • the delta ( ⁇ ) isoform of class I PI3K has been implicated, in particular, in a number of diseases and biological processes.
  • PI3K5 is expressed primarily in hematopoietic cells including leukocytes such as T-cells, dendritic cells, neutrophils, mast cells, B-cells, and macrophages.
  • PI3K5 is integrally involved in mammalian immune system functions such as T-cell function, IB- cell activation, mast cell activation, dendritic cell function, and neutrophil activity.
  • PI3K ⁇ Due to its integral role in immune system function, PI3K ⁇ is also involved in a number of diseases related to undesirable immune response such as allergic reactions, inflammatory diseases, inflammation mediated angiogenesis, rheumatoid arthritis, autoimmune diseases such as lupus, asthma, emphysema and other respiratory diseases.
  • Other class I PI3K involved in immune system function includes ⁇ , which plays a role in leukocyte signaling and has been implicated in inflammation, rheumatoid arthritis, and autoimmune diseases such as lupus.
  • WO2009/081105A1, WO2008/118454A1, WO2008/11455A1, WO2008/118468A1, WO2009/088986A1, WO2009/088986A1, WO2010/057048 Al, WO2011/146882A1, WO2013/012915A1, WO2013/012918A1 and WO2013032591A1 describe various series of quinoline and quinozoline derivatives that are structurally relates to each other and are stated to be useful to inhibit the biological activity of human PI3K and to be used in treating PI3K mediated diseases or disorders.
  • novel 2-amino pyrimidine derivatives of formula (1) according to the present invention may possess inhibitory activity of one or more protein kinases including PI3K, Akt, m- TOR, and are, therefore, expected to be useful in the treatment of kinase-associated diseases or disorders.
  • the present invention relates to substituted 2-amino pyrimidine derivatives of formula (1) which are useful as kinase inhibitors.
  • Ring A is bicyclic heterocyclyl ring containing 1-5 heteroatoms/heterogroups independently selected from N and -C(O)-;
  • R is selected from hydrogen, halogen and alkyl
  • R is selected from an optionally substituted heterocyclyl and optionally substituted aryl; wherein the optional substituents are selected from alkyl and halogen;
  • R 3 is selected from hydrogen and alkyl
  • R 4 is selected from hydrogen, alkyl, alkoxyalkyl and heterocyclyl
  • R 5 is selected from -S(0) 2 R 5a , -S(0) 2 NR 5a R 5b , -NHS(0) 2 R 5a and -C(0)NHR 5a ;
  • R 5a is selected from hydrogen and alkyl
  • R 5b is selected from hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted aryl; wherein the optional substituents are independently selected from halogen and alkyl;
  • R 5a and R 5b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-7 membered heterocyclyl ring; wherein the optional substituent is alkyl;
  • R 6 is selected from hydrogen, alkyl, halo, haloalkyl, nitro and amino;
  • R 7 and R 8 are independently selected from hydrogen or alkyl
  • R is selected from hydrogen, , , optionally substituted heterocyclyl; wherein the optional substituent is selected from alkyl or alkoxy;
  • R 8 and R 9 may be taken together with the carbon atom to which they are attached to form a 4-7 membered heterocyclyl ring having 1-4 heteroatoms/heterogroups independently selected from N, S and -C(O)-;
  • R 10 is selected from
  • each R a is independently selected from hydrogen and alkyl
  • each R b and R c are independently selected from hydrogen, alkyl, cycloalkyl and optionally substituted heterocyclyl; wherein the optional substituent is alkyl;
  • R b and R c can be taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclyl ring having 1-3 heteroatoms independently selected from N and O;
  • 'n' is an integer selected from 1 and 2.
  • it relates to the pharmaceutical composition comprising substituted 2-amino pyrimidine derivatives of formula (1) and process for preparing them.
  • Embodiments of the present invention provide substituted 2-amino pyrimidine derivatives of formula (1) which are useful as kinase inhibitors.
  • One of the embodiment of the present invention provide the compound of formula (1)
  • Ring A is bicyclic heterocyclyl ring containing 1-5 heteroatoms/heterogroups independently selected from N and -C(O)-;
  • R is selected from an optionally substituted heterocyclyl and optionally substituted aryl; wherein the optional substituents are selected from alkyl and halogen;
  • R 3 is selected from hydrogen and alkyl
  • R 4 is selected from hydrogen, alkyl, alkoxyalkyl and heterocyclyl; selected R and
  • R 5 is selected from -S(0) 2 R 5a , -S(0) 2 NR 5a R 5b , -NHS(0) 2 R 5a and -C(0)NHR 5a ;
  • R , 5a i ⁇ s selected from hydrogen and alkyl
  • R 5b is selected from hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted aryl; wherein the optional substituents are independently selected from halogen and alkyl;
  • R 5a and R 5b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-7 membered heterocyclyl ring; wherein the optional substituent is alkyl;
  • R 6 is selected from hydrogen, alkyl, halo, haloalkyl, nitro and amino;
  • R 7' and R 8° are independently selected from hydrogen or alkyl
  • R is selected from hydrogen
  • optionally substituted heterocyclyl wherein the optional substituent is selected from alkyl or alkoxy;
  • R 8 and R 9 may be taken together with the carbon atom to which they are attached to form a 4-7 membered heterocyclyl ring having 1-4 heteroatoms/heterogroups independently selected from N, S and -C(O)-;
  • R is selected from each R a is independently selected from hydrogen and alkyl
  • each R b and R c are independently selected from hydrogen, alkyl, cycloalkyl and optionally substituted heterocyclyl; wherein the optional substituent is alkyl;
  • R b and R c can be taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclyl ring having 1-3 heteroatoms independently selected from N and O;
  • 'n' is an integer selected from 1 and 2.
  • R 1 is selected from hydrogen, halogen (such as fluoro) and alkyl (such as methyl).
  • R 3 is hydrogen and alkyl (such as methyl).
  • R 4 is hydrogen, alkyl (such as ethyl), alkoxyalkyl (such as -( ⁇ 2 ) 2 0 ⁇ 3 ⁇ 4) and heterocyclyl (such as pyridine).
  • R 4 is hydrogen, alkyl (such as ethyl), alkoxyalkyl (such as -( ⁇ 2 ) 2 0 ⁇ 3 ⁇ 4) and heterocyclyl (such as pyridine).
  • com ounds of formula (1) in which R 4 is hydrogen, alkyl (such as ethyl), alkoxyalkyl (such as -( ⁇ 2 ) 2 0 ⁇ 3 ⁇ 4) and heterocyclyl (such as pyridine).
  • R 7 and R 8 are alkyl (such as methyl).
  • the compound of formula (1) is a compound of formula (la)
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A and ' n' are same as defined in formula (1), or a
  • the compound of formula (1) is a compound of formula (lb)
  • R 1 , R 2 , R 3 , R 4 , R 5 , A and 'n' are same as defined in formula (1), or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.
  • R 5 is -S(0) 2 R 5a ; wherein R 5a is alkyl (such as methyl and isopropyl).
  • the compound of formula (1) is a compound of formula (lc)
  • R 1 , R 2", R 3 J , R 4", R V', R 8°,R9", A and 'n' are same as defined in formula (1), or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.
  • the compound of formula (1) is a compound
  • R 1 , R 2 , R 3 , R 4 , R 10 , A and ' n' are same as defined in formula (1), or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.
  • the compound of formula ( 1 ) is selected from the group consisting of
  • 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 PI3K/Akt/m-TOR pathway kinase contribute to the pathology and/or symptomology of such diseases and/or disorders.
  • diseases and/or disorders mediated by one or more of these kinases are provided herein.
  • 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 PI3K kinase; more particularly ⁇ and PI3K5 isoforms.
  • the compounds of formula ( 1) are inhibitors of specific PI3K5 isoform and are used in the treatment and/or prevention of diseases and/or disorders associated with aberrant, abnormal or deregulated activity of PI3K5 isoform.
  • the compounds of formula (1) are specific dual inhibitors of ⁇ 3 ⁇ and PI3K5 isoforms and are used in the treatment and/or prevention of diseases and/or disorders associated with aberrant, abnormal or deregulated activity of PI3K5 and ⁇ 3 ⁇ isoforms.
  • Diseases and/or disorders associated with aberrant, abnormal or deregulated activity of PI3K/Akt/M-TOR pathway kinases 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, preferably all types of solid cancers and malignant lymphomas but not limited to leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumor, etc.
  • 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.
  • Alkoxy lalkyl 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 includes 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
  • 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 .
  • Niro refers to -N0 2 group.
  • 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 C6-C14 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 non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system.
  • Representative examples of a cycloalkyl include, but are not limited to cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-l-yl, octahydro-lH- inden-2-yl and decahydro-lH-benzo[7] annulen-2-yl.
  • a cycloalkyl 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 heteroatoms selected from oxygen, sulfur 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, azabenzimi
  • 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.
  • Hetero group refers to -C(O)-, -S(O), -NH and S(0) 2 .
  • Bicyclic ring containing 1-5 heteroatoms/groups refers to a saturated, partially saturated or unsaturated bicyclic ring, in which 9 to 12 of the ring carbon atoms have been independently replaced with a heteroatom/heterogroups such as N, O, S,-C(0)-, -S(O), -NH and S(0) 2 .
  • Representative examples of a 9 to 12 membered ring include, but are not limited to quinazolin-4(3H)-one, quinoline, lH-pyrazolo[3,4-d]pyrimidin-4(5H)-one, 3H-pyrrolo[3,4- d]pyrimidin-4(7H)-one, pyrido[2,3-d]pyrimidin-4(3H)-one and the like.
  • 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 2-amino pyrimidine 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.
  • the abbreviations used in the entire specification may be summarized herein below with their particular meaning.
  • Iodosuccinamide O/N (Overnight range: 8 to 8 hrs); PDA (photo diode array detector); Pd 2 (dba) 3 (tris dibenzylidene acetone) dipalladium; Pd(OAc) 2 (Palladiumdiacetate); Pd(dppf)Cl 2 ([l, l'-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane; Pd(Pph 3 ) 4 (Tetrakis (triphenylphosphine)palladium, P0C1 3 (Phsophorousoxychloride); ppm- ⁇ (parts per million); R.T(Room temperature range: 20 to 40°C); S (singlet); S0C1 2 (thionylchloride); t (triplet); TLC (Thin Layer Chromatography); THF (tetrahydrofuran); T
  • Scheme-b The general approach for the synthesis of intermediate- K is depicted in scheme-b.
  • the compound of formula H reacts with R -amine and compound of formula I in presence of triphenylphosphine to give compound of formula J, which on deprotection results in the formation of compound of formula K.
  • the Pd-catalyzed C-C coupling reaction can be carried out in suitable polar solvents such as DMF, propionitrile, ACN, THF or DMSO and the like, in a suitable organic bases such as TEA, DIPEA and the like by using catalysts such as Pd(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 or Pd 2 (dba) 3 and the like, at a temperature of about 100-130°C to give compound of formula (1A) and (IB) respectively.
  • suitable polar solvents such as DMF, propionitrile, ACN, THF or DMSO and the like
  • a suitable organic bases such as TEA, DIPEA and the like
  • catalysts such as Pd(OAc) 2 , Pd(PPh 3 ) 2 Cl 2 or Pd 2 (dba) 3 and the like
  • suitable ligands such P(o-tolyl) 3 , P(m-tolyl) 3 , BINAP or P(p-tolyl) 3 and the like, under standard back coupling condition gives compound of formula (1C).
  • the compound (1C-A) was prepared similar to the procedure depicted in the compound of formula (1C) by using compound 1.3 and compound 1.7, wherein the compound (1C-A) further undergoes cyclization with TMSI in presence of base such as NaH at appropriate conditions results in the compound of formula (ID).
  • work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent.
  • Purification includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.
  • Method B Column name: XTerra RP18 (250 mm x 4.6 mm), 5 ⁇
  • MobilePhase_used A: 0.1M KH 2 P0 4 (PH6.5); B: ACN.
  • MobilePhase_used A: 0.1M KH 2 P0 4 (PH6.5); B: ACN.
  • Method D Column_name: Chromolith RP18 (100 mm x 4.6 mm)
  • MobilePhase_used A: 0.01M KH 2 P0 4 (PH6.5); B: ACN.
  • Step-(iv) 1 -(2-(4-methylpiperazin- 1 - yl)quinolin-3 - vDpropan- 1 -ol (2D)
  • intermediate- 18F (0.035 g, 0.13 mmol), intermediate- 1C (0.046 mg, 0.19 mmol) and DIPEA (0.03 6g, 0.26 mmol) in n-butanol (2 ml) was stirred at 100°C for 48 h. The progress of the reaction was monitored by TLC. The reaction mixture cooled to room temperature, water (100 ml) was added and then extracted the aqueous layer with ethyl acetate (2 x 300 ml).
  • Triphenyl phosphite pyridine, 70°C, 7h; (11) TFA, DCM, 10°C-RT, 12h; (22C) (iii) DIPEA, n-Butanol, 1 10°C, 12h.
  • Intermediate-24 was prepared by following similar procedure as depicted in intermediate- 23, by using approprite raw materials at suitable conditions.
  • reaction mixture was cooled to room temperature, filtered through celite, washed celite bed with ethyl acetate and concentrated under reduced pressure to get the crude compound, which was purified by column chromatography using 100-200 mesh silica gel and 30% ethyl acetate in hexane.as eluent to achieve the pure product as a white solid (0.61 g, 38.3 %).
  • intermediates are prepared by using similar procedure as depicted in intermediate -29, by using approprite raw materials in presence of suitable reagents, ractants and solvents at suitable conditions. Most of these intermediates were used in the next step without further purification. Structure information and characterization data are given in below table.
  • Intermediate-46 was prepared by following similar procedure as depicted in intermediate- 45, by using approprite rawmaterials in presence of suitable reagents, reactants and solvents at suitable conditions
  • intermediate-47A 0.8 g, 3.01 mmol
  • 1,4-dioxane 30 ml
  • Pd(dppf) 2 Cl 2 Pd(dppf) 2 Cl 2 .
  • reaction mixture was stirred for 12 h at 100°C in a sealed tube. The progress of the reaction was monitored by TLC. After the reaction was completed, reaction mixture was filtered through celite and concentrated under reduced pressure to get the crude required compound (0.6 g, crude). MS (ES) m/z 243 (M+l).
  • Intermediate- 51 was prepared by following similar procedure as depicted in intermediate- 50, by using approprite rawmaterials in presence of suitable reactants, reagents and solvents at suitable conditions.
  • the present invention is further exemplified, but not limited, by the following examples that illustrate the preparation of compounds according to the invention.
  • EtOH: H 2 0 (7: 2: 1) was added LiOH (0.5 g, 20.8 mmol). The reaction mixture was stirred for overnight at room temperature. The solvents were evaporated under vacuum and acidified using dil.
  • Step-iii (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl) amino)pyr imidin- 5 - yl) aery licacid ( 1 )
  • ethyl acrylate 0.1 g, 1.0 mmol
  • Pd(OAc) 2 0.2 g, 0.1 mmol
  • K 2 C0 3 0.2 g, 1.2 mmol
  • BINAP 0.12 g, 0.2 mmol
  • step-(ii) of compound-2 The process of this step was adopted from step-(ii) of compound-2.
  • step-(i) of compound- 1 in method- 1 was adopted from step-(i) of compound- 1 in method- 1 by using intermediate-3 as starting compound.
  • MS (ES) m/z 527 (M+l) + .
  • Example-V Synthesis of tert-butyl 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)cyclopropane carboxylate (Compound-7) and 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydro quinazoli -2- l)propyl)amino)pyrimidin-5-yl)cyclopropanecarboxylic acid (Compound-8)
  • step-(iii) of compound- 1 from method- 1 by using compound- 1.1 as starting material.
  • MS (ES) m/z 499 (M+l) + .
  • Example- VII Synthesis of 2-(l-((2-amino-5-((lE, 3Z)-3-(hydroxyimino)but-l-en-l-yl)-6- methylpyrimidin-4-yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one (Compound- 11)
  • step-(i) of compound-3 The process of this step was adopted from step-(i) of compound-3.
  • MS (ES) m/z 547 (M+l) + .
  • step-(i) Ethyl acrylate, Pd(OAc) 2 , ⁇ , K 2 C0 3 , Toluene, H 2 0, Sealed tube, 120°C, Overnight
  • the process of this step was adopted from step-(i) of compound- 1 from method-2 by using intermediate-6 as starting compound.
  • Example-XII Synthesis of (Z)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylate (Compound-32) and (E)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin- 2-yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylate (Compound-33)
  • step-(i) of compound- 1 from method-2 by using intermediate-4 as starting compound and separated by coloumn chromatography.
  • Example-XIII Synthesis of (Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylic acid (Compound-34) and (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylicacid (Compound-35)
  • step-(ii) of compound- 1 in method- 1 was adopted from step-(ii) of compound- 1 in method- 1 by using ompound-32 and compound-33 as starting compounds.
  • the process of this step was adopted from compound-36 by using intermediate-2 as starting compound.
  • Example-XVIII Synthesis of (E)-ethyl 3-(2-amino-4-((l-(l,3-dimethyl-4-oxo-5-phenyl-4,5- dihydro-lH-pyrazolo[3,4-d]pyrimidin-6-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylate (Compound-59) and (E)-3-(2-amino-4-((l-(l,3-dimethyl-4-oxo-5-phenyl-4,5-dihydro-lH- pyrazolo[3,4-d]pyrimidin-6-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylic acid (Compound-60) (Interne diate-9) (Compound-59) (Compound-60)
  • step-(ii) of compound- 1 in method-2 The process of this step was adopted from step-(ii) of compound- 1 in method-2.
  • 'H-NMR 400 MHz, DMSO-Je) ⁇ 7.61-7.44 (m, 5H), 6.55 (brs, IH), 6.16 (s, 2H), 4.74 (s, IH), 3.9-3.8 (m, 2H), 2.38 (s, 3H), 2.18 (s, 3H), 1.76-1.59 (m, 2H), 1.23 (s, 3H), 0.64-0.61 (m, 3H).
  • Example-XXI Synthesis of 5-(2-amino-4-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydro quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-N-(tert-butyl)pyridine-3-sulfonamide (Compound-91)
  • PI3K assay kit obtained from Millipore, USA (cat # 33-016).
  • the PI3 kinase catalyses the phosphorylation of phosphatidylinositol, 5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5- trisphosphate (PIP3) in the presence of ATP and Mg2+.
  • the PIP3 product is detected by displacement of biotin-PIP3 from an energy transfer complex consisting of Europium labelled anti-GST monoclonal antibody, a GST-tagged pleckstrin homology (PH) domain, biotinylated PIP3 and Streptavidin-Allophycocyanin (APC). Excitation of Europium in the complex results in an energy transfer to the APC and a fluorescence emission at 665 nm.
  • an energy transfer complex consisting of Europium labelled anti-GST monoclonal antibody, a GST-tagged pleckstrin homology (PH) domain, biotinylated PIP3 and Streptavidin-Allophycocyanin (APC).
  • mTOR enzyme was obtained from Millipore, USA. 5 ⁇ g mTOR was used in the assay.
  • the reaction buffer was 50mM HEPES pH7.5, lmM EGTA, 3mM MnC12. Test compound was pre-incubated with mTOR for 30 min, and 50 nM Light-p70 S6K (Thr 389) Peptide was added along with 20 ⁇ ATP. After incubating the reaction mixture for 30 min, 1 nM Eu- labeled anti-phospho-substrate antibody (obtained from Perkin Elmer, USA) was added.
  • Fluorescence emission at 615 and 665 nM was measured upon excitation at 340 nM
  • the compound dilution was carried out in 100% DMSO followed by a buffer dilution.
  • the kinase reaction was incubated for lhr at room temperature followed by the addition of substrate- ATP mix and incubated for lhr at room temperature, the reaction was terminated by the addition of EDTA followed by the addition of detection mix.
  • IC50 values were subsequently determined using a sigmoidal dose -response curve.
  • the compounds were screened at ⁇ concentration and the results are summarized in the table below along with the IC 50 ( ⁇ ) details for selected examples.
  • the IC 50 values of the compounds are set forth in below Table wherein "A” refers to an IC 50 value of less than 0.01 ⁇ , "B” refers to IC 50 value in range of ⁇ . ⁇ to 0.1 ⁇ and "C” refers to IC 50 value of greater than 0.1 ⁇ .
  • PI3K assay kit obtained from Millipore, USA (cat # 33-016).
  • the PI3 kinase catalyses the phosphorylation of phosphatidylinositol, 5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5- trisphosphate (PIP3) in the presence of ATP and Mg2+.
  • the PIP3 product is detected by displacement of biotin-PIP3 from an energy transfer complex consisting of Europium labelled anti-GST monoclonal antibody, a GST-tagged pleckstrin homology (PH) domain, biotinylated PIP3 and Streptavidin-Allophycocyanin (APC). Excitation of Europium in the complex results in an energy transfer to the APC and a fluorescence emission at 665 nm.
  • an energy transfer complex consisting of Europium labelled anti-GST monoclonal antibody, a GST-tagged pleckstrin homology (PH) domain, biotinylated PIP3 and Streptavidin-Allophycocyanin (APC).
  • PI3 kinase(pl20y) /PIP2 mixture was added to compound wells and incubated for 30 min at room temp for 60 min.
  • PI3 kinase ( ⁇ 120 ⁇ ) was procured from Millipore (cat No: 14-558).
  • 150 ng of PI3 kinase ( ⁇ 120 ⁇ ) was used in the assay.
  • the kinase reaction was started by the addition of ATP.
  • the assay concentrations of both PIP2 and ATP were 10 ⁇ .
  • the reaction mixture was incubated for 30 minutes and was terminated by the addition of stop mix and detection mix.
  • PI3K assay kit obtained from Millipore, USA (cat # 33-016).
  • the PI3 kinase catalyses the phosphorylation of phosphatidylinositol, 5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5- trisphosphate (PIP3) in the presence of ATP and Mg2+.
  • the PIP3 product is detected by displacement of biotin-PIP3 from an energy transfer complex consisting of Europium labelled anti-GST monoclonal antibody, a GST-tagged pleckstrin homology (PH) domain, biotinylated PIP3 and Streptavidin-Allophycocyanin (APC). Excitation of Europium in the complex results in an energy transfer to the APC and a fluorescence emission at 665 nm.
  • an energy transfer complex consisting of Europium labelled anti-GST monoclonal antibody, a GST-tagged pleckstrin homology (PH) domain, biotinylated PIP3 and Streptavidin-Allophycocyanin (APC).
  • the reaction mixture was incubated for 30 minutes and was terminated by the addition of stop mix and detection mix. Fluorescence was measured at 615 and 665 nm upon excitation at 340 nm in a Victor X5 fluorimeter (Perkin Elmer, USA). The fluorescence emission ratio at 665 to 615 nm, proportional to the kinase activity, was plotted against the compound concentration to generate dose -response curves and IC50 values were determined.
  • the compounds were screened for selective inhibition of ⁇ and PI3K5 at 1 nM concentration and the results are summarized in the table below along with the IC 50 (nM) details for selected compounds.
  • the IC 50 values of the compounds are set forth in below Table, wherein "A” refers to an IC 50 value in less than 20 nM, “B” refers to IC 50 value in range of 20.01 to 100 nM and “C” refers to IC 50 value in range of 100.1 nM to 1000 nM.
  • % inhibition of ⁇ 3 ⁇ and PI3K5 at ⁇ M concentration of selected compounds are set forth in below table.

Abstract

The present invention provides novel substituted 2-amino pyrimidine derivatives kinase enzyme inhibitor compounds of formula (1), which may be therapeutically useful kinase inhibitor, more particularly PI3K inhibitors. Formula (1) in which A, R1, R2 R3. R4, Q and 'n' have the same meanings given in the specification, and pharmaceutically acceptable salts and stereoisomers thereof that are useful in the treatment and prevention in diseases or disorder, in particular their use in diseases or disorder where there is an advantage in inhibiting kinase enzyme, more particularly PI3K enzyme. The present invention also provides methods for synthesizing and administering the kinase inhibitor compounds. The present invention also provides pharmaceutical formulations comprising at least one of the kinase inhibitor compounds together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

Description

"SUBSTITUTED 2-AMINO PFRIMIDINE DERIVATIVES AS KINASE INHIBITORS"
This application claims the benefit of Indian provisional application number 39/CHE/2013 filed on 04th January 2013 and 3029/CHE/2013 filed on 05th July 2013 which hereby incorporated by reference.
FIELD OF THE INVENTION
The present invention relates to substituted 2-amino pyrimidine derivatives of formula (1) which are useful as kinase inhibitors.
Figure imgf000002_0001
The present invention relates also to the process for preparation of compounds of present invention and pharmaceutical composition thereof and their use 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 PI3K or at least one of such target.
BACKGROUND AND PRIOR ART
Protein kinases play crucial role in regulating the different cell processes which include, but are not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation, signaling process and various regulatory mechanisms, by adding phosphate groups to the target protein residues (Hardie, G. and Hanks, S., The Protein Kinase Facts Book, I and II, Academic Press, San Diego, CA: 1995). This phosphorylation event acts as molecular on/off switches that can modulate or regulate the target position biological function. Phosphorylation of targeted proteins occurs in response to a variety of extracellular signals. The appropriate protein kinase functions in signaling pathways to activate or deactivate. Uncontrolled signaling due to defective control of protein phosphorylation is known to contribute to various diseases. In the case of cancer, kinases are known to regulate many aspects of the cell growth, invasion that intrudes upon and destroys adjacent tissues and sometimes metastasis, or spreading to other locations in the body via lymph or blood.
Phosphatidylinositol (PI) 3-kinases (PI3Ks) are ubiquitous lipid kinases that function both as signal transducers down stream of cell surface receptors and in constitutive intracellular membrane and protein trafficking pathways. PI is known to play an important role in intracellular signal transduction. Cell signaling via 3'-phosphorylated phosphoinositides has been implicated in a variety of cellular processes, e.g. malignant transformation, growth factor signaling, inflammation, and immunity (Rameh et al (1999) J. Biol Chem, 274:8347-8350). The enzyme responsible for generating these phosphorylated signaling products, phosphatidylinositol 3-kinase (also referred to as PI3-kinase or PI3K), was originally identified as an activity associated with viral oncoproteins and growth factor receptor tyrosine kinases that phosphorylate phosphatidylinositol (PI) and its phosphorylated derivatives at the 3'-hydroxyl of the inositol ring (Panayotou et al (1992) Trends Cell Biol 2:358-60).
All PI3Ks are dual-specificity enzymes with a lipid kinase activity that phosphorylates phosphoinositides at the 3-hydroxy position, and a less well characterized protein kinase activity (such as AKT, PDK1 and PKB). The lipid products of PI3K catalysed reactions comprising phosphatidylinositol(3,4,5)-trisphosphate [PI(3,4,5)P3], [PI(3,4)P2] and [PI(3)P] act as second messengers apparently by recruiting kinases with lipid binding domains (including plekstrin homology (PH) regions), such as Akt and phosphoinositide-dependent kinase-1 (PDK1). Binding of Akt to membrane PIP3s causes the translocation of Akt to the plasma membrane, binding Akt into contact with PDK1, which is responsible for activating Akt. The tumor-suppressor phosphatase i.e. Phosphatase and tensin homolog (PTEN), dephosphorylates PIP3 and therefore acts as a negative regulator of Akt activation. The PI3-kinases Akt and PDK1 are important in the regulation of many cellular processes including cell cycle regulation, proliferation, survival, apoptosis and motility and are significant components of the molecular mechanisms of diseases such as cancer, diabetes and immune inflammation (Vivanco et al ; Nature Rev. Cancer 2: 489 (2002); Phillips et al ; Cancer 83 :41(1998)). mTOR also known as mammalian target of rapamycin or mechanistic target of rapamycin is a protein which in humans is encoded by the FRAP1 gene also belongs to the phosphatidylinositol 3-kinase-related kinase protein family.
Presently, the PI3-kinase enzyme family has been divided into three classes based on their substrate specificities. Class I PI3Ks can phosphorylate phosphatidylinositol (PI), phosphatidylinositol-4-phosphate, and phosphatidylinositol-4,5-biphosphate (PIP2) to produce phosphatidylinositol-3-phosphate (PIP), phosphatidylinositol-3,4-biphosphate, and phosphatidylinositol-3,4,5-triphosphate, respectively. Class II PI3Ks phosphorylate PI and phosphatidylinositol-4-phosphate, whereas Class III PI3Ks can only phosphorylate PI.
The initial purification and molecular cloning of PI3-kinase revealed that it was a heterodimer consisting of p85 and pi 10 subunits (Otsu et al., Cell , 65:91-104 (1991); Hiles et al., Cell , 70:419-29 (1992)). Since then, four distinct Class I PI3Ks have been identified, designated PI3K α, β, δ, and γ, each consisting of a distinct 110 kDa catalytic subunit and a regulatory subunit. More specifically, three of the catalytic subunits, i.e., pi 10a, ρΐ ΐθβ and ρΐ ΐθδ, each interact with the same regulatory subunit, p85; whereas ρΐ ΐθγ interacts with a distinct regulatory subunit, plOl. As described below, the patterns of expression of each of these PI3Ks in human cells and tissues are also distinct. Though a wealth of information has been accumulated in recent past on the cellular functions of PI 3-kinases in general, the roles played by the individual isoforms are largely unknown.
The delta (δ) isoform of class I PI3K has been implicated, in particular, in a number of diseases and biological processes. PI3K5 is expressed primarily in hematopoietic cells including leukocytes such as T-cells, dendritic cells, neutrophils, mast cells, B-cells, and macrophages. PI3K5 is integrally involved in mammalian immune system functions such as T-cell function, IB- cell activation, mast cell activation, dendritic cell function, and neutrophil activity. Due to its integral role in immune system function, PI3K δ is also involved in a number of diseases related to undesirable immune response such as allergic reactions, inflammatory diseases, inflammation mediated angiogenesis, rheumatoid arthritis, autoimmune diseases such as lupus, asthma, emphysema and other respiratory diseases. Other class I PI3K involved in immune system function includes ΡΒΚγ, which plays a role in leukocyte signaling and has been implicated in inflammation, rheumatoid arthritis, and autoimmune diseases such as lupus.
WO2009/081105A1, WO2008/118454A1, WO2008/11455A1, WO2008/118468A1, WO2009/088986A1, WO2009/088986A1, WO2010/057048 Al, WO2011/146882A1, WO2013/012915A1, WO2013/012918A1 and WO2013032591A1 describe various series of quinoline and quinozoline derivatives that are structurally relates to each other and are stated to be useful to inhibit the biological activity of human PI3K and to be used in treating PI3K mediated diseases or disorders. The novel 2-amino pyrimidine derivatives of formula (1) according to the present invention may possess inhibitory activity of one or more protein kinases including PI3K, Akt, m- TOR, and are, therefore, expected to be useful in the treatment of kinase-associated diseases or disorders.
SUMMARY OF THE INVENTION
The present invention relates to substituted 2-amino pyrimidine derivatives of formula (1) which are useful as kinase inhibitors.
In one aspect of the present invention relates to the compound of formula (1)
Figure imgf000005_0001
or a pharmaceutically acceptable salts or a pharmaceutically acceptable stereoisomers thereof; wherein,
Ring A is bicyclic heterocyclyl ring containing 1-5 heteroatoms/heterogroups independently selected from N and -C(O)-;
R is selected from hydrogen, halogen and alkyl;
R is selected from an optionally substituted heterocyclyl and optionally substituted aryl; wherein the optional substituents are selected from alkyl and halogen;
R3 is selected from hydrogen and alkyl;
R4 is selected from hydrogen, alkyl, alkoxyalkyl and heterocyclyl;
and
Figure imgf000005_0002
R5 is selected from -S(0)2R5a, -S(0)2NR5aR5b, -NHS(0)2R5a and -C(0)NHR5a;
R5a is selected from hydrogen and alkyl;
R5b is selected from hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted aryl; wherein the optional substituents are independently selected from halogen and alkyl;
alternatively, R5a and R5b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-7 membered heterocyclyl ring; wherein the optional substituent is alkyl;
R6 is selected from hydrogen, alkyl, halo, haloalkyl, nitro and amino;
R 7 and R 8 are independently selected from hydrogen or alkyl;
R is selected from hydrogen,
Figure imgf000006_0001
, ,
Figure imgf000006_0002
optionally substituted heterocyclyl; wherein the optional substituent is selected from alkyl or alkoxy;
alternatively, R 8 and R 9 may be taken together with the carbon atom to which they are attached to form a 4-7 membered heterocyclyl ring having 1-4 heteroatoms/heterogroups independently selected from N, S and -C(O)-;
R10 is selected from
Figure imgf000006_0003
each Ra is independently selected from hydrogen and alkyl;
each Rb and Rc are independently selected from hydrogen, alkyl, cycloalkyl and optionally substituted heterocyclyl; wherein the optional substituent is alkyl;
alternatively, Rb and Rc can be taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclyl ring having 1-3 heteroatoms independently selected from N and O; and
'n' is an integer selected from 1 and 2. In another aspect of the present invention, it relates to the pharmaceutical composition comprising substituted 2-amino pyrimidine derivatives of formula (1) and process for preparing them.
In further another aspect of the present invention, it relates to the use of compounds of formula (1), its pharmaceutically acceptable salts or pharmaceutically acceptable stereoisomers thereof, including mixtures thereof in all suitable ratios wherever applicable as a medicament for the treatment and prevention of disorders or diseases by inhibitory action on enzymes- PI3K, AKT and m-TOR thereof.
DETAILED DESCRIPTION OF THE INVENTION
Embodiments of the present invention provide substituted 2-amino pyrimidine derivatives of formula (1) which are useful as kinase inhibitors.
One of the embodiment of the present invention provide the compound of formula (1)
Figure imgf000007_0001
(1)
or a pharmaceutically acceptable salts or a pharmaceutically acceptable stereoisomers thereof; wherein,
Ring A is bicyclic heterocyclyl ring containing 1-5 heteroatoms/heterogroups independently selected from N and -C(O)-;
selected from hydrogen, halogen and alkyl;
R is selected from an optionally substituted heterocyclyl and optionally substituted aryl; wherein the optional substituents are selected from alkyl and halogen;
R3 is selected from hydrogen and alkyl;
R4 is selected from hydrogen, alkyl, alkoxyalkyl and heterocyclyl; selected
Figure imgf000008_0001
R and
Figure imgf000008_0002
R5 is selected from -S(0)2R5a, -S(0)2NR5aR5b, -NHS(0)2R5a and -C(0)NHR5a;
R , 5a i ·s selected from hydrogen and alkyl;
R5b is selected from hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted aryl; wherein the optional substituents are independently selected from halogen and alkyl;
alternatively, R5a and R5b can be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-7 membered heterocyclyl ring; wherein the optional substituent is alkyl;
R6 is selected from hydrogen, alkyl, halo, haloalkyl, nitro and amino;
R 7' and R 8° are independently selected from hydrogen or alkyl;
R is selected from hydrogen,
Figure imgf000008_0003
Figure imgf000008_0004
optionally substituted heterocyclyl; wherein the optional substituent is selected from alkyl or alkoxy;
alternatively, R 8 and R 9 may be taken together with the carbon atom to which they are attached to form a 4-7 membered heterocyclyl ring having 1-4 heteroatoms/heterogroups independently selected from N, S and -C(O)-;
R is selected from
Figure imgf000008_0005
each Ra is independently selected from hydrogen and alkyl;
each Rb and Rc are independently selected from hydrogen, alkyl, cycloalkyl and optionally substituted heterocyclyl; wherein the optional substituent is alkyl;
alternatively, Rb and Rc can be taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclyl ring having 1-3 heteroatoms independently selected from N and O; and
'n' is an integer selected from 1 and 2.
The embodiment below are illustrative of the present invention and are not intended to limit the claims to the specific embodiments exemplified.
According to one embodiment, specifically provided are compounds of formula (1), in which Ring A is selected from
Figure imgf000009_0001
According to yet another embodiment, specifically provided are compounds of formula (1), in which R1 is selected from hydrogen, halogen (such as fluoro) and alkyl (such as methyl).
According to yet another embodiment, specifically provided are compounds of formula in which
Figure imgf000009_0002
According to yet another embodiment, specifically provided are compounds of formula (1), in which R3 is hydrogen and alkyl (such as methyl).
According to yet another embodiment, specifically provided are compounds of formula (1), in which R4 is hydrogen, alkyl (such as ethyl), alkoxyalkyl (such as -(ϋί2)20Ο¾) and heterocyclyl (such as pyridine). Accordin to yet another embodiment, specifically provided are com ounds of formula
Figure imgf000010_0001
According to yet another embodiment, specifically provided are compounds of formula (1), in which R6 is hydrogen or amino.
According to yet another embodiment specifically provided are compounds of formula
(1), in which R 7 and R 8 are alkyl (such as methyl).
According to yet another embodiment, specifically provided are compounds of formula
Figure imgf000010_0002
Figure imgf000011_0001
According to yet another embodiment, specifically provided are compounds of formula
(1), in which R10 is selected
Figure imgf000011_0002
,
According to yet another embodiment, specifically provided are compounds of formula (1), in which 'n' is an integer selected from 1 and 2.
According to yet another embodiment of the present invention, the compound of formula (1) is a compound of formula (la)
Figure imgf000011_0003
wherein, R1, R2, R3, R4, R5, R6, A and ' n' are same as defined in formula (1), or a
pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.
According to preceding embodiment, specifically provided are compounds of formula (la), in which ring A is selected from
Figure imgf000011_0004
According to yet another embodiment of the present invention, the compound of formula (1) is a compound of formula (lb)
Figure imgf000012_0001
wherein, R1, R2, R3, R4, R5, A and 'n' are same as defined in formula (1), or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.
According to preceding embodiment, specifically provided are compounds of formula
(lb), in which ring A is
Figure imgf000012_0002
According to one of the preceding embodiment, specifically provided are compounds of formula (lb), in which R5 is -S(0)2R5a; wherein R5a is alkyl (such as methyl and isopropyl).
According to further yet another embodiment of the present invention, the compound of formula (1) is a compound of formula (lc)
Figure imgf000012_0003
wherein, R 1 , R 2", R 3J, R 4", R V', R 8°,R9", A and 'n' are same as defined in formula (1), or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.
According to preceding embodiment, specifically provided are compounds of formula (lc wherein Rin A is selected from
Figure imgf000013_0001
According to further yet another embodiment of the present invention, the compound of formula (1) is a compound
Figure imgf000013_0002
wherein, R1, R2, R3, R4, R10, A and ' n' are same as defined in formula (1), or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.
According to preceding embodiment, specifically provided are compounds of formula
(Id), wherein Ring A is
Figure imgf000013_0003
In yet another particular embodiment of the present invention, the compound of formula ( 1 ) is selected from the group consisting of
Comp. Compound Name
No
1. (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl) amino) pyrimidin-5-yl) acrylic acid; (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5 -yl) acrylamide ;
(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-isopropylacrylamide;
(E)-2-(l-((2-amino-6-methyl-5-(3-oxo-3-(piperazin-l-yl)prop-l-en-l-yl)pyrimidin-4 yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-( l-((2-amino-6-methyl-5-(3-morpholino-3-oxoprop- 1 -en- 1 -yl)pyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-cyclopropylacrylamide;
tert-butyl 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydro quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)cyclopropanecarboxylate;
2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl) amino)pyr imidin- 5 - yl)cyclopropanecarboxylic acid ;
(E)-tert -butyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydro quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acrylate;
(E)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acrylate;
2-( 1 -((2-amino-5-(( lE,3Z)-3-(hydroxyimino)but- 1 -en- 1 -yl)-6-methylpyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-ethyl 3-(2-amino-4-methyl-6-((l-(2-(4-methylpiperazin-l-yl)quinolin-3-yl) propyl) amino)pyr imidin- 5 - yl)acry late ;
(E)-3-(2-amino-4-methyl-6-(( 1 -(2-(4-methylpiperazin- 1 -yl)quinolin-3-yl)propyl) amino)pyrimidin- 5 - yl)acr ylic acid ;
(Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)but-2-enoic acid;
(Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(tert-butyl)but-2-enamide;
(Z)-2-(l-((2-amino-6-methyl-5-(4-morpholino-4-oxobut-2-en-2-yl)pyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one; (Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-cyclopropylbut-2-enamide;
(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(pyridin-2-yl)acrylamide;
(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(pyridin-3-yl)acrylamide;
(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(pyridin-4-yl)acrylamide;
(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(thiazol-2-yl)acrylamide;
(E)-2-( l-((2-amino-6-methyl-5-(3-oxo-3-(lH-pyrazol- l-yl)prop- 1-en- l-yl)pyrimidin- 4-yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-methylacrylamide;
(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-ethylacrylamide;
2-(l-((2-amino-6-methyl-5-vinylpyrimidin-4-yl)amino)propyl)-5-methyl-3-phenyl quinazolin-4(3H)-one;
(E)-ethyl 3-(2-amino-4-methyl-6-((l-(l-methyl-4-oxo-5-phenyl-4,5-dihydro-lH- pyrazolo[3,4-d]pyrimidin-6-yl)propyl)amino)pyrimidin-5-yl)acrylate;
(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(6-methylpyridin-2-yl)acrylamide;
(E)-2-(l-((2-amino-6-methyl-5-(3-oxo-3-(pyrrolidin-l-yl)prop-l-en-l-yl)pyrimidin- 4-yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((2-amino-6-methyl-5-(3-oxo-3-(piperidin-l-yl)prop-l-en-l-yl)pyrimidin-4- yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N,N-dimethylacrylamide;
(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-ethyl-N-methylacrylamide; (Z)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydro quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylate;
(E)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydro quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylate;
(Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylic acid;
(E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylic acid;
(E)-2-(l-((2-amino-6-methyl-5-(3-oxo-3-(pyrrolidin-l-yl)prop-l-en-l-yl) pyrimidin- 4-yl) amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((2-amino-6-methyl-5-(2-(pyridin-2-yl)vinyl)pyrimidin-4-yl) amino)propyl) -5-fluoro-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((2-amino-6-methyl-5-(2-(4-methylthiazol-2-yl)vinyl)pyrimidin-4-yl)amino) propyl) -5-fluoro-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((5-(2-(lH-imidazol-4-yl)vinyl)-2-amino-6-methylpyrimidin-4-yl)amino) propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((5-(2-(lH etrazol-5-yl)vinyl)-2-amino-6-methylpyrimidin-4-yl)amino) propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
(E)-2-( l-((5-(2-( lH-tetrazol-5-yl)vinyl)-2-amino-6-methylpyrimidin-4-yl) amino) propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((2-amino-6-methyl-5-(3-oxobut-l-en-l-yl)pyrimidin-4-yl) amino) propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((5-(2-(lH-imidazol-4-yl)vinyl)-2-amino-6-methylpyrimidin-4-yl)amino) propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((2-amino-6-methyl-5-(2-(6-methylpyridin-2-yl)vinyl)pyrimidin-4- yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((2-amino-6-methyl-5-(2-(5-methylpyridin-2-yl)vinyl)pyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((2-amino-6-methyl-5-(2-(pyridin-2-yl)vinyl)pyrimidin-4-yl)amino)propyl) -5-methyl-3-phenylquinazolin-4(3H)-one; (E)-2-(l-((2-amino-6-methyl-5-(2-(pyridin-3-yl)vinyl)pyrimidin-4-yl) amino)propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((2-amino-6-methyl-5-(2-(pyridin-4-yl)vinyl)pyrimidin-4-yl) amino)propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((2-amino-5-(2-(3-methoxy-6-methylpyridin-2-yl)vinyl)-6-methylpyrimidin- 4-yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((2-amino-6-methyl-5-(2-(3-methylpyridin-2-yl)vinyl)pyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((2-amino-6-methyl-5-(2-(4-methylpyridin-3-yl)vinyl)pyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((2-amino-5-(2-(6-methoxypyridin-3-yl)vinyl)-6-methylpyrimidin-4-yl) amino) propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((2-amino-6-methyl-5-(2-(l-methyl-lH-tetrazol-5-yl)vinyl)pyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-( l-((2-amino-6-methyl-5-(2-(thiazol-2-yl)vinyl)pyrimidin-4-yl) amino) propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;
(E)-2-(l-((2-amino-6-methyl-5-(2-(l-methyl-lH-imidazol-2-yl)vinyl)pyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl)amino)pyrimidin-5-yl)cyclopropanecarboxamide;
(E)-6-methyl-N4-(l-(2-(4-methylpiperazin-l-yl)quinolin-3-yl)propyl)-5-(2-(pyridin- 2-yl)vinyl)pyrimidine-2,4-diamine;
(E)-5-(2-(6-methoxypyridin-3-yl)vinyl)-6-methyl-N4-( 1 -(2-(4-methylpiperazin- 1 -yl) quino lin- 3 - yl)propyl)pyrimidine-2 ,4-diamine ;
(E)-ethyl 3-(2-amino-4-((l-(l,3-dimethyl-4-oxo-5-phenyl-4,5-dihydro-lH-pyrazolo [3,4-d]pyrimidin-6-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylate;
(E)-3-(2-amino-4-((l-(l,3-dimethyl-4-oxo-5-phenyl-4,5-dihydro-lH-pyrazolo [3,4-d] pyrimidin-6-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylic acid;
(E)-ethyl 3-(2-amino-4-((l-(3-(4-fluorophenyl)-5-methyl-4-oxo-3,4-dihydro quinazolin2- yl)propyl) amino )- 6- methylpyr imidin- 5 - yl) aery late ; (E)-3-(2-amino-4-((l-(3-(4-fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino )- 6-methylpyr imidin- 5 - yl) acrylic acid ;
(E)-3-(2-amino-4-((l-(3-(4-fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino )- 6-methylpyr imidin- 5 - yl) acrylamide ;
(E)-3-(2-amino-4-((l-(3-(4-fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)-6-methylpyrimidin-5-yl)-N-(pyridin-3-yl)acrylamide;
(E)-2-(l-((5-(2-(lH-tetrazol-5-yl)vinyl)-2-amino-6-methylpyrimidin-4-yl)amino) propyl)-3-(4-fluorophenyl)-5-methylquinazolin-4(3H)-one;
(E)-ethyl 3-(2-amino-4-methyl-6-((l-(8-methyl-2-(4-methylpiperazin-l-yl)quinolin- 3 - yl) propyl) amino)pyr imidin- 5 - yl) aery late ;
(E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-(4-methylpiperazin-l-yl)quinolin-3-yl) propyl) amino)pyr imidin- 5 - yl)acry lie acid ;
(E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-(4-methylpiperazin-l-yl)quinolin-3-yl) propyl) amino)pyr imidin- 5 - yl)acry lamide ;
(E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2-(4-methylpiperazin-l- yl) quino lin- 3 - yl)propyl)pyrimidine-2 ,4-diamine ;
(E)-ethyl 3-(2-amino-4-methyl-6-((l-(2-thiomorpholinoquinolin-3-yl)propyl)amino) pyr imidin- 5 - yl)acry late ;
(E)-3-(2-amino-4-methyl-6-((l-(2-thiomorpholinoquinolin-3-yl)propyl)amino) pyrimidin-5-yl)acrylic acid;
(E)-3-(2-amino-4-methyl-6-((l-(2-thiomorpholinoquinolin-3-yl)propyl)amino) pyr imidin- 5 - yl)acry lamide ;
(E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(2-thiomorpholinoquinolin-3- yl)propyl)pyrimidine-2,4-diamine;
(E)-ethyl 3-(2-amino-4-methyl-6-((l-(8-methyl-2-thiomorpholinoquinolin-3-yl) propyl) amino)pyr imidin- 5 - yl)acry late ;
(E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-thiomorpholinoquinolin-3-yl)propyl) amino)pyrimidin- 5 - yl)acr ylic acid ;
(E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-thiomorpholinoquinolin-3-yl)propyl) amino)pyrimidin- 5 - yl)acr ylamide ; 77. (E)-5-(2 lH etrazol-5-yl)vinyl)-6-methyl-N4-(l 8-methyl-2-thiomorpholino quino lin- 3 - yl)propyl)pyrimidine-2 ,4-diamine ;
78. (E)-ethyl 3-(2-amino-4-methyl-6-((l-(8-methyl-2-morpholinoquinolin-3-yl) propyl) amino)pyrimidin- 5 - yl)acr ylate ;
79. (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-morpholinoquinolin-3-yl) propyl)
amino)pyrimidin- 5 - yl)acr ylic acid ;
80. (E)-5-(2-(lH etrazol-5-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2-morpholinoquinolin -3 -yl)propyl)pyrimidine-2,4-diamine ;
81. (E)-5-(2-(3-methoxypyridin-2-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2-morpholino quino lin- 3 - yl)propyl)pyrimidine-2 ,4-diamine ;
82. (E)-6-methyl-5-(2-(l-methyl-lH-tetrazol-5-yl)vinyl)-N4-(l-(8-methyl-2-morpholino quino lin- 3 - yl)propyl)pyrimidine-2 ,4-diamine ;
83. (E)-ethyl 3-(2-amino-4-((l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methylquinolin -3-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylate;
84. (E)-3-(2-amino-4-((l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methylquinolin-3-yl) propyl)amino)-6-methylpyrimidin-5-yl)acrylic acid;
85. N4-(l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methylquinolin-3-yl)propyl)-6- methyl-5-((E)-2-(l-methyl-lH-tetrazol-5-yl)vinyl)pyrimidine-2,4-diamine;
86. N4-(l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methylquinolin-3-yl)propyl)-5-((E)-2- (3-methoxypyridin-2-yl)vinyl)-6-methylpyrimidine-2,4-diamine;
87. 5-((E)-2-(lH-tetrazol-5-yl)vinyl)-N4-(l-(2-((2S,6R)-2,6-dimethylmorpholino)-8- methylquinolin-3-yl)propyl)-6-methylpyrimidine-2,4-diamine;
88. (E)-4-(3-(l-((2-amino-5-(2-(3-methoxypyridin-2-yl)vinyl)-6-methylpyrimidin-4-yl) amino)propyl)-8-methylquinolin-2-yl)thiomorpholine 1, 1-dioxide;
89. (E)-3-((2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin -2-yl) propyl)amino)pyrimidin-5-yl)methylene)pyrrolidine-2,5-dione; and
90. (Z)-5-((2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin -2-yl)propyl)amino)pyrimidin-5-yl)methylene)thiazolidine-2,4-dione,
or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof. In further yet another particular embodiment of the present invention, the compound of formula ( 1 ) is selected from the group consisting of
Figure imgf000020_0001
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)
104.
propyl)amino)pyrimidin-5-yl)-N-(2-fluorophenyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)
105.
propyl)amino)pyrimidin-5-yl)-N,N-dimethylpyridine-3-sulfonamide;
2-(l-((2-amino-5-(5-(pyrrolidin-l-ylsulfonyl)pyridin-3-yl)pyrimidin-4-yl)
106.
amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
N-(tert-butyl)-5-(2-(ethylamino)-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-
107.
dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)pyridine-3-sulfonamide;
5-(2-(ethylamino)-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
108.
yl)propyl)amino)pyrimidin-5-yl)pyridine-3-sulfonamide;
N-(tert-butyl)-5-(4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
109.
yl)propyl)amino)-2-((2-methoxyethyl)amino)pyrimidin-5-yl)pyridine-3-sulfonamide;
2-(l-((2-amino-5-(5-((3,3-dimethylpyrrolidin-l-yl)sulfonyl)pyridin-3-yl)pyrimidin-4-
110.
yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
111.
yl)propyl)amino)pyrimidin-5-yl)-N-(2-chlorophenyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
112.
yl)propyl)amino)pyrimidin-5-yl)-N-(2,2,2-trifluoroethyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
113.
yl)propyl)amino)pyrimidin-5-yl)-N-(2,3-difluorophenyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
114.
yl)propyl)amino)pyrimidin-5-yl)-N-(2,3-dichlorophenyl)pyridine-3-sulfonamide;
5-(4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)amino)-2-
115.
(pyr idin-2- ylamino)pyr imidin- 5 - yl)pyridine- 3 - sulfonamide ;
2-(l-((2-amino-5-(5-(methylsulfonyl)pyridin-3-yl)pyrimidin-4-yl)amino)propyl)-5-
116.
fluoro-3-phenylquinazolin-4(3H)-one;
2-(l-((2-amino-5-(5-(isopropylsulfonyl)pyridin-3-yl)pyrimidin-4-yl)amino)propyl)-5-
117.
fluoro-3-phenylquinazolin-4(3H)-one;
2-(l-((2-amino-5-(5-(propylsulfonyl)pyridin-3-yl)pyrimidin-4-yl)amino)propyl)-5-
118.
fluoro-3-phenylquinazolin-4(3H)-one; N-(5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
119.
yl)propyl)amino)pyrimidin-5-yl)pyridin-3-yl)ethanesulfonamide;
N-(5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
120.
yl)propyl)amino)pyrimidin-5-yl)pyridin-3-yl)propane-2-sulfonamide;
N-(5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
121.
yl)propyl)amino)pyrimidin-5-yl)pyridin-3-yl)methanesulfonamide;
2-(l-((2-amino-5-(l-(isopropylsulfonyl)-2,3-dihydro-lH-pyrrolo[2,3-c]pyridin-4-
122.
yl)pyrimidin-4-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
2-(l-((2-amino-5-(l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[2,3-c]pyridin-4-
123.
yl)pyrimidin-4-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one; and
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
124.
yl)propyl)amino)pyrimidin-5-yl)-N-(tert-butyl)nicotinamide,
or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.
In further yet another particular embodiment, 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. The word 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. When 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. Thus when a compound of formula (1) is for instance specified as (R), this means that the compound is substantially free of (S) isomer; when the compound of formula (1) is for instance specified as E, this means that the compound is free of the Z isomer; when the compound of formula (1) is for instance specified as cis isomer, this means that the compound is free of the trans isomer.
In yet another embodiment, 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 PI3K/Akt/m-TOR pathway kinase contribute to the pathology and/or symptomology of such diseases and/or disorders. Such diseases and/or disorders mediated by one or more of these kinases are provided herein.
In yet another embodiment, 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 PI3K kinase; more particularly ΡΒΚγ and PI3K5 isoforms.
According to preceding embodiment, the compounds of formula ( 1) are inhibitors of specific PI3K5 isoform and are used in the treatment and/or prevention of diseases and/or disorders associated with aberrant, abnormal or deregulated activity of PI3K5 isoform.
According to one of the preceding embodiment, the compounds of formula (1) are specific dual inhibitors of ΡΙ3Κγ and PI3K5 isoforms and are used in the treatment and/or prevention of diseases and/or disorders associated with aberrant, abnormal or deregulated activity of PI3K5 and ΡΙ3Κγ isoforms.
Diseases and/or disorders associated with aberrant, abnormal or deregulated activity of PI3K/Akt/M-TOR pathway kinases 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. In particular, the compounds according to the present invention possess potential of providing cancer cell growth inhibiting effects and are effective in treating cancers, preferably all types of solid cancers and malignant lymphomas but not limited to leukemia, skin cancer, bladder cancer, breast cancer, uterus cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer, brain tumor, etc.
Without limiting the scope of present invention, the following definitions are provided in order to aid those skilled in the art in understanding the detailed description of the present invention. "Alkyl" refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms; 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-C6 alkyl group which may have 1 to 6 (inclusive) carbon atoms in it and in more preferred particular alkyl is C\- C4 alkyl group which may have 1 to 4 (inclusive) carbon atoms in it. Examples of 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.
" Alkoxy lalkyl" 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 includes but are not limited to -CH2OCH3, -CH2CH2OCH3, -CH2OCH2CH3, - CH2CH2OCH2CH3 and the like
"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 -CH2F, -CC13, -CF3, -CH2C1, -CH2CH2Br, - CH2CH2I, -CH2CH2CH2F, - CH2CH2CH2C1, -CH2CH2CH2CH2Br, -CH2CH2CH2CH2I, - CH2CH2CH2CH2CH2Br, -CH2CH2CH2CH2CH2I, -CH2CH(Br)CH3, -CH2CH(C1)CH2CH3, and - CH(F)CH2CH3.
"Nitro" refers to -N02 group.
"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 -NH2, -NHCH3 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 C6-C14 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 non-aromatic, saturated, monocyclic, bicyclic or polycyclic hydrocarbon ring system. Representative examples of a cycloalkyl include, but are not limited to cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl, decahydronaphthalen-l-yl, octahydro-lH- inden-2-yl and decahydro-lH-benzo[7] annulen-2-yl. A cycloalkyl can be unsubstituted or substituted with one or more suitable groups.
The term "Heterocyclyl" includes the definitions of "heterocycloalkyl" and "heteroaryl". The term "Heterocycloalkyl" refers to a non-aromatic, saturated or partially saturated, monocyclic or polycyclic ring system 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 heteroatoms selected from oxygen, sulfur and nitrogen. Examples of 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, azabenzimidazole, indazole, quinazoline, quinoline, and isoquinoline. Bicyclic heteroaryl groups include those where a phenyl, pyridine, pyrimidine or pyridazine ring is fused to a 5 or 6-membered monocyclic heterocyclyl ring having one or two nitrogen atoms in the ring, one nitrogen atom together with either one oxygen or one sulfur atom in the ring, or one O or S ring atom. A heteroaryl group can be unsubstituted or substituted with one or more suitable groups.
"Hetero atom" refers to a sulfur, nitrogen or oxygen atom.
"Hetero group" refers to -C(O)-, -S(O), -NH and S(0)2.
"Bicyclic ring containing 1-5 heteroatoms/groups" refers to a saturated, partially saturated or unsaturated bicyclic ring, in which 9 to 12 of the ring carbon atoms have been independently replaced with a heteroatom/heterogroups such as N, O, S,-C(0)-, -S(O), -NH and S(0)2. Representative examples of a 9 to 12 membered ring include, but are not limited to quinazolin-4(3H)-one, quinoline, lH-pyrazolo[3,4-d]pyrimidin-4(5H)-one, 3H-pyrrolo[3,4- d]pyrimidin-4(7H)-one, pyrido[2,3-d]pyrimidin-4(3H)-one and the like.
"Optionally substituted or substituted" as used herein means that at least one or two hydrogen atoms of the optionally substituted group has been substituted with suitable groups as exemplified but not limited to alkyl, alkenyl, alkoxy, alkynyl, aryl, amido, amino, carboxy, cyano, cycloalkyl, guanidine, halogen, imidamide, hydroxy, nitro, haloalkyl, haloalkoxy, heterocyclyl, oxo(=0), thio(=S), -P(0)3H, -P(0)2NH2, -P(0)2NH(alkyl), -P(0)2NH(cycloalkyl),- P(0)2NH(heterocyclyl), -P(0)2NH(aryl), -C(0)(alkyl), -C(0)(aryl), -C(0)(cycloalkyl), - C(0)(heterocyclyl), or two substituents on the same carbon atom combined together to form an optionally substituted 3-8 member ring containing 0-3 heteroatoms independently selected form N, O and S in any stable combination;
"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 use of the term "including" as well as other forms, such as "include", "includes" and
"included" is not limiting.
As used herein, the terms "treat", "treating" or "treatment" encompass either or both responsive and prophylaxis measures, e.g., measures designed to inhibit or delay the onset of the disease or disorder, achieve a full or partial reduction of the symptoms or disease state, and/or to alleviate, ameliorate, lessen, or cure the disease or disorder and/or its symptoms. The terms "treat," "treating" or "treatment", include, but are not limited to, prophylactic and/or therapeutic treatments.
As used herein the terms "subject" or "patient" are well-recognized in the art, and, are used interchangeably herein to refer to a mammal, including dog, cat, rat, mouse, monkey, cow, horse, goat, sheep, pig, camel, and, most preferably, a human. In some embodiments, the subject is a subject in need of treatment or a subject with a disease or disorder. However, in other embodiments, the subject can be a normal subject. The term does not denote a particular age or sex. Thus, adult and newborn subjects, whether male or female, are intended to be covered.
As used herein the term "therapeutically effective amount" refers to a sufficient amount of a compound or a composition being administered which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
"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.
Pharmaceutical formulations 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. Such formulations can be prepared using all processes known in the pharmaceutical art by, for example, combining the active ingredient with the excipient(s) or adjuvant(s).
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. However, 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. Thus, 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.
In a further aspect, the present invention relates to a process for preparing 2-amino pyrimidine 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.
In a further aspect, the compounds of the present invention can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the present invention also embraces isotopically-labeled variants of the present invention which are identical to those recited herein, but for the fact that one or more atoms of the compound are replaced by an atom having the atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specified are contemplated within the scope of the compounds of the invention, and their uses. Exemplary isotopes that can be incorporated in to compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, chlorine and iodine, such as 2H ("D"), 3H, nC, 13C, 14C, 13N, 15N, 150, 170, 180, 32P, 33P, 35S, 18F, 36C1, 123I and 125I. Isotopically labeled compounds of the present inventions can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. The abbreviations used in the entire specification may be summarized herein below with their particular meaning.
Ac20(Acetic anhydride); ACN (acetonitrile); Ar (Argon); brine (NaCl solution); BINAP (2,2'-bis(diphenylphosphino)-l, l'-binaphthyl); bs (broad singlet); C2Cl6 (hexachloroethane) ; CDCI3 (deuteriated chloroform); CS2CO3 (cesium carbonate); °C (degree Celsius); d (doublet); CH2C12/DCM (dichloromethane); dd (doublet of doublet); diLHCl (diluted hydrochloric acid); DIPEA/DIEA (Ν,Ν-Diisopropylethylamine); DMAP (dimethylaminopyridine) ; DME (dimethoxyethane); DMF (dimethylformamide) ; DMSO(Dimethylsulfoxide); DMSO-d6 (Deuteriateddimethylsulfoxide); EDC.HC1 (l-(3-Dimethyl aminopropyl)-3-carbodiimide hydrochloride); ES-MS (Electrospray Ionisation Mass Spectrometry)EtOH (ethanol); Et3N (Triethylamine); Et20 (diethyl ether); g (gram); H (hydrogen); 1H (proton NMR); Hz(Hertz); h (hours); HCl (hydrochloric acid); H20 (water); HOBT (1 -Hydroxy benzotriazole); HPLC (High- performance liquid chromatography); IPA (Isopropylalcohol); J (coupling constant); K2C03 (potassium carbonate); LC/MS (Liquid chromatography-mass spectrometry) ;LiOH (Lithium hydroxide); mmol (millimol); M (molar); ml (milli litre); mg (milli gram); m (multiplet); MeOH (methanol); MHz (mega hertz); MS (ES) (mass spectroscopy-electro spray); min (minutes); m/z (molecular weight); Na2C03(Sodium carbonate) ; NaHC03 (Sodium bicarbonate); N2 (nitrogen); NaBH4 (Sodium borohydride); Na2S04 (Sodium sulphate); nm (nano molar); NMP (N- Methylpyrrolidone); NMR (nuclear magnetic resonance spectroscopy); NIS (N-
Iodosuccinamide) ; O/N (Overnight range: 8 to 8 hrs); PDA (photo diode array detector); Pd2(dba)3 (tris dibenzylidene acetone) dipalladium; Pd(OAc)2 (Palladiumdiacetate); Pd(dppf)Cl2 ([l, l'-Bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane; Pd(Pph3)4 (Tetrakis (triphenylphosphine)palladium, P0C13 (Phsophorousoxychloride); ppm-δ (parts per million); R.T(Room temperature range: 20 to 40°C); S (singlet); S0C12 (thionylchloride); t (triplet); TLC (Thin Layer Chromatography); THF (tetrahydrofuran); TFA (trifluoroaceticacid); TPP (Triphenylphosphine); TMSI (Trimethylsulfoxoniumiodide); q (Quartet); μπι (micro molar); PCI5 (Phosphorous pentachloride) ; Br2 (bromine); h (hours); CH3COOK (potassiumacetate), Oxone (Potassium peroxy monosulfate); KH2P04 (potassium dihydrogen phosphate); μηι (micro molar); LC/MS (Liquid chromatography-mass spectrometry); m/z (molecular weight); HPLC (High-performance liquid chromatography); ES- MS (Electrospray Ionisation Mass Spectrometry) etc. General modes of preparation:
Compounds of this invention may be made by synthetic chemical processes, examples of which are shown herein. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.
A general approach for the synthesis of compounds of general formula (I) is depicted in below schemes. As used herein the below schemes the terms 'R1', 'R2', 'R3', 'R4', 'R5', 'R6',
'R 7 ', 'R 8 ', 'R 9 ', 'R 10 ', 'n', Q and 'A' represents all the possible substitutions as disclosed in formula (1).
A general approach for the synthesis of critical intermediates of the present invention are depicted in scheme-a, scheme-b and scheme-c.
S
Figure imgf000030_0001
The general approach for the synthesis of intermediate of formula G is depicted in scheme-a. The intermediate of formula A reacts with acetic anhydride to give aldehyde compound of formula B. On cyclization of compound of formula B in presence of POCl3 gives compound of formula C, which on reaction with R in presence of suitable base gives compound of formula D. On reaction of compound of formula D with Grignard reagent (alkyl magnesium halide) under suitable conditions results in the formation of compound E, which on chlorination with thionyl chloride gives the compound of formula F. Amination of compound of formula F in presence of Aq. ammonia gives compound of formula G.
Scheme-b: The general approach for the synthesis of intermediate- K is depicted in scheme-b. The compound of formula H reacts with R -amine and compound of formula I in presence of triphenylphosphine to give compound of formula J, which on deprotection results in the formation of compound of formula K.
S
Figure imgf000031_0001
The general approach for the synthesis of intermediate-R is depicted in scheme-c. The compound (S)-2-aminobutanoic acid reacts with pthalic anhydride (L) to give intermediate M. the intermediate M on reaction with intermediate N in presence of SOCl2 gives intermediate O, which on reaction with R -NH in presence of triphenylphosphite gives intermediate P. The intermediate P on cyclisation in presence of EDC.HC1 and HOBT gives the intermediate Q, which on reaction with hydrazine.hydrate gives the intermediate R.
A general approach for the synthesis of compounds of the present invention is depicted in scheme- 1.
Scheme- 1:
Figure imgf000032_0001
The general approach for the synthesis of compound of formula 1A, IB, 1C and ID are depicted in scheme- 1. On reaction of compound of formula 1.1 with compound of formula 1.2 in presence of DIPEA at suitable conditions results in the formation of compound of formula 1.3. The compound of formula 1.3 on Suzuki coupling with compound of formula 1.4 and 1.5 respectively in presence of suitable palladium catalyst. The Pd-catalyzed C-C coupling reaction can be carried out in suitable polar solvents such as DMF, propionitrile, ACN, THF or DMSO and the like, in a suitable organic bases such as TEA, DIPEA and the like by using catalysts such as Pd(OAc)2, Pd(PPh3)2Cl2 or Pd2(dba)3 and the like, at a temperature of about 100-130°C to give compound of formula (1A) and (IB) respectively. The compound of formula 1.3 on heck coupling with compound 1.6 in presence of suitable palladium catalyst, suitable ligands such P(o-tolyl)3, P(m-tolyl)3, BINAP or P(p-tolyl)3 and the like, under standard heck coupling condition gives compound of formula (1C). The compound (1C-A) was prepared similar to the procedure depicted in the compound of formula (1C) by using compound 1.3 and compound 1.7, wherein the compound (1C-A) further undergoes cyclization with TMSI in presence of base such as NaH at appropriate conditions results in the compound of formula (ID).
EXPERIMENTAL
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. The scope of the processes according to the present invention for preparing compounds of formula (1) shall not construed limited to the depictions as given below, however, it also covers obvious workable changes of steps either prior or later during the entire process.
The specifics of the process for preparing compounds of the present invention are detailed in the experimental section.
In the following, the present invention shall be illustrated by means of some examples, which are not construed to be viewed as limiting the scope of the invention.
Unless otherwise stated, work-up includes distribution of the reaction mixture between the organic and aqueous phase indicated within parentheses, separation of layers and drying the organic layer over sodium sulphate, filtration and evaporation of the solvent. Purification, unless otherwise mentioned, includes purification by silica gel chromatographic techniques, generally using ethyl acetate/petroleum ether mixture of a suitable polarity as the mobile phase. Use of a different eluent system is indicated within parentheses.
Analysis for the compounds of the present invention unless mentioned, was conducted in the general methods well known to the person skilled in the art. Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples, describing in detail the analysis of the compounds of the invention.
It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
The HPLC data provided in the examples described below were obtained as followed. HPLC (Method A): ColumnName: Inertsil ODS3V (150 mm x 4.6 mm), 5μπι
Column_Serial-no: 3JI84045 at a flow of 1 ml/15min gradient MobilePhase_used: A: 0.1M KH2P04 (PH6.5); B: ACN.
Diluents: MeOH+ACN+H20 (Sonicated); Wavelength: PDA 210.00nm.
(Method B): Column name: XTerra RP18 (250 mm x 4.6 mm), 5μπι
Column_Serial-no: 01933823313683 at a flow of lml/15min gradient
MobilePhase_used: A: 0.1M KH2P04 (PH6.5); B: ACN.
Diluents: MeOH+ACN+H20 (Sonicated); Wavelength: PDA 215.00nm.
(Method C): Column_name: Symmetry Shield RP18 (150 mm x 4.6 mm), 5μπι
Column_Serial-no: 01613610313630 at a flow of lml/15min gradient
MobilePhase_used: A: 0.1M KH2P04 (PH6.5); B: ACN.
Diluents: MeOH+ACN+H20 (Sonicated); Wavelength: PDA 210.00nm.
(Method D): Column_name: Chromolith RP18 (100 mm x 4.6 mm)
Column_Serial-no: UM8078/066 at a flow of lml/15min gradient
MobilePhase_used: A: 0.01M KH2P04 (PH6.5); B: ACN.
Diluents: DMSO+ACN+MeOH+H20 (Sonicated); Wavelength: PDA 210.00nm.
The MS data provided in the examples described below were obtained as followed: Mass spectrum: LC/MS Agilent 6120 Quadrapole LC/MS
The NMR data provided in the examples described below were obtained as followed: 1H- NMR: Varian 400 MHz.
Examples:
The procedure for the preparation of compounds of formula (1) are detailed herein below stepwise including the general synthesis of various intermediates involved in process of preparation of the compounds according to the present invention. The scope of the processes according to the present invention for preparing compounds of formula (1) shall not construed limited to the depictions as given below, however, it also covers obvious workable changes of steps either prior or later during the entire process.
Intermediate- 1: Synthesis of 4-chloro-2-(2, 5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl pyrimidine (ID)
Figure imgf000035_0001
(i) Ethyl acetoacetate, K2C03, ethanol, 80°C, overnight; (ii) POCl3, 100°C, Overnight:
(iii) NIS, ACN, Methanol, Reflux, 8 h; (iv) 2,5-Hexanedione, PTSA, Toluene, 140°C, Overnight.
Step-(i): 2-amino-6-methylpyrimidin-4-ol ( 1A)
Ethyl acetoacetate ( 1 g, 7.6 mmol), guanidine hydrochloride (0.72 g, 7.60 mmol) in ethanol (30 ml) and potassium carbonate ( 1.15 g, 36.0 mmol) are stirred at 80°C for overnight. The mixture is allowed to cool to room temperature. Then the precipitate formed was filtered off and dried (0.8 g, 80%). MS (ES) m/z 126 (M+l)+.
Step-(ii): 4-chloro-6-methylpyrimidin-2-amine ( IB)
POCl3 ( 15 ml) was added to intermediate- 1 A (0.8 g, 6.4 mmol) at 0-5°C and refluxed the reaction mixture for overnight. Then the reaction mixture was poured slowly into the crushed ice, the precipitate is filtered and dried under vacuo to get the crude compound as yellow solid (0.5 g, 51 %).1H-NMR (400 MHz, DMSO-J6) δ 6.98 (s, 2H), 6.56 (s, 1H), 2.21 (m, 3H). MS (ES) m/z 144 (M+l)+.
Step-(iii): 4-chloro-5-iodo-6-methylpyrimidin-2-amine ( 1C)
NIS (0.1 18 g, 0.52 mmol) was added to intermediate- 1B(0.05 g, 0.35 mmol) in ACN ml) and methanol (0.7 ml), refluxed the reaction mixture for 5 h. Then the solvent is eliminated in vacuo to get the crude compound as yellow solid (0.02 g, 31%).1H-NMR (400 MHz, DMSO- de) δ 7.13 (s, 2H), 2.47 (s, 3H). MS (ES) m/z 269 (M+l )+.
Step-(iv): 4-chloro-2-(2, 5-dimethyl- l H-pyrrol- l -yl)-5-iodo-6-methylpyrimidine ( ID)
To a stirred solution of intermediate- 1C (0.2 g, 0.74 mmol) and 2,5-hexanedione (0.29 g,
2.6 mmol) in toluene ( 10 ml), was added PTSA (0.01 g). The reaction mixture was stirred at 140°C for overnight using dean-stark trap. Then the residue was diluted with water ( 10 ml) and extracted with ethyl acetate (2 x 10 ml). The combined organic phases were dried over sodium sulphate and concentrated. The residue was chromato graphed on 100-200 mesh silica gel eluting with 100% hexane as eluent to achieve the pure product as a yellow solid (0.025 g, 10%). 1H-
NMR (400 MHz, DMSO-J6) δ 5.89 (s, 2H), 2.79 (s, 3H), 2.37 (s, 6H). MS (ES) m/z 348 (M+ l) Intermediate-2: Synthesis of 2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl-N-(l-(2-(4- methylpiperazin-l-yl)quinolin-3-yl)propyl)pyrimidin-4-amine (2G)
Figure imgf000036_0001
(i) Ac20, 0°C - R.T, 4 ; (ii) POCl3, DMF, 0°C - Reflux, Overnight; (iii) 1-methylpiperazine, K2C03, DMSO, 100°C, 48 h; (iv) Ethylmagnesium bromide, THF, -15°C - R.T, 4 h; (v) SOC1,, DCM, 0°C - Reflux, 4h; (vi) Aqueous ammonia,
Sealed tube, 100°C, Overnight; (vii) Intermediate- ID, DIPEA, IP A, Microwave, 110°C, 40 min;
Step-(i): N-phenylacetamide (2A)
Acetic anhydride (5 ml, 53.7 mmol) was added to aniline (5 g, 53.7 mmol) at 0°C and the reaction mixture was stirred for 4h at room temperature. Then the reaction mixture is poured into ice water, the precipitate was separated by filtering and dried under vacuo to give the crude compound as white solid (5 g, 70%). *H-NMR (400 MHz, DMSO-J6) δ 9.9 (bs, 1H), 7.50(d, 2H, J=8.0 Hz), 7.28 (t, 2H, J=8.0 Hz), 7.0 (t, 1H, J=7.3 Hz), 2.00 (s, 3H). MS (ES) m/z 136 (M+l)+. Step-(ii): 2-chloroquinoline-3-carbaldehvde (2B)
DMF (8 ml, 111.1 mmol) was added to POCl3 (28 ml, 185.1 mmol) at 0-5°C and then intermediate-2A (5 g, 37.0 mmol) was added. The mixture was stirred at 100°C for overnight. Then the reaction mixture is poured into the ice water, the precipitate was separated off by filtering and dried under vacuo to give the crude compound as yellow solid (3 g, 42%). 'H-NMR (400 MHz, DMSO-Je) δ 10.39 (s, 1H), 9.0 (s, 1H), 8.30 (d, 1H, J=8.3 Hz), 8.0 (m, 1H), 7.90 (m, 1H), 7.70 (m, 1H). MS (ES) m/z 192 (M+l)+.
Step-(iii): 2-(4-methylpiperazin- l-yl)quinoline-3-carbaldehvde (2C)
To a stirred solution of 1-methylpiperazine (7.7 g, 78.5 mmol) and K2C03 (21.6 g, 157.0 mmol) in DMSO, intermediated (10 g, 52.3 mmol) was added and stirred for 48 h at 100°C. Then the cooled residue was diluted with water (100 ml) and extracted with ethyl acetate (2 x 300 ml). The combined organic phases were dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 3% methanol in dichloromethane to give the title compound as a yellow solid (5 g, 38%). 'H-NMR (400 MHz, DMSO-Je) 510.0 (s, 1H), 8.60 (s, 1H), 8.0 (d, 1H, J=7.8 Hz), 7.7 (s, 2H), 7.4 (d, 1H, J=8.9 Hz), 3.4 (m, 4H), 2.5 (m, 4H), 2.20 (s, 3H). MS (ES) m/z 256 (M+l)+.
Step-(iv) : 1 -(2-(4-methylpiperazin- 1 - yl)quinolin-3 - vDpropan- 1 -ol (2D)
To a stirred solution of intermediate-2C (10 g, 39.2 mmol) in THF (100 ml), was added ethyl magnesium bromide (30 ml) at -15°C and stirred at room temperature for 4 h. The obtained residue was cooled to 0°C and acidified with dil.HCl then extracted with water (100 ml) and ethyl acetate (3 x 150 ml). The combined organic phases were dried over sodium sulphate and concentrated under vacuo to get the desired product as a yellow solid (8.0 g, 10%). 'H-NMR (400 MHz, DMSO-Je) δ 8.24 (s, 1H), 7.83 (d, 2H, J=7.6 Hz), 7.59 (m, 1H), 7.39-7.37 (m, 1H), 5.28 (s, 1H), 4.79-4.75 (m, 1H), 3.22-3.05 (m, 8H), 2.25 (s, 3H), 1.74-1.67 (m, 2H), 0.87 (m, 3H). MS (ES) m/z 285 (M+l)+.
Step-(v): 3-(l-chloropropyl)-2-(4-methylpiperazin-l-yl)quinoline (2E)
SOCl2 (0.4 ml, 4.90 mmol) was added to intermediate-2D (0.25 g, 0.9 mmol) in DCM at 0°C. The reaction mixture was refluxed for 4 h. DCM was then eliminated in vacuo and the residue was washed with excess of diethyl ether to get desired compound. 'H-NMR (400 MHz, DMSO-Je) δ 8.27 (s, 1H), 7.88 (d, 1H, J=8.3 Hz), 7.76 (d, 1H, J=8.0 Hz), 7.69-7.65 (m, 1H), 7.48-7.45 (m, 1H), 5.06-5.04 (m, 1H), 4.20-4.14 (m, 1H), 3.97-3.73 (m, 3H), 3.54-3.48 (m, 3H), 2.99-2.98 (m, 1H), 2.86 (s, 3H), 2.29-2.25 (m, 2H), 1.04-1.02 (m, 3H). MS (ES) m/z 304 (M+l)+.
Step-(vi) : 1 -(2-(4-methylpiperazin- 1 - yl)quinolin-3 - vDpropan- 1 -amine (2F)
Ammonium hydroxide (5 ml) and intermediate-2E (0.2 g) in a sealed tube was heated to
100°C for overnight. The reaction mass was cooled to room temperature and extracted with ethyl acetate (2 x 20 ml). The combined organic phases were dried over sodium sulphate and concentrated under vacuo to get the desired product. 'H-NMR (400 MHz, DMSO-Je) δ 8.28 (s, 1H), 7.88 (d, 1H, J=8.3 Hz), 7.76 (d, 1H, J=8.0 Hz), 7.67-7.65 (m, 1H), 7.48-7.45 (m, 1H), 4.07 -
4.03 (m , 1H), 3.32-3.03 (m, 8H), 2.25 (s, 3H), 1.66-1.62 (m, 2H), 0.82 (t, 3H, J=6.7 Hz).
Step-(vii): 2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl-N-(l-(2-(4-methylpiperazin-l-yl) quinolin-3-yl)propyl)pyrimidin-4-amine (2G)
To a stirred solution of intermediate-2F (0.2 g, 0.68 mmol) and intermediate- ID (0.25 g, 0.75 mmol) in IPA (2 ml), DIPEA (0.4 ml) was added and stirred at 110°C for 40 min in CEM
Microwave. Then the cooled residue was diluted with water (10 ml) and extracted with ethyl acetate (2 x 10 ml). After brine wash, the combined organic phases were dried over sodium sulphate and concentrated. The residue was chromato graphed on 100-200 mesh silica gel eluting with 1% methanol in dichloromethane to give the title compound as a yellow solid (0.2 g, 50%). 'H-NMR (400 MHz, DMSO-Je) δ 8.34 (s, 1H), 7.80 (m, 2H), 7.60 (m, 1H), 7.40 (m, 1H), 6.94 (d, 1H, J=8.3 Hz), 5.7 (s, 2H), 5.40 (m, 1H), 3.40 (m, 6H), 2.8 (m, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 2.0 (s, 6H), 0.9 (m, 3H). MS (ES) m/z 596 (M+l)+.
Intermediate-3: Synthesis of 2-(l-((2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl pyrimidin-4- l)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one (3C)
Figure imgf000038_0001
(i) Trip enyl phosphite, Pyridine, 70CC, 8h; (ii) TFA, DCM, 10°C - RT, Overnight; (iii) Intermediate- ID, DIPEA, IPA,
Microwave, 110°C, 40 min. Step-(i): tert -butyl (l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)carbamate (3A1
To a stirred solution of 2-amino-6-methylbenzoic acid (5.0 g, 33.1 mmol) and Boc-L-2- aminobutyric acid (6.72 g, 33.1 mmol) in pyridine (20 ml), was added triphenylphosphite (25.68 g, 82.8 mmol). The reaction mixture was stirred at 70°C for 2 h, and then aniline (3.6 g, 39.7 mmol) was added and stirred for another 6 hrs at same temperature. The obtained mixture was diluted with sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (2 x 10 ml). After brine wash, the combined organic phases were dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 15% ethyl acetate in hexane to give the title compound as a yellow solid (2.5 g, 20%). 'H-NMR (400 MHz, CDCI3) δ 7.62-7.60 (m, 5H), 7.37 (d, 1H, J=7.8 Hz), 7.58-7.50 (m, 1H), 7.28-7.22 (m, 1H), 5.50 (d, 1H, J=8.8 Hz), 4.39 - 4.38 (m, 1H), 2.80 (s, 3H), 1.77-1.74 (m, 1H), 1.42 (s, 9H), 1.40 (s, 1H), 0.77-0.74 (m, 3H). MS (ES) m/z 394 (M+l)+.
Step-(ii): 2-( l-aminopropyl)-5-methyl-3-phenylquinazolin-4(3H)-one (3B)
To a stirred solution of intermediate-3A (3.5 g, 8.90 mmol) in DCM (35 ml), was added TFA (15 ml) at 10°C. The reaction mixture was stirred at room temperature for overnight. The progress of the reaction was monitored by TLC. After the reaction was completed, TFA was removed under vacuum and neutralized with sodium bicarbonate solution then extracted with ethyl acetate (2 x 100 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product as a yellow solid (2.2 g, 90%). MS (ES) m/z 294 (M+l)+.
Step-(iii): 2-(l-((2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methylpyrirmdin-4-yl)amino) propyl)-5-methyl-3-phenylquinazolin-4(3H)-one (3C)
The process of this step was adopted from intermediate-2G by using intermediate-3B and intermediate- ID as starting compounds. 1H-NMR (400 MHz, DMSO-J6) δ 7.71-7.70 (m, 2H), 7.69-7.60 (m, IH), 7.56-7.51 (m, IH), 7.48-7.29 (m, 2H), 7.11 (d, IH, J=8.3 Hz), 6.85 (d, IH, J=8.3 Hz), 5.82 (s, 2H), 5.03 (bs, IH), 4.21 (m, IH), 2.81 (s, 3H), 2.59 (s, 3H), 2.13 (s, 6H), 1.87 (m, IH), 1.68 (m, IH), 0.79 (m, 3H). MS (ES) m/z 605 (M+l)+.
Intermediate-4: Synthesis of 2-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)propyl)- 5-methyl-3-phenylquinazolin-4(3H)-one (4B)
Figure imgf000039_0001
(i) n-Butanol, Sealed tube, 140°C, Overnight; (ii) S, ACN, Methanol, 80°C, 3h;
Step-(i): 2-(l-((2-amino-6-methylpyrimidin-4-yl)amino)propyl)-5-methyl-3-phenyl
quinazolin -4(3H)-one (4A)
To a solution of intermediate- IB (0.3 g, 2.09 mmol) and intermediate-3B (0.55 g, 1.80 mmol) in n-butanol were stirred at 140°C for overnight in sealed tube. The n-butanol was eliminated in vacuo and the residue was chromatographed on 100-200 mesh silica gel eluting with 4% methanol in dichloromethane to give the title compound as a yellow solid (0.25 g, 24%). 'H-NMR (400 MHz, DMSO-J6): δ 8.64 (s, IH), 7.70-7.66 (m, IH), 7.59-7.52 (m, 5H), 7.38 (d, IH, J=16 Hz), 7.03 (s, 2H), 5.94 (s, IH), 4.48 (s, IH), 2.72 (s, 3H), 2.16 (s, 3H), 1.87 - 1.16 (m, 2H), 0.83 (t, 3H, J=7.3 Hz). MS (ES) m/z 401 (M+l)+. Step-(ii): 2-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)propyl)-5-methyl-3^heny quinazolin-4(3H)-one (4B)
To a stirred solution of intermediate- (4 A) (0.25 g, 0.62 mmol) in acetonitrile (5 ml) and methanol (7 ml), NIS (0.21 g, 0.93 mmol) was added and refluxed for 3 h. Excess of solvents were eliminated in vacuo to get the crude compound as yellow color solid (0.2 g, 61%).1H-NMR (400 MHz, DMSO-Je) δ 11.04 (s, 1H), 7.74-7.72 (m, 1H), 7.57-7.51 (m, 5H), 7.34 (d, 2H, J= 3 Hz), 6.80 (s, 2H), 4.78 (s, 1H), 2.70 (s, 3H), 2.35 (s, 3H), 1.61-1.58 (m, 2H), 0.70-0.68 (m, 3H). MS (ES) m/z 527 (M+l)+.
Intermediate-5: Synthesis of Ethyl 5-amino-l-methyl-lH-pyrazole-4-carboxylate (5)
Figure imgf000040_0001
(I) Et3N, Elhanol, 70°C, Overnight; (5)
To a stirred solution of methyl hydrazine sulfate (10 g, 59.17 mmol) and (E)-ethyl 2- cyano-3-ethoxyacrylate (8.5 g, 59.17 mmol) in ethanol (100 ml) was added Et3N (18 ml, 177.5 mmol) and stirred at 70°C for overnight. Then the solvent is eliminated in vacuo and the residue was purified by chromatography on 100-200 mesh silica gel, eluting with 30% ethyl acetate in hexane to give the title compound as a yellow solid (8 g, 94%). !H-NMR (400 MHz, DMSO-Je) δ 7.43 (s, 1H), 6.20 (bs, 2H), 4.16 (m, 2H), 3.54 (s, 3H), 1.24 (t, 3H, J=7 Hz). MS (ES) m/z 169.9 (M+l)+.
Intermediate-6: Synthesis of 6-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)propyl)- l-methyl-5-phenyl-lH-pyrazolo[3, 4-d]pyrimidin-4(5H)-one (6G)
(i) Et3N, Toluene, 120°C, 12 li; (ii) SOCl2, Reflux, overnight; DIPEA, Toluene, 0°C-R.T, overnight; (iii) C2C16, TPP, DCM, R.T, 4 h; Aniline, R.T, Overnight; (iv) K2C03, DMF, 100°C, Overnight; EDC.HC1, HOBT, Et3N, R.T, Overnight;(v) NH2NH2.H20, Ethanol, Reflux, 4 h; (vi) n-butanol, Sealed tube, 140°C, Overnight; (vii) NIS, ACN, Methanol, 80°C, 3 h.
Step-(i): (S)-2-(L3-dioxoisoindolin-2-yl)butanoicacid (6A)
To a stirred solution of phthalic anhydride (1.48 g, 10.0 mmol) and (S)-2-aminobutanoic acid (1.03 g, 10.0 mmol) in toluene (20 ml), was added triethylamine (0.13 ml, 1.0 mmol). The obtained mixture was heated to 120°C for 12 h and distilled under a reduced pressure to remove toluene. The solid obtained was filtered under suction and washed with excess of water to give the desired product as a yellow solid (2.7 g, 90%). 'H-NMR (400 MHz, DMSO-J6) δ 12.0 (brs, 1H), 7.88 (m, 4H), 4.53 (m, 1H), 2.08 (m, 2H), 0.81 (t, 3H, J=7.4 Hz).
Step-(ii): (S, Z)-2-(l, 3-dioxoisoindolin-2-yl)-N-(4-(ethoxycarbonyl)-l-methyl-lH-pyrazol -5-yl)butanimidicacid (6B)
Intermediate- 6 A (14.8 g, 100.0 mmol) was taken in SOCl2 (50 ml) and was refluxed for overnight. After elimination of SOCl2 in vacuo, to the obtained residue in toluene DIPEA (15 ml, 120.0 mmol) and intermediate- 5 (16.9 g, 100.0 mmol) was added at 0°C and stirred was for overnight at room temperature. The obtained residue was diluted with sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (2 x 10 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with hexane / ethyl acetate (85: 15) to give the title compound as a yellow solid (23 g, 60%).1H-NMR (400 MHz, DMSO-J6) δ 10.25 (s, IH), 7.96-7.88 (m, 4H), 7.81 (s, IH), 4.80-4.73 (m, IH), 4.19 (m, 2H), 3.60 (s, 3H), 2.33-2.25 (m, IH), 2.12-2.04 (m, IH), 1.26 (t, 3H, J=5 Hz), 0.87 (t, 3H, J=8 Hz). MS (ES) m/z 383 (M-l). Step-(iii): (S, Z)-ethyl 5-((2-(L3-dioxoisoindolin-2-yl)-l-(phenylamino)butylidene)amino)-l- methyl- 1 H-pyrazole-4-carboxylate (6C)
Hexachloroethane (14.16 g, 60.0 mmol) was added to a stirred solution of intermediate- 6B(19.2 g, 50.0 mmol) and triphenylphosphine (15.72 g, 60.0 mmol) in DCM (20 ml).The obtained mixture was stirred at room temperature for 4 h, then aniline (5.6 g, 90.0 mmol) was added and continued stirring for overnight. The obtained mixture was diluted with sodium bicarbonate solution (20 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with hexane / ethyl acetate (50:50) to give the title compound as a yellow solid (25 g, 55%).1H-NMR (400 MHz, DMSO-J6) δ 9.24 (s, IH), 7.86-7.84 (m, 4H), 7.35-7.20 (m, 5H), 7.05-7.00 (m, IH), 4.95-4.65 (m, IH), 4.00 -3.98 (m, 2H), 3.32 (s, 3H), 2.33-2.26 (m, 2H), 1.19 (t, 3H, J=7 Hz), 0.87 (t, 3H, J=8 Hz). MS (ES) m/z 460 (M+l)+.
Step-(iv): (R)-2-(l-(l-methyl-4-oxo-5-phenyl-4,5-dihvdro-lH-pyrazolo[3,4-dlpyrimidin-6-yl) propyDisoindoline- 1 ,3-dione (6D)
To a stirred solution of intermediate-6C( 11.45 g, 25.0 mmol) in DMF (20 ml), K2C03 was added (6.9 g, 50.0 mmol). The reaction mixture was stirred at 100°C for overnight and allowed to cool. To the obtained mixture, Et3N (5.05 ml, 0.05 mmol), EDC.HCl (9.55 g, 50.0 mmol) and HOBT (6.75 g, 50.0 mmol) were added and stirred at room temperature overnight. Then the residue was diluted with water (20 ml) and extracted with ethyl acetate (2 x 100 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with hexane / ethyl acetate (50:50) to give the title compound as a yellow solid (2.58 g, 25%).1H-NMR (400 MHz, DMSO-Je) δ 8.12 (s, IH), 7.86-7.85 (m, 2H), 7.84-7.83 (m, IH), 7.76-7.73 (m, 3H), 7.34 (t, IH, J=7 Hz), 6.99 (t, IH, J=8 Hz), 6.80-6.77 (m, IH), 5.06-5.04 (t, IH, J=7 Hz), 3.96 (s, 3H), 2.50-2.23 (m, 2H), 0.87 (t, 3H, J=7 Hz). MS (ES) m/z 414 (M+l)+.
Step-(v): (R)-6-(l-aminopropyl)-l-methyl-5-phenyl-lH-pyrazolo[3,4-dlpyrimidin-4(5H)-one (6E)
To a stirred solution of intermediate-6D(1.03 g, 2.0 mmol) in ethanol was added hydrazine hydrate (0.5 ml, 10.0 mmol). The reaction mixture was refluxed for 4 h and distilled under a reduced pressure to remove the solvent. The residue was chromatographed on 100-200 mesh silica gel eluting with methanol/dichloromethane (10:90) to give the title compound as a yellow solid (0.35 g, 50%). *H-NMR (400 MHz, DMSO-J6) δ 8.00 (s, IH), 7.67-7.54 (m, 3H), 7.50-7.40 (m, IH), 7.30-7.24 (m, IH), 3.97 (s, 3H), 3.23-3.19 (m, IH), 2.27-1.71 (m, 3H), 1.49- 1.35 (m, IH), 0.86 (t, 3H, J=7 Hz). MS (ES) m/z 284 (M+l)+.
Step-(vi): (R)-6-( l-((2-amino-6-methylpyrimidin-4-yl)amino)propyl)- l-methyl-5-phenyl- 1H- pyrazolo[3,4-dlpyrimidin-4(5H)-one (6F)
The process of this step was adopted from intermediate-4A by using intermediate-6E and intermediate- IB. *H-NMR (400 MHz, DMSO-J6) δ 8.89 (bs, IH), 8.12 (s, IH), 7.59-7.51 (m, 5H), 7.28 (bs, 2H), 5.98 (s, IH), 4.53 (bs, IH), 3.92 (s, 3H), 2.19 (s, 3H), 1.98-1.86 (m, IH), 1.68-1.64 (m, IH), 0.68 (t, 3H, J=7.3 Hz). MS (ES) m/z 391 (M+l)+.
Step-(vii): (R)-6-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)propyl)-l-methyl-5-phenyl -lH-pyrazolor3,4-dlpyrimidin-4(5H)-one (6G)
The process of this step was adopted from intermediate-4B from intermediate-6F.1H-
NMR (400 MHz, DMSO-J6) δ 8.10(s, IH), 7.64-7.49 (m, 5H), 6.20 (d, IH, J=8.3 Hz), 6.06 (bs, 2H), 4.74-4.70 (m, IH), 3.95 (s, 3H), 2.28 (s, 3H), 1.79-1.76 (m, IH), 1.56-1.53 (m, IH), 0.65 (t, 3H, J=7.4 Hz). MS (ES) m/z 517 (M+l)+.
Intermediate-7: Synthesis of 2-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)propyl)- 5-fluoro-3-phenylquinazolin-4(3H)-one (7D)
Figure imgf000044_0001
(7D)
(i) Triphenyl phosphite, Pyridine, 70°C, 8 h; (ii) TFA, DCM, 10°C - RT, Overnight; (iii) n-Butanol, Sealed tube,
140°C, Overnight; (iv) NIS, ACN, Methanol, 80°C, 3h
Step-(i) and (ii): The process of these steps was adopted from intermediate-3B using 2-amino-6- fluorobenzoic acid. MS (ES) m/z 298 (M+l)+.
Step-(iii) and (iv): This process of these steps was adopted from intermediate-3B usingintermediate-7B. MS (ES) m/z 531 (M+l)+.
Intermediate-8: Synthesis of Ethyl 5-amino-l,3-dimethyl-lH-pyrazole-4-carboxylate (8)
Figure imgf000044_0002
(i) Et3N, Ethanol, 70°C, Overnight;
The process of this step was adopted from intermediate- 5 using ethyl 2-cyano-3- ethoxybut-2-enoate. MS (ES) m/z 184 (M+l)+.
Intermediate-9: Synthesis of (R)-6-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino) propyl)-l,3-dimethyl-5-phenyl-lH-pyrazolo[3,4-d]pyrimidin-4(5H)-one (9G)
(i) Et3N, Toluene, 120°C, 12 h; (ii) SOCl2, Reflux, overnight; DIPEA, Toluene, 0°C-R.T, overnight; (iii) C2C16, TPP, DCM, R.T, 4 h; Aniline, R.T, Overnight; (iv) K2C03, DMF, 100°C, Overnight; EDC.HC1, HOBT, Et3N,
R.T, Overnight; (v) NH2NH2.H20, Ethanol, Reflux, 4 h; (vi) n-butanol, Sealed tube, 140°C, Overnight; (vii)
NIS, ACN, Methanol, 80°C, 3 h.
The process of this step was adopted from intermediate-6G using phthalic anhydride and (S)-2- aminobutanoic acid. MS (ES) m/z 531 (M+l)+.
Intermediate-10: Synthesis of 2-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino) prop l)-3-(4-fluorophenyl)-5-methylquinazolin-4(3H)-one (10D)
Figure imgf000045_0001
(i) Triphenyl phosphite, Pyridine, 70°C, 8 h; (ii) TFA, DCM, 10°C - RT, Overnight; (iii) n-Butanol, Sealed tube, 140°C,
Overnight; (iv) NIS, ACN, Methanol, 80°C,3 h Step-(i) and (ii): The process of these step were adopted from intermediate-3B using 2-amino-6- methylbenzoic acid. MS (ES) m/z 312 (M+l)+.
Step-(iii) and (iv): The process of these steps were adopted from intermediate-4B using intermediate- 1 OB. MS (ES) m/z 545 (M+l)+.
Intermediate-11: Synthesis of 2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl-N-(l-(8- methyl-2-(4-methylpiperazin-l-yl)quinolin-3-yl)propyl)pyrimidin-4-amine (11G)
Figure imgf000046_0001
(i) Ac20, 0°C - R.T, 4 h; (ii) POCl3, DMF, 0°C - Reflux, Overnight; (iii) 1-methylpiperazine, K2C03, DMSO, 100°C, 48 h;
(iv) Ethylmagnesium bromide, THF, -15°C - R.T, 4 h; (v) SOCl2, DCM, 0°C - Reflux, 4 h; (vi) Aqueous ammonia, Sealed tube, 100°C, Overnight; (vii) Intermediate- ID, DIPEA, IP A, Microwave, 110°C, 40 min;
The process of this step was adopted from intermediate-2G using o-toluidine .MS (ES) m/z 610 (M+l)+.
Intermediate-12: Synthesis of 2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl-N-(l-(2- thiomorpholinoquinolin-3-yl)propyl)pyrimidin-4-amine (12G)
Figure imgf000046_0002
(i) Ac20, 0°C - R.T, 4 h; (ii) POCl:„ DMF, 0°C - Reflux, Overnight; (iii) Thiomorpholine, K2C03, DMSO, 100°C, 48 h;
(iv) Ethylmagnesium bromide, TFIF, -15DC - R.T, 4 h; (v) SOCl2, DCM, 0°C - Reflux, 4 h; (vi) Aqueous ammonia, Sealed tube, 100°C, Overnight; (vii) Intermediate-ID, DIPEA, IP A, Microwave, 110°C, 40 min;
The process of this step was adopted from intermediate-2G using from aniline. MS (ES) m/z 599 (M+l)+. Intermediate-13: Synthesis of 2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl-N-(l-(8- methyl-2-thiomorpholinoquinolin-3-yl)propyl)pyrimidin-4-amine (13G)
Figure imgf000047_0001
(i) Ac20, 0°C - R.T, 4 h; (ii) POCl,, DMF, 0°C - Reflux, Overnight; (iii)Thiomorpholine, K2C03, DMSO, 100°C, 48 h;
(iv) Ethylmagnesium bromide, THF, -15°C - R.T, 4h; (v) SOCl2, DCM, 0°C - Reflux, 4 h; (vi) Aqueous ammonia, Sealed tube, 100°C, Overnight; (vii) Intermediate-ID, DIPEA, ΓΡΑ, Microwave, 110°C, 40 min;
The process of this step was adopted from intermediate-2G using o-toluidine. MS (ES) m/z 613 (M+l)+.
Intermediate-14: Synthesis of 2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl-N-(l-(8- methyl-2-morpholinoquinolin-3-yl)propyl)pyrimidin-4-amine (14G)
Figure imgf000047_0002
(i) Ao20, 0°C - R.T, 4 h; (ii) POCl3, DMF, 0°C - Reflux, Overnight; (iii) Morpholine, K2C03, DMSO, 100°C, 48 h;
(iv) Ethylmagnesium bromide, THF, -15°C - R.T, 4h; (v) SOCl2, DCM, 0°C - Reflux, 4h; (vi) Aqueous ammonia,
Sealed tube, 100°C, Overnight; (vii) Intermediate-ID, DIPEA, IP A, Microwave, 110°C, 40 min;
The process of this step was adopted from intermediate-2G using o-toluidine. MS (ES) m/z 597 (M+l)+.
Intermediate-15: Synthesis of 2-(2,5-dimethyl-lH-pyrrol-l-yl)-N-(l-(2-((2S,6R)-2,6- dimethylmoipholino)-8-methylquinolin-3-yl)propyl)-5-iodo-6-methylpyrimidin-4-amine
(15G)
(i) Ao20, 0°C - R.T, 4 h; (ii) POCl3, DMF, 0°C - Reflux, Overnight; (iii) (2S,6i?)-2,6-dimethylmorpholine, K2C03, DMSO,
100°C, 48 h; (iv) Ethylmagnesium bromide, THF, -15°C - R.T, 4 h; (v) SOCl2, DCM, 0°C - Reflux, 4 h; (vi) Aqueous ammonia, Sealed tube, 100°C, Overnight; (vii) Intermediate-ID, DIPEA, IP A, Microwave, 110°C, 40 min;
This process was adopted from intermediate-2G using o-toluidine. MS (ES) m/z 625 (M+l)+.
Intermediate-16: Synthesis of 4-(3-(l-((2-(2,5-dimethyl-lH-pyrrol-l-yl)-5-iodo-6-methyl pyrimidin-4-yl)amino)propyl)-8-methylquinolin-2-yl)thiomoipholinel,l-dioxide (16E)
Figure imgf000048_0001
Step-(i): To a stirred solution of intermediate- 13D (0.2 g, 0.6 mmol) in DCM was added m- CPBA (0.57 g, 0.3 mmol) and stirred at room temperature for 12 h. Then quenched with aquesous solution of NaHC03 and extracted with ethyl acetate (2 x 15 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated to achieve the crude product as yellow oil (0.13 g, 60%). MS (ES) m/z 351 (M+l)+. Step-(ii): To a solution of intermediate- 16B(0.05 g, 0.14 mmol) in ethanol was added Re-Ni (0.05 g, 0.3 mmol) and stirred at room temperature for 12 h under H2 atmosphere.Then the reaction mixture was filtered through celite and concentrated the filterate to achieve the crude product as a brown pasty compound (0.026 g, 55%). MS (ES) m/z 335 (M+l)+.
Intermediates 16C, 16D and 16E are prepared according to the procedure depicted in intermediate-2. MS (ES) m/z 645 (M+l)+.
Intermediate-17: 4-chloro-5-iodopyrimidin-2-amine (17B)
Figure imgf000049_0001
(17A) (17B)
(i) POC13, 100°C, 12h; (ii) NIS, DMF, room temperature, 12h.
Step-(i): 4-chloropyrimidin-2-amine (17A)
POCI3 (100 ml) was added to 2-aminopyrimidin-4-ol (10 g, 90.0 mmol) at 0°C and refluxed the reaction mixture for 12 h. After the reaction was completed, it was poured slowly onto the crushed ice and the solid formed was filtered and dried under vacuum to get the crude compound as yellow solid (5 g, 43 %). MS (ES) m/z 130 (M+l)+.
Step-(ii): 4-chloro-5-iodopyrimidin-2-amine (17B)
NIS (15 g, 60.0 mmol) was added to intermediate- 17A (5 g, 30.0 mmol) in DMF (50 ml), stirred the reaction mixture for 12 h. After the reaction was completed, it was poured slowly onto the crushed ice and the solid formed was filtered and dried under vacuum to get the crude compound as yellow solid (7 g, 71 %). MS (ES) m/z 256 (M+l)+.
Intermediate-18: 5-iodo-6-methyl-N4-(l-(8-methyl-2-morpholinoquinolin-3-yl)propyl) pyrimidine-2,4-diamine (18G)
(18D) (18E) (18F)
(vii) Reflux, 12h;
4h; (v) SOCl2 , Sealed tube, utanol,100°C,
Figure imgf000050_0001
Step-(i): N-(o-tolyl)acetamide (18A)
Acetic anhydride (5 ml, 53.7 mmol) was added to o-toluidine (5 g, 53.7 mmol) at 0°C and allowed to room temperature. The mixture was stirred at the same temperature for 4h. After the reaction was completed, it was poured slowly into the crushed ice and the solid formed was filtered and dried under vacuum to get the crude compound as white solid (5 g, 70 %). MS (ES) m/z 150 (M+l)+.
Step-(ii): 2-chloro-8-methylquinoline-3-carbaldehyde (18B)
DMF (8 ml, 111.1 mmol) was added to POCl3 (28 ml, 185.1 mmol) at 0°C to 5°C and then intermediate- 18A (5 g, 37.0 mmol) was added. The mixture was stirred at 100°C for 12 h. After the reaction was completed, it was poured slowly into the crushed ice and the solid formed was filtered and dried under vacuum to get the crude compound as yellow solid (3 g, 42 %). MS (ES) m/z 206 (M+l)+.
Step-(iii): 8-methyl-2-morpholinoquinoline-3-carbaldehyde (18C)
To a stirred solution of morpholine (7.7 g, 78.5 mmol) and K2C03 (21.6 g, 157.0 mmol) was taken in DMF, add intermediate- 18B (10 g, 52.3 mmol) to the reaction mixture. The reaction mixture was stirred at 100°C for 48 h. The progress of the reaction was monitored by TLC. The reaction mixture cooled to room temperature, water (100 ml) was added and the extracted the aqueous layer with ethyl acetate (2 x 300 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product, which was purified by column chromatography using 100-200 mesh silica gel and 3 % methanol in dichloro methane as eluent to achieve the pure product as a yellow solid (5 g, 38 %). MS (ES) m/z 257 (M+l)+.
Step-(iv): l-(8-methyl-2-morpholinoquinolin-3-yl)propan-l-ol (18D)
To a stirred solution of intermediate- 18C( 10 g, 39.2 mmol) in THF (100 ml), was added ethyl magnesium bromide (30 ml) at -15°C. The reaction mixture was stirred at room temperature for 4 h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to 0°C and acidified with dil.HCl then extracted with water (100 ml) and ethyl acetate (3 x 150 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired product as a yellow solid (8.0 g, 10 %). MS (ES) m/z 287 (M+l)+.
Step-(v): 4-(3-(l-chloropropyl)-8-methylquinolin-2-yl)morpholine (18E)
SOCl2 (4.90 mmol) was added to intermediate- 18D (0.25 g, 0.9 mmol) in DCM. The reaction mixture was refluxed for 4 h. The progress of the reaction was monitored by TLC. DCM was removed from the reaction mixture under reduced pressure. Crude was washed with excess of diethyl ether to get desired compound as yellow solid (0.2 g, 72 %). MS (ES) m/z 305 (M+l)+. Step-(vi) : 1 -(8-methyl-2-morpholinoquinolin-3-yl)propan- 1 -amine ( 18F)
Ammonium hydroxide (5 ml) was added to intermediate- 18E (0.2 g) in a sealed tube. The above mixture was heated to 120°C for 12 h. The reaction mass was cooled to room temperature and extracted with ethyl acetate (2 x 20 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired product (0.05 g, 82 %). MS (ES) m/z 286 (M+l)+.
Step-(vii): 5-iodo-6-methyl-N4-((2-(4-methylpiperazin-l-yl)quinolin-3-yl)methyl)pyrimidine- 2.4-diamine (18G)
The mixture of intermediate- 18F (0.035 g, 0.13 mmol), intermediate- 1C (0.046 mg, 0.19 mmol) and DIPEA (0.03 6g, 0.26 mmol) in n-butanol (2 ml) was stirred at 100°C for 48 h. The progress of the reaction was monitored by TLC. The reaction mixture cooled to room temperature, water (100 ml) was added and then extracted the aqueous layer with ethyl acetate (2 x 300 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product which was purified by column chromatography using 100-200 mesh silica gel and 3 % methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (0.006 g, 10 %). MS (ES) m/z 519 (M+l)+. Intermediate-19: 5-iodo-N4-(l-(8-methyl-2-morpholinoquinolin-3-yl)propyl)pyrimidine- 2,4-diamine (19)
Figure imgf000052_0001
The process of this step was adopted from intermediate- 18G by using intermediate- 18F and inter mediate- 17. MS (ES) m/z 505 (M+l)+.
Intermediate-20: 2-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)propyl)-5-fluoro-3- phenylquinazolin-4(3H)-one (20C)
Figure imgf000052_0002
Step-(i): tert-butyl(l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)carbamate (20A
To a stirred solution of 2-amino-6-fluorobenzoic acid (5.0 g, 33.1 mmol) and Boc-L-2- aminobutyric acid (6.72 g, 33.1 mmol) in pyridine (20 ml), was added triphenylphosphite (25.68 g, 82.8 mmol). The reaction mixture was stirred at 70°C for 2 h, then aniline (3.6 g, 39.7 mmol) was added, stirring was continued for another 5h at same temperature, monitor the reaction by TLC, after the reaction was completed, it was cooled to room temperature and extracted with sodium bicarbonate solution (20 ml) and ethyl acetate (2 x 10 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product. Which was purified by column chromatography using 100-200 mesh silica gel and 15% ethyl acetate in hexane as eluent to achieve the pure product as a yellow solid (2.5 g, 20 %). MS (ES) m/z 398 (M+l)+.
Step-(ii): 2-( l-aminopropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (20B)
To a solution of intermediate-20A (3.5 g, 8.90 mmol) in DCM (35 ml), was added TFA (15 ml) at 10°C. The reaction mixture was stirred at room temperature for 12 h. The progress of the reaction was monitored by TLC. After the reaction was completed, TFA was removed under vacuum and neutralized with sodium bicarbonate solution then extracted with ethyl acetate (2 x 100ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product as a yellow solid (2.2 g, 90 %). MS (ES) m/z 298 (M+l)+.
Step-(iii): 2-(l-((2-amino-5-iodo-6-methylpyrimidin-4-yl)amino)propyl)-5-fluoro-3-phenyl quinazolin-4(3H)-one (20C)
The process of this step was adopted from intermediate- 18G by using intermediate-20B and intermediate- 1C. MS (ES) m/z 531 (M+l)+.
Intermediate-21 : 2-(l-((2-amino-5-iodopyrimidin-4-yl)amino)propyl)-5-fluoro-3-phenyl quinazol -4(3H)-one (21A)
Figure imgf000053_0001
The process of this step was adopted from intermediate- 18G by using intermediate-20B and intermediate- 17. MS (ES) m/z 517 (M+l)+.
Intermediate 22: 2-(l-((2-amino-5-iodopyrimidin-4-yl)amino)propyl)-5-methyl-3-phenyl quinazolin-4(3H)-one (22C)
(1) Triphenyl phosphite, pyridine, 70°C, 7h; (11) TFA, DCM, 10°C-RT, 12h; (22C) (iii) DIPEA, n-Butanol, 1 10°C, 12h.
Step-(i): tert-butyl(l-(5-methyl-4-oxo-3-phenyl-3^-dihydroquinazolin-2-yl)propyl)carbamate (22A)
To a stirred solution of 2-amino-6-methylbenzoicacid (5.0 g, 33.1 mmol) and Boc-L-2- aminobutyric acid (6.72 g, 33.1 mmol) in pyridine (20 ml), was added triphenylphosphite (25.68 g, 82.8 mmol). The reaction mixture was stirred at 70°C for 2 h, and then aniline (3.6 g, 39.7 mmol) was added, stirring was continued for another 5 h at same temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to room temperature and extracted with sodium bicarbonate solution(20 ml) and ethylacetate (2 x 10 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product, further purified by column chromatography using 100-200 mesh silica gel and 15 % ethyl acetate in hexane as eluent to achieve the pure product as a yellow solid (2.5 g, 20 %). MS (ES) m/z 394 (M+l)+.
Step-(ii): 2-( l-aminopropyl)-5-methyl-3-phenylquinazolin-4(3H)-one (22B)
The process of this step was adopted from intermediate-20B by using intermediate-22A.
MS (ES) m/z 294 (M+l)+.
Step-(iii): 2-( l-((2-amino-5-iodopyrimidin-4-yl)amino)propyl)-5-methyl-3-phenylquinazolin-4 (3H)-one (22C)
The process of this step was adopted from intermediate- 18G by using intermediate-22B and intermediate- 17. MS (ES) m/z 514 (M+l)+.
Intermediate-23: 4-chloro-N-ethyl-5-iodopyrimidin-2-amine (23B) (23A) (23B)
(i) ethanamine, Et3N, n-Butanol, 70°C; 3h; (ii) NIS, DMF, 50°C, 3h.
Step-(i): 4-chloro-N-ethylpyrimidin-2-amine (23 A)
To a stirred solution of 2,4-dichloropyrimidine (3.0 g, 20.13 mmol) and ethanamine (1.97 g, 24.16 mmol) in n-butanol (20 ml), was added triethylamine (5.57 ml, 40.27 mmol) . The reaction mixture was stirred at 70°C for 3 h. The progress of the reaction was monitored by TLC. After the reaction was completed, it was cooled to room temperature and extracted with sodium bicarbonate solution(20 ml) and ethyl acetate (2 x 10 ml). The organic layer was washed with brine, dried over sodium sulfate and evaporated the solvent under vacuum to get the desired crude product, further purified by column chromatography using 100-200 mesh silica gel and 15 % ethyl acetate in hexane as eluent to achieve the pure product as a yellow solid (2.12 g, 67 %). MS (ES) m/z 158 (M+l)+.
Step-(ii): 4-chloro-N-ethyl-5-iodopyrimidin-2-amine (23B)
NIS (4.2 g, 19.1 mmol) was added to intermediate-23A (1 g, 6.36 mmol) in DMF (10 ml), stirred the reaction mixture for 3 h at 50°C. After the reaction was completed, it was poured slowly onto the crushed ice and the solid formed was filtered and dried under vacuum to get the crude compound as yellow color solid (0.52 g, 28 %). MS (ES) m/z 284 (M+l)+.
Intermediate-24 was prepared by following similar procedure as depicted in intermediate- 23, by using approprite raw materials at suitable conditions.
Figure imgf000055_0001
Intermediate-25 : 4-chloro-5-iodo-N-(pyridin-2-yl)pyrimidin-2-amine (25B)
Figure imgf000056_0001
Step-(i): 4-chloro-N-(pyridin-2-yl)pyrimidin-2-amine (25A)
To a stirred solution of 4-chloropyrimidin-2-amine (1 g, 7.75 mmol), 2-bromo-pyridine (1.46 g, 9.3 mmol) and xantphos (0.44 g, 0.775 mmol) in 1,4-dioxane (10 ml) was added K2CO3 (3.20 g, 23.25 mmol) and purged with argon gas for 10 minutes. pd2(dba)3 (0.700 g, 0.775 mmol) was added under argon atmosphere. The reaction mixture was stirred for 16 h at 120°C. The progress of the reaction was monitored by TLC. After the reaction was completed, reaction mixture was cooled to room temperature, filtered through celite, washed celite bed with ethyl acetate and concentrated under reduced pressure to get the crude compound, which was purified by column chromatography using 100-200 mesh silica gel and 30% ethyl acetate in hexane.as eluent to achieve the pure product as a white solid (0.61 g, 38.3 %).
Step-(ii): 4-chloro-5-iodo-N-(pyridin-2-yl)pyrimidin-2-amine (25B)
To a stirred solution of intermediate-25A (0.5 g, 2.42 mmol) in DMF (10 ml), was added NIS (0.81 g, 3.63 mmol) at room temperature. Stirred the reaction mixture for 3 h at 50°C. After the reaction was completed, cool the reaction mixture temperature to rt, it was poured slowly onto the crushed ice and the solid formed was filtered and dried under vacuum to get the crude compound as yellow color solid (0.46 g, 57.5 %).
Intermediate-26: 2-(l-((2-(ethylamino)-5-iodopyrimidin-4-yl)amino)propyl)-5-fluoro-3- phenylquinazolin-4(3H)-one (26)
Figure imgf000056_0002
(i) DIPEA, n-ButanoU 10°C,12h. (26) Step-(i): 2-(l-((2-(ethylamino)-5-iodopyrimidin-4-yl)amino)propyl)-5-fluoro-3-phenyl quinazolin-4(3H)-one (26)
The process of this step was adopted from intermediate- 18G by using intermediate-20B and intermediate-23B. MS (ES) m/z 545 (M+l)+.
Below intermediates were prepared by following similar procedure as depicted in intermediate 26, by using approprite raw materials at suitable conditions.
Figure imgf000057_0002
Intermediate-29: (5-(N-(tert-butyl)sulfamoyl)pyridin-3-yl)boronic acid (29C)
Figure imgf000057_0001
Step-(i): 5-bromopyridine-3-sulfonyl chloride (29A)
To a stirred solution of pyridine-3-sulfonic acid (2.0 g, 12.57 mmol) in POCl3 (3.27 ml, 21.3 mmol) was added PCI5 (3.92 g, 18.8 6mmol) at room temperature. The reaction mixture was stirred for 18 h at 125-130°C. The progress of the reaction was monitored by TLC. After the reaction was completed, excess of POCI3 was removed under reduced pressure. To this Br2 (1.6 g, 10.5 mmol) was added at room temperature and stirred for 4 h at 130°C. Excess of bromine was removed from the reaction mixture and it was extracted with water (15 ml) and ethyl acetate (2 X 15 ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude, which was purified by column chromatography using 100-200 mesh silica gel and 2% methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (1.5 g, 46.5 %). MS (ES) m/z 257 (M+l)+. Step-(ii): 5-bromo-N-(tert-butyl) pyridine-3-sulfonamide (29B)
To a solution of intermediate-29A (2.0 g, 7.7 rnmol) in DCM (6 ml) was added tert-butyl amine (1.08 g, 11.6 mmol) at 0°C. Then reaction mixture was stirred for 12 h at room temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15 ml) and ethyl acetate (2 X 15 ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude, which was purified by column chromatography using 100-200 mesh silica gel and 1 % methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (1 g, 43 %). MS (ES) m/z 294 (M+l)+.
Step-(iii): (5-(N-(tert-butyl)sulfamoyl)pyridin-3-yl)boronic acid (29C)
To a solution of 5-bromo-N-(tert-butyl)pyridine-3-sulfonamide (29B) (0.5 g, 1.7 mmol) in 1,4-dioxane (15 ml) was added 4,4,4',4', 5,5,5', 5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.65 g, 2.5 mmol), Pd(dppf)Cl2, DCM complex (0.069 g, 0.08 mmol) and Potassium acetate (0.5 g, 5.1 mmol) under argon atmosphere. The reaction mixture was stirred for 12 h at 100°C in a sealed tube. The progress of the reaction was monitored by TLC. After the reaction was completed, reaction mixture was filtered through celite and concentrated under reduced pressure to get the crude .Which was purified by column chromatography using 100-200 mesh silica gel and 2 % methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (0.6 g, crude). MS (ES) m/z 259 (M+l)+.
Following intermediates are prepared by using similar procedure as depicted in intermediate -29, by using approprite raw materials in presence of suitable reagents, ractants and solvents at suitable conditions. Most of these intermediates were used in the next step without further purification. Structure information and characterization data are given in below table.
Figure imgf000058_0001
Intermediate-44: (5-(meth lsulfonyl)pyridin-3-yl)boronic acid (44C)
Figure imgf000059_0002
(i) N-BuLi,Dimethyl Disulfide, -78°C to RT ,5 h (ii) Oxone,Aq NaHC03 ,THF+Methanol,RT ,4h; (iii)
4,4,4',4,,5,5,5,,5,-octamethyl-2,2,-bi(l,3,2-dioxaborolane), CH3COOK, PdCl2(dppf)2 DCM complex,l,4- dioxane,110°C,12h.
Step-(i): 3-bromo-5-(methylthio)pyridine (44A)
To a stirred solution of 3,5-dibromopyridine (1.0 g, 4.22 mmol) in diethyl ether (20 ml) was added 2.5M n-BuLi (1.68 ml, 4.22 mmol) at -78°C .The reaction mixture was stirred for 4 h at-78°C. Dimethyl sulphide (400 mg, 4.22 mmol) was added to the reaction mixture. The reaction mixture was stirred for 1 h at room temperature. The progress of the reaction was monitored by TLC. Reaction mixture was quenched with water and the product was extracted with diethyl Ether (2x50 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude product this was taken up for next step without purification (1 g, crude). MS (ES) m/z 204 (M+l)+.
Step-(ii): 3-bromo-5-(methylsulfonvi)pyridine (44B)
To a solution of 3-bromo-5-(methylsulfonyl)pyridine (1.0 g, 4.9 mmol) in THF (25 ml) and methanol (7 ml) was added oxone (6 g, 39.2 mmol ) portion wise at RT. To this reaction mixture was added aq NaHC03 (25 ml) solution was added up to PH of the reaction becomes to basic. Stir the reaction mass at room temperature for 4 h. The progress of the reaction was monitored by TLC. The reaction mixture was extracted with ethyl acetate (2 X 15 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude, which was triturated with 20% ethyl acetate and n- hexane offered pure compound as solid.(100 mg, 9 %). MS (ES) m/z 237.9 (M+l)+.
Step-(iii): (5-(methylsulfonyl)pyridin-3-yl)boronicacid (44C)
To a solution of 3-bromo-5-(methylsulfonyl) pyridine (1 g, 4.237 mmol) in 1,4-dioxane (30 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.6 g, 6.355 mmol), Pd(dppf)2Cl2.DCM complex (0.172 g, 0.02 mmol) and Potassium acetate (1.03 g, 10.59 mmol) under argon atmosphere. The reaction mixture was stirred for 12 h at 100°C in a sealed tube. The progress of the reaction was monitored by TLC. After the reaction was completed, reaction mixture was filtered through celite and concentrated under reduced pressure to get the crude (0.7 g, crude). MS (ES) m/z 201 (M+l)+.
Intermediate-45: 5-(methylsulfonyl)pyridin-3-yl)boronicacid
Figure imgf000060_0001
octamethyl-2,2'-bi(l,3,2-dioxaborolane), CH3COOK, PdCl2(dppf)2.DCM complex, 1,4-dioxane, 90°C, 2h.
Step-(i): 3-(benzylthio)-5-bromopyridine (45 A)
To a stirred solution of 60% NaH (2.02 g, 84.42 mmol), phenylmethanethiol (10.46 g, 84.42 mmol) in DMF (250 ml) at 0°C and stirred the reaction mixture for 15 min at 0°C. 3,5- dibromopyridine (20 g, 84.42 mmol) was added to the reaction mixture. The reaction mixture was warmed to room temperature and stirred at 90°C for 1 h. The progress of the reaction mixture was monitored by TLC. After the reaction was completed, quenched the reaction mixture with water. The reaction mixture was extracted ethyl acetate (2 X 100 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude product. This was purified by silica gel column chromatography eluted at 5% ethyl acetate in hexane (20 g, 84.63 %). MS (ES) m/z 257 (M+l)+. Step-(ii): 5-bromopyridine-3-thiol (45B)
To a solution of intermediate-45A (20 g, 71.42 mmol) in toluene (400 ml) was added AICI3 (16.19 g, 121.42 mmol) at 0°C. Then reaction mixture was stirred for 1 h at room temperature. The progress of the reaction was monitored by TLC. Quenched the reaction mixture with ice water. The reaction mixture was extracted with ethyl acetate (2 X 150 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude material (25 g) which was carried out for further steps without any purification. MS (ES) m/z 294 (M+l)+.
Step-(iii): 3-bromo-5-(isopropylthio)pyridine (45C)
To a stirred solution of intermediate-45B (3 g, 15.78 mmol) in THF (30 ml) was cooled to 0°C. Then DIPEA (6.11 g, 47.63 mmol) was added followed by 2-bromopropane was added to the reaction mixture at 0°C and the reaction mixture was stirred for 4 h at RT. The progress of the reaction was monitored by TLC. After the reaction was completed, quenched the reaction mixture with ice water. The reaction mixture was extracted with ethyl acetate (2 X 100 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude. This was taken up for Next step without purification (3.6 g, crude). MS (ES) m/z 232 (M+l)+.
Step-(iv): 3-bromo-5-(isopropylsulfonyl)pyridine (45D)
To a solution of 3-bromo-5-(isopropylthio)pyridine (1.5 g, 6.46 mmol) in methanol (80 ml) was added oxone (9.92 g, 32.32 mmol) at RT. Then reaction mixture was stirred for 12 h at room temperature. The progress of the reaction was monitored by TLC. After the reaction was completed, distill of the methanol under vacuum. The residue was diluted with water, it was extracted with ethyl acetate (2 X 45 ml). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to get the crude.which was purified by column chromatography using 100-200 mesh silica gel and 20 % ethyl acetate in hexane as eluent to afford the target compound. (1.1 g, 64.7 %). MS (ES) m/z 264 (M+l)+.
Step-(v): 5-(methylsulfonyl)pyridin-3-yl)boronicacid (45E)
To a solution of 3-bromo-5-(isopropylsulfonyl)pyridine (1 g, 3.78 mmol) in 1,4-dioxane (10 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.44 g, 5.68 mmol), Pd(dppf)2Cl2.DCM (0.015 g, 0.18 mmol) and potassium acetate (1.11 g, 11.36 mmol) under argon atmosphere. The reaction mixture was stirred for 2 h at 90°C in a sealed tube.. The progress of the reaction was monitored by TLC. After the reaction was completed, reaction mixture was filtered through celite and concentrated under reduced pressure to get the crude product (1 g, crude). MS (ES) m/z 230 (M+l)+.
Intermediate-46 was prepared by following similar procedure as depicted in intermediate- 45, by using approprite rawmaterials in presence of suitable reagents, reactants and solvents at suitable conditions
Figure imgf000062_0002
Intermediate-47: 5-(ethylsulfonamido)pyridin-3-yl)boronicacid (47B)
Figure imgf000062_0001
Step-(i): N-(5-bromopyridin-3-yl)ethanesulfonamide (47 A)
To a stirred solution of 5-bromopyridin-3-amine (1 g, 5.78 mmol) in DCM (15 ml)was added pyridine (1.36 g, 17.34 mmol) and ethanesulfonylchloride (1.1 g, 8.67 mmol) at 0°C.and the reaction mixture was stirred for 12 h at RT. The progress of the reaction was monitored by TLC. After the reaction was completed, distill off the solvent under vacuum to the residue ice cold water was added, and stirred for 30 min, solid was precipitated, filtered off the solid and dried under vacuum to get the desired compound as light brown color solid (1.2 g crude) Step-(ii): 5-(ethylsulfonamido)pyridin-3-yl)boronicacid (47B) To a solution of intermediate-47A (0.8 g, 3.01 mmol) in 1,4-dioxane (30 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (1.16 g, 4.528 mmol), Pd(dppf)2Cl2. DCM complex (0.245 g, 0.30 mmol) and Potassium acetate (0.737 g, 7.52 mmol) under argon atmosphere. The reaction mixture was stirred for 16 h at 100°C in a sealed tube. The progress of the reaction was monitored by TLC. After the reaction was completed, reaction mixture was filtered through celite and concentrated under reduced pressure afforded the crude material ( 1 g, crude). MS (ES) m/z 259 (M+l).
Intermediates listed in below table weree prepared by following similar procedure as depicted in intermediate-47, by using approprite rawmaterials in presence of suitable reactants, reagents and solvents at suitable conditions.
Figure imgf000063_0002
Intermediate-50: l-(alkylsulfonyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-2,3- dihydro- 1 H-py rrolo [2,3-c] pyridine (50 J)
Figure imgf000063_0001
Step-(i): 3-bromo -5-nitropyridine-4-ol (50A)
To a stirred solution of 3-nitropyridine-4-ol (20 g, 142.85 mmol) in water was added bromine (9.2 ml, 178.56 mmol) at room temperature. The reaction mixture was stirred for 1 h at room temperature and 3 h at 50°C. The reaction mixture was cooled to room temperature the precipitated solid was filtered to afford the crude material (25 g, 80 %). 1HNMR (400 MHz, DMSO-d6) δ: 12.73 (bs, 1H), 8.0 (d, J=l Hz, IH), 8.35 (s, 1H), MS (ES) m/z 217 (M+), 219 (M+2).
Step-(ii): 3-bromo -4-chloro-5-nitropyridine (50B)
To a stirred solution of intermediate-50A (5.0 g, 22.83 mmol) in POCl3 (17.46 g, 114.16 mmol) was added N,N-Diethylaniline (4 g, 27.39 mmol) at 10°C temperature. The reaction mixture was stirred for 3 h at 100°C. POCl3was concentrated under reduced pressure and the residue was poured into ice cold water. The solid obtained was filtered to afford the target compound (4 g, 74 %). *HNMR (400 MHz, DMSO-d6) δ: 9.20 (s, 1H), 9.17 (s, 1H), MS (ES) m/z 237 (M+l).
Step-(iii): Diethyl 2-(3-bromo-5-nitropyridin-4-yl)malonate (50C)
To a suspension of 60% NaH (315 mg, 13.13 mmol) in DMF (5 ml) was added diethyl malonate (1.35 g, 8.47 mmol) drop wise at 0°C. The reaction mixture was stirred for 45 min at 0°C. 3-bromo-4-chloro-5-nitropyridine (1 g, 4.23 mmol) was added in DMF (1 ml) at 0°C. Stirred the reaction mixture at rt for a period of for 2 h. The reaction mixture was poured in ice water. The product extracted with ethyl acetate (3 XI 00 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude material was purified by column chromatography using 100-200 mesh silica gel and 15% ethyl acetate in hexane as eluent to afford the desired compound as a yellow liquid (0.8 g, 52 %). *HNMR (400 MHz, DMSO-d6) δ: 9.22 (d, J=2.9 Hz, 1H), 5.64 (s, 1H), 4.21-4.11 (m, 4H), 1.17 (t, J=7.3 Hz, 6H), MS (ES) m/z 361 (M+), 363(M+2,) .
Step (iv): Ethyl 2— (3-bromo-5-nitropyridin-4-yl)acetate (50D)
To a suspension of diethyl 2-(3-bromo-5-nitropyridin-4-yl)malonate (4 g, 11.07 mmol) and LiCl (1.17 g, 27.68 mmol) in DMSO (2 ml) and water (0.5 ml) at room temperature. The reaction mixture was stirred for 3 h at 150°C. The reaction mixture was cooled to room temperature and poured into ice water. The product was extracted with ethyl acetate (3 X 100 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude material was purified by column chromatography using 100-200 mesh silica gel and 8 % ethyl acetate in hexane as eluent to afford the desired compound as a yellow liquid (2.5 g, 78 %). MS (ES) m/z 289 (M+). 292 (M+2).
Step-(v): Ethyl-2-(3-amino-5-bromopyridin-4-yl)acetate (50E)
To a stirred solution of ethyl 2-(3-bromo-5-nitropyridin-4-yl)acetate (0.500 g, 1.73 mmol) in IPA (10 ml) was added ammonium chloride (183 mg, 3.46 mmol) and iron powder (289 mg, 5.19 mmol) at RT. The reaction mixture was stirred for 30 min at 80°C. The reaction mixture was filtered through celite washed with ethyl acetate. The organic layer was collected and concentrated under reduced pressure to get the crude product. (300 mg, crude). MS (ES) m/z 259 (M+).
Step-(vi): Ethyl 2-(3-bromo-5-pivalamidopyridin-4-yl)acetate (50F)
To a stirred solution of ethyl-2-(3-amino-5-bromopyridin-4-yl)acetate (2.0 g, 7.72 mmol) and TEA (2.33 g, 23.1 mmol) in DCM (40 ml) was added Pivolyl Chloride (2.32 g, 19.30 mmol) at 10°C. The reaction mixture was stirred for overnight at room temperature. The reaction mixture was poured in ice water. The product was extracted with ethyl acetate (3 X 100 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude material, was purified by column chromatography using 100-200 mesh silica gel and 20 % ethyl acetate in hexane as eluent to afford the desired compound as a yellow liquid (2 g, 86 %). MS (ES) m/z 343 (M+).
Step-(vii): N-(5-bromo-4-(2-hydroxyethyl)pyridin-3-yl)pivalamide (50G)
To a stirred solution ofethyl 2-(3-bromo-5-pivalamidopyridin-4-yl) acetate (1.0 g, 2.92 mmol) in THF & EtOH (1: 1) 10 ml was added NaBH4 (555 mg, 14.6 mmol) at 10°C. The reaction mixture was stirred for 4 h at room temperature. Solvent was concentrated under reduced pressure. The reaction mixture was poured in ice water. The product was extracted with ethyl acetate (3 X 50 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude material was purified by column chromatography using 100-200 mesh silica gel and 3% methanol in dichloromethane as eluent to afford the desired compound as brown solid. (600 mg, 68 %), !HNMR (400 MHz, DMSO-d6) δ 9.02 (bs, 1H), 8.83 (s, 1H), 8.41 (s, 1H), 4.03 (s, 2H), 3.02 (s, 2H), 2.89 (bs, 1H), 1.25 (s, 9H). MS (ES) m/z 301 (M+). Step-(viii): 4-bromo-2,3-dihydro-lH-pyrrolor2,3-clpyridine (50H)
To a stirred solution of N-(5-bromo-4-(2-hydroxyethyl) pyridin-3-yl)pivalamide (1.0 g, 3.32 mmol) in Con HC1 (30 ml) was reflux for 48 h. Solvent was removed under reduced pressure, and the residue was diluted with water, basified with saturated sodium bicarbonate solution (10 ml). The product was extracted with ethyl acetate (3 X 50 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude material was purified by column chromatography using 100-200 mesh silica gel and 3% methanol in dichloro methane as eluent to afford the desired compound as brown solid. (600 mg, 90 %). !HNMR (400 MHz, DMSO-d6) δ 7.80 (s, 1H), 7.70 (s, 1H), 6.08 (bs, 1H), 3.53-3.48 (m, 2H), 2.29-2.94 (m, 1H). LCMS (ES) m/z 199 (M+), 201 (M+2).
Step-(ix): 4-bromo- l-(methylsulfonyl)-2,3-dihydro- lH-pyrrolor2,3-c1pyridine (501)
To a stirred solution of4-bromo-2,3-dihydro-lH-pyrrolo[2,3-c]pyridine (0.5 g, 2.51 mmol) and TEA (507 mg, 5.025 mmol) in DCM (20 ml)was added methanesulfonylchloride (429 mg, 3.71 mmol) at 10°C. The reaction mixture was stirred for overnight at room temperature. The reaction mixture was poured in ice water. The product was extracted with DCM (3x 100 ml). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The obtained crude material, was purified by column chromatography using 100-200 mesh silica gel and 20 % ethyl acetate in hexane as eluent to afford the desired compound as yellow solid. (650 mg, 93 %), 1HNMR (400 MHz, DMSO-d6), δ 8.38 (s, 2H), 4.02 (t, J=8.8 Hz, 2H), 3.17 (t, J=8.8 Hz, 2H), 3.13 (s, 3H), MS (ES) m/z 277 (M+), 279 (M+2).
Step-(x): l-(methylsulfonyl)-2,3-dihvdro-lH-pyrrolo[2,3-clpyridin-4-yl)boronicacid (50J)
To a solution of 4-bromo- l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[2,3-c]pyridine (0.6 g, 2.16 mmol) in 1,4-dioxane (15 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2- dioxaborolane) (0.825 g, 3.24 mmol), Pd(dppf)2Cl2.DCM complex (0.088 g, 0.10 mmol) and potassium acetate (0.424 g, 5.1 mmol) under argon atmosphere. The reaction mixture was stirred for 12 h at 100°C in a sealed tube. The progress of the reaction was monitored by TLC. After the reaction was completed, reaction mixture was filtered through celite and concentrated under reduced pressure to get the crude required compound (0.6 g, crude). MS (ES) m/z 243 (M+l). Intermediate- 51 was prepared by following similar procedure as depicted in intermediate- 50, by using approprite rawmaterials in presence of suitable reactants, reagents and solvents at suitable conditions.
Figure imgf000067_0002
Intermediate-52: (5-(tert-butylcarbamoyl)pyridin-3-yl) boronic acid (52B)
Figure imgf000067_0001
(52A) (52B)
(i)HATU,DIPEA,Tert -Butyl Amine,DMF,RT,16h (II)4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane),
C¾COOK, PdCl9(dppf).DCM, l,4-dioxaneJ20°CJ6h.
Step-(i): 5-bromo-N-(tert-butyl)nicotinamide (52A)
To a stirred solution of 5 -bro mo nicotinic acid (1.0 g, 4.975 mmol) in DMF (5 ml) at room temperature, HATU (2.8 g, 7.462 mmol) and DIPEA (2.6 ml, 14.92 mmol) were added at room temperature. The reaction mixture was stirred for 30 min at RT. tert-Butyl amine (0.63 ml, 5.97 mmol) was added at RT. The reaction mixture was stirred for 16 h at RT. The progress of the reaction was monitored by TLC. After the reaction was completed, Quenched the reaction mass with ice water, solid precipitated .filter off the solid and washed with chilled water dried under vacuum to get the desired compound as off white solid (0.91 g, 71.65 %).
*HNMR (400 MHz, DMSO-d6) δ 8.90 (d, J=1.4 Hz, 1H), 8.38 (t, J=1.5 Hz, 1H) 8.21 (d, J=2 Hz, 1H), 8.1 (bs, 1H), 1.38 (s, 9H), MS (ES) m/z 259 (M+2).
Step-(ii): 5-(tert-butylcarbamoyl)pyridin-3-yl)boronicacid (52B)
To a solution of 5-bromo-N-(tert-butyl)nicotinamide (0.5 g, 1.7 mmol) in 1,4-dioxane (5 ml) was added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(l,3,2-dioxaborolane) (0.740 g, 2.91 mmol), Pd(dppf)2Ci2 (0.158 g, 0.19 mmol) and Potassium acetate (0.381 g, 3.88 mmol) under argon atmosphere. The reaction mixture was stirred for 16 h at 120°C in a sealed tube. The progress of the reaction was monitored by TLC. After the reaction was completed, the reaction mixture was filtered through celite and concentrated under reduced pressure to afford the crude material (0.5 g, crude), MS (ES) m/z 223 (M+l).
The present invention is further exemplified, but not limited, by the following examples that illustrate the preparation of compounds according to the invention.
Example-I: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acrylic acid (Compound-1)
Method- 1:
Figure imgf000068_0001
(Intermediate 3) (1.1) (1.2) (Compound-1)
(i) Ethylacrylate, Pd(dppf )C12, Et3N, DMF, Η2θ, sealed tube, 100°C, Overnight; (ii) LiOH, THF, Ethanol, Η2θ, Overnight, R.T;
(iii) Hydroxylamine hydrochloride, Ethanol, H20, Reflux, Overnight.
Step-(i): (E)-ethyl 3-(2-(2,5-dimethyl-lH-pyrrol-l-yl)-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl- 3 , 4-dihydroquinazo lin-2- yPpropyl) amino )pyrimidin-5 - yPacr ylate (1.1)
To a stirred solution of Intermediate-3 (2.0 g, 3.3 mmol) in DMF (6 ml) was added ethyl acrylate (0.7 g, 8.27 mmol), Pd(dppf)Cl2 (0.12 g, 0.16 mmol), Et3N (1.6 ml, 16.5 mmol) and 0.5 ml of H2O.The reaction mixture was stirred for overnight at 100°C. The obtained residue was diluted with water (15 ml) and extracted with ethyl acetate (2 X 15 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 2% methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (1.5 g, 79 %). !H-NMR (400 MHz, CDC13) δ 7.87 (d, 1H, J=17 Hz), 7.71-7.40 (m, 4H), 7.34-7.24 (m, 2H), 7.15 (d, 1H, J=7.0 Hz), 6.87 (d, 1H, J=8.3 Hz), 6.72 (d, 1H, J=16.6 Hz), 5.83 (s, 2H), 5.19-5.14 (m, 1H), 4.76-4.74 (m, 1H), 4.39 (q, 2H, J,=7.4 Hz, J2=6.3 Hz), 2.82 (s, 3H), 2.46 (s, 3H), 2.17 (s, 6H), 1.89-1.82 (m, 2H), 1.45 (t, 3H, J=7 Hz), 0.75 (t, 3H, J=7.8 Hz). MS (ES) m/z 577 (M+l)+.
Step-(ii): (E)-3-(2-(2,5-dimethyl-lH-pyrrol-l-yl)-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)armno)pyrirmdin-5-yl)acrylic acid (1.2) To a stirred solution of compound- 1.1 (1.2 g, 2.0 mmol) in THF: EtOH: H20 (7: 2: 1) was added LiOH (0.5 g, 20.8 mmol). The reaction mixture was stirred for overnight at room temperature. The solvents were evaporated under vacuum and acidified using dil. HCl then diluted with water (15 ml) and extracted with ethyl acetate (2 x 15 ml). The combined organic phases were dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 4% methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (1 g, 85%). !H-NMR (400 MHz, DMSO-J6) δ 13.0 (bs, IH), 7.70- 7.62 (m, 4H), 7.57-7.47 (m, 2H), 7.41-7.13 (m, 4H), 6.45 (d, IH, J=16.1 Hz), 5.76 (s, 2H), 4.75- 4.71 (m, IH), 2.71 (s, 3H), 2.38 (s, 3H), 2.02 (s, 6H), 1.93-1.91 (m, 2H), 0.71 (t, 3H, J=7.3 Hz). MS (ES) m/z 549 (M+l)+.
Step-iii: (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl) amino)pyr imidin- 5 - yl) aery licacid ( 1 )
To a stirred solution of compound- 1.2 (0.14 g, 0.25 mmol) in ethanol (6 ml) was added hydroxylamine hydrochloride (0.88 g, 12.7 mmol). The reaction mixture was refluxed for overnight. After the elimination of the solvents in vacuo, the residue was chromatographed using 100-200 mesh silica gel, eluting with 4% methanol in dichloromethane to give the title compound as a yellow solid (0.03 g, 25 %). !H-NMR (400 MHz, DMSO-J6) δ 12.0 (bs, IH), 7.72-7.50 (m, 6H), 7.30 (d, IH, J=7.3 Hz), 6.91 (d, IH, J=6.4 Hz), 6.28 (bs, 2H), 6.24 (s, IH), 4.76-4.75 (m, IH), 2.70 (s, 3H), 2.20 (s, 3H), 1.85-1.80 (m, IH), 1.75-7.35 (m, IH), 0.63 (m, 3H). MS (ES) m/z 471 (M+l)+.
Method-2:
Figure imgf000069_0001
Step-(i): (E)-ethyl 3-(2-amino-4-methyl-6-(( l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin- 2-yl)propyl)amino)pyrimidin-5-yl)acrylate ( 1.2) To a stirred solution of intermediate-4(0.52 g, 1 mmol) in toluene (6 ml) was added ethyl acrylate (0.1 g, 1.0 mmol), Pd(OAc)2 (0.02 g, 0.1 mmol), K2C03 (0.2 g, 1.2 mmol), BINAP (0.12 g, 0.2 mmol) and 0.5 ml of H20 and stirred for overnight at 120°C. The obtained mixture was diluted with water (15 ml) and extracted with ethyl acetate (2 X 15 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 5 % methanol in dichloro methane to give the title compound as a yellow solid (0.29 g, 60 %). MS (ES) m/z 499 (M+l)+.
Step-(ii): (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl) amino) pyrimidin-5-yl) acrylic acid (Compound- 1).
The process of this step was adopted from step-(ii) of compound- 1 (method- 1). MS (ES) m/z 471 (M+l)+.
Example-II: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acrylamide (Compound-2)
Figure imgf000070_0001
(1-2) (2.1) (Compound-2)
(i) 1 -hydroxy- IH-benzotriazole ammonium salt, EDC.HCl, DMF, 10°C- R.T, Overnight; (ii) Hydro xylamine.HCl,
Ethanol, H20, Reflux, Overnight.
Step-(i): (E)-3-(2-(2,5-dimethyl-lH-pyrrol-l-yl)-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)armno)pyrimidin-5-yl)acrylamide (2.1)
1 -hydroxy- IH-benzotriazole ammonium salt (0.066 g, 0.437 mmol) and EDC.HCl (0.084 g, 0.437 mmol) are added at 10°C to a stirred solution of compound-1.2 (0.2 g, 0.36 mmol) in DMF (5 ml). The reaction mixture was stirred at room temperature for overnight. The obtained mixture was poured into ice water. The solid formed was filtered under suction to give the title compound as a yellow solid (0.08 g, 40%). 1H-NMR (400 MHz, DMSO-J6) δ 7.70-7.66 (m, 2H), 7.52-7.44 (m, 3H), 7.40-7.23 (m, 6H), 7.13-7.11 (m, 1H), 6.44 (d, 1H, J=6.1 Hz), 5.74 (s, 2H), 4.68-4.67 (m, 1H), 2.71 (s, 3H), 2.35 (s, 3H), 2.00 (s, 6H), 1.92-1.90 (m, 1H), 1.75-1.72 (m, 1H), 0.73 (t, 3H, J=7.4 Hz). MS (ES) m/z 548 (M+l)+.
Step-(ii): (E)-3-(2-armno-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl) amino )pyrimidin-5-yl)acrylamide (2) The process of this step was adopted from step-(iii) of compound- 1. 'H-NMR (400 MHz, CDCI3) δ 7.73 (bs, 2H), 7.69-7.52 (m, 6H), 7.35-7.32 (m, 2H), 7.26-7.24 (m, IH), 6.52 (bs, IH), 6.35 (d, 2H, J=16.1 Hz), 4.23-4.20 (m, IH), 2.81 (s, 3H), 2.32 (s, 3H), 2.06-2.01 (m, 2H), 0.77 (t, 3H, J=7.3 Hz). MS (ES) m/z 470 (M+l)+.
Example-Ill: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-di hydro uinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-N-isopropylacrylamide (Compound-3)
Figure imgf000071_0001
(!-2) (3.1) (Compound-3)
(i) Propan-2-amine, EDC .HC1, HOBT, Et3N, DMF, 0°C - R.T, overnight; (ii) Hydroxylamine. HC1, Ethanol,
H20, Reflux, Overnight.
Step-(i): (E)-3-(2-(2,5-dimethyl-lH-pyrrol-l-yl)-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-N-isopropylacrylamide (3.1)
To a stirred solution of compound- 1.2 (0.026 g, 0.43 mmol) in DMF (5 ml) was added propan-2-amine (0.066 g, 0.437 mmol), Et3N (0.055 g, 0.54 mmol), EDC.HCl (0.14 g, 0.72 mmol) and HOBT (0.084 g, 0.54 mmol) at 0°C and stirred at room temperature for overnight. The obtained mixture was poured into ice water. The solid formed was filtered under suction to achieve the pure product as a yellow solid (0.09 g, 42%). !H-NMR (400 MHz, DMSO-J6) δ 8.01 (d, IH, J=7.3 Hz), 7.69-7.66 (m, IH), 7.51-7.38 (m, 6H), 7.32-7.25 (m, 2H), 7.15-7.14 (m, IH), 6.45 (d, IH, J=16.1 Hz), 5.74 (s, 2H), 4.70-4.69 (m, IH), 4.02-4.01 (m, IH), 2.72 (s, 3H), 2.35 (s, 3H), 2.02 (s, 6H), 1.97-1.85 (m, IH), 1.80-1.62 (m, IH), 1.16-1.14 (s, 6H), 0.73 (t, 3H, J=7.4 Hz). MS (ES) m/z 590 (M+l)+.
Step-(ii): (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl) amino)pyr imidin- 5 - yl) -N-isopropylacrylamide ( 3 )
The process of this step was adopted from step-(ii) of compound-2. 'H-NMR (400 MHz, DMSO-Je) δ 7.61-7.50 (m, 6H), 7.35-7.25 (m, 2H), 6.70 (d, IH, J=8.3 Hz), 6.22 (d, IH, J=15.3 Hz), 5.48 (d, IH, J=7.8 Hz), 5.06-5.02 (m, 3H), 4.31-4.20 (m, IH), 2.82 (s, 3H), 2.33 (s, 3H), 2.01-1.91 (m, 2H), 1.30 (d, 3H, J=6.4 Hz), 1.25 (d, 3H, J=6.4 Hz), 0.76 (t, 3H, J=7.5 Hz). MS (ES) m/e 512 (M+l)+. The below compounds were prepared by procedure similar to the one described in Example-Ill with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.
Figure imgf000072_0001
7.70-7.65 (m, 2Η), 7.59-7.49 (m, 4Η), 7.42 (d, 1Η,
J=7.8 Hz), 7.28 (d, 1H, J=7.3 Hz), 6.18 (s, 1H), 5.90
16 (bs, 2H), 4.65-4.60 (m, 1H), 3.61-3.45 (m, 8H), 2.70
(s, 3H), 2.24 (s, 3H), 2.01 (s, 3H), 1.80-1.71 (m, 1H), 1.50-1.41 (m, 1H), 0.65-0.61 (m, 3H); MS (ES) m/z 554 (M+l)+.
8.04 (d, 1H, J=4 Hz), 7.65 (d, 2H, J=8.0 Hz), 7.57- 7.50 (m, 5H), 7.39 (d, 1H, J=l l Hz), 7.28 (d, 1H,
17 Η2Ν χ Ν ΝΗ Η J=7.0 Hz), 5.78 (s, 2H), 4.64 (m, 1H), 2.71 (s, 3H),
2.08 (s, 5H), 1.96 (s, 3H), 1.74-1.72 (m, 1H), 1.37- 1.35 (m, 1H), 0.68-0.62 (m, 3H), 0.44-0.43 (m, 2H); MS (ES) m/z 524 (M+l)+.
Example-IV: Synthesis of (E)-tert-butyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3- phenyl-3, 4-dihydroquinazolin-2-yl) propyl) amino) pyrimidin-5-yl)acrylate (Compound-9)
Figure imgf000073_0001
(i) tert- u\y\ acrylate, Pd(dppf )C12, Et3N, DMF, H20, Sealed tube, 100°C, Overnight; (ii) Hydroxylamine.HCl,
Ethanol, H20, Reflux. Overnight
Step-(i): (E)-tert-butyl 3-(2-(2,5-dimethyl-lH-pyrrol-l-yl)-4-methyl-6-((l-(5-methyl-4-oxo-3- phenyl-3^-dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acryl^^ (9.1)
The process of this step was adopted from step-(i) of compound- 1 in method- 1 by using intermediate-3 as starting compound. MS (ES) m/z 604 (M+l)+.
Step-(ii): (E)-tert-butyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4dihydro quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acrylate (9)
The process of this step was adopted from step-(iii) of compound- 1 in method- 1 .1H- NMR (400 MHz, DMSO-J6) δ 7.72-7.60 (m, 2H), 7.58-7.50 (m, 5H), 7.33 (d, 1H, J=7 Hz), 7.10- 7.00 (m, IH), 6.40-6.27 (m, 3H), 4.81-4.80 (m, IH), 2.72 (s, 3H), 2.23 (s, 3H), 1.98-1.80 (m, 2H), 1.53 (s, 9H), 0.64 (t, 3H, J=8 Hz). MS (ES) m/z 527 (M+l)+.
The below compounds were prepared by procedure similar to the one described in Example-IV with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.
Figure imgf000074_0002
Example-V: Synthesis of tert-butyl 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)cyclopropane carboxylate (Compound-7) and 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydro quinazoli -2- l)propyl)amino)pyrimidin-5-yl)cyclopropanecarboxylic acid (Compound-8)
Figure imgf000074_0001
Step-(i): tert -butyl 2-(2-amino-4-methyl-6-(( l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin- 2-yl)propyl)amino)pyrimidin-5-yl)cyclopropane carboxylate (Compound-7)
To a stirred solution of NaH (0.04 g, 0.9 mmol) and TMSI (0.21 g, 0.9 mmol) in DMF (5 ml) was added pre dissolved solution of compound-9 (0.026 g, 0.43 mmol,) at 0°C and stirred at room temperature for 30 min. Then the residue was diluted with water (15 ml) and extracted with ethyl acetate (2 X 15 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 5% methanol in dichloromethane to give the title compound as a yellow solid (0.06g, 37%). 'H-NMR (400 MHz, DMSO-J6) δ 7.63-7.51 (m, 5H), 7.47 (t, 1H, J=8 Hz), 7.35- 7.24 (m, 2H), 5.80-5.78 (m, 2H), 4.91-4.86 (m, 1H), 2.80 (s, 3H), 2.26 (s, 3H), 1.89-1.99 (m, 4H), 1.43 (s, 9H), 0.89-0.74 (m, 5H). MS (ES) m/z 541 (M+l)+.
Step-(ii): 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl)amino)pyrimidin-5-yl)cvclopropanecarboxylic acid (Compound-8)
TFA (0.2 ml) was added at 0°C to a stirred solution of compound-7 (0.035 g, 60.0 mmol) in DCM (5 ml) and stirred at room temperature for 16 h. After the elimination of excess of solvents in vacuo, the residue was chromatographed using 100-200 mesh silica gel , eluting with 4% methanol in dichloromethane to give the title compound as a yellow solid (0.012 g, 41 %). 'H-NMR (400 MHz, DMSO-Je) δ 12.10 (brs, 1H), 7.73-7.71 (m, 1H), 7.69-7.26 (m, 7H), 7.24- 7.08 (m, 2H), 4.81-4.80 (m, 1H), 2.72 (s, 3H), 2.23 (s, 3H), 2.22-1.84 (m, 2H), 1.35-1.15 (m, 3H), 0.85-0.63 (m, 4H). MS (ES) m/z 485 (M+l)+.
Example- VI: Synthesis of (E)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl- 3,4-dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acrylate (Compound-10)
Figure imgf000075_0001
(Com pound- 1.1) (Compound-10)
(i) Hydroxylamine hydrochloride, Ethanol, H20, reflux, overnight
The process of this step was adopted from step-(iii) of compound- 1 from method- 1 by using compound- 1.1 as starting material. !H-NMR (400 MHz, DMSO-J6) δ 7.78-7.60 (m, 2H), 7.58-7.51 (m, 6H), 7.32-7.30 (m, 1H), 7.05-7.03 (m, 1H), 6.35 (d, 1H, J=17.8 Hz), 4.80-4.77 (m, IH), 4.25-4.22 (m, 2H), 2.72 (s, 3H), 2.23 (s, 3H), 1.85-1.61 (m, 2H), 1.31 (d, 3H, J=7.8 Hz), 0.63 (t, 3H, J=7.3 Hz). MS (ES) m/z 499 (M+l)+.
Example- VII: Synthesis of 2-(l-((2-amino-5-((lE, 3Z)-3-(hydroxyimino)but-l-en-l-yl)-6- methylpyrimidin-4-yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one (Compound- 11)
Figure imgf000076_0001
(intermediate-3) (H-l) (Compound-11)
(i) Methyl vinylketone, Pd(dppf )C12 _ Et3N, DMF, H20, Sealed tube, 100°C, Overnight; (ii) Hydroxylamine. HCl,
Ethanol, II9O, Reflux, Overnight.
Step-(i): (E)-2-(l-((2-(2,5-dimethyl-lH-pyrrol-l-yl)-6-methyl-5-(3-oxobut-l-en-l-yl)pyrimidin-4- yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one (11.1)
The process of this step was adopted from step-(i) of compound- 1 from method- 1 by using intermediate-3 as starting material.MS (ES) m/z 547 (M+l)+.
Step-(ii): 2-(l-((2-amino-5-((lE,3Z)-3-(hydroxyimino)but-l-en-l-yl)-6-methylpyrimidin-4-yl) amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one (11)
The process of this step was adopted from step-(iii) of compound- 1. 'H-NMR (400 MHz,
DMSO-Je) δ 10.6-9.80 (bs, IH), 7.62-7.52 (m, 4H), 7.46-7.42 (m, 2H), 7.33-7.26 (m, IH), 6.69 (d, IH, J=16.6 Hz), 6.55-6.50 (m, IH), 4.94-4.90 (m, 3H), 3.50-3.45 (m, IH), 2.80 (s, 3H), 2.22
(s, 3H), 2.17 (s, 3H), 1.84-1.71 (m, 2H), 0.76 (t, 3H, J=7.4 Hz). MS (ES) m/z 484 (M+l)+.
Example- VIII: Synthesis of (E)-3-(2-amino-4-methyl-6-(l-(2-(4-methylpiperazin-l-yl) quinolin-3-yl)propylamino)pyrimidin-5-yl)acrylicacid (Compound-13)
Figure imgf000076_0002
The process of this step was adopted from step-(ii) of compound- 1 from method-2 by g compound-12 as starting material. MS (ES) m/z 460 (M+l)+. Example-IX: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phi dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-N-(pyridin-2-yl)acrylamide
(Compound-18
Figure imgf000077_0001
The process of this step was adopted from step-(i) of compound-3. 'H-NMR (400 MHz, DMSO-Je) δ 10.27 (s, IH), 8.84 (s, IH), 8.16-8.14 (m, 2H), 7.69-7.41 (m, 9H), 7.36 (d, 2H, J=7.3 Hz), 7.17 (d, IH, J=7.4 Hz), 6.44 (d, IH, J=15.7 Hz), 6.21 (bs, 2H), 4.68-4.66 (bs, IH), 2.80 (s, 2H), 2.20 (s, 3H), 1.77-1.68 (m, 2H), 0.70-0.61(m, 3H). MS (ES) m/z 547 (M+l)+.
The below compounds were prepared by procedure similar to the one described in Example-IX by using suitable starting material with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.
Figure imgf000077_0002
Figure imgf000078_0001
Figure imgf000079_0001
(m, IH), 0.73 (t, IH, J=6.9 Hz). MS (ES) m/z 565 (M+l,
100%).
Example-X: Synthesis of 2-(l-((2-amino-6-methyl-5-vinylpyrimidin-4-yl) amino) propyl)-5- methyl-3-phenylquinazolin-4 3H)-one (Compound-25)
Figure imgf000080_0001
(Intermediate-4) (Compound-25)
(i) 2,4,6-trivinyl-l,3,5,2,4,6-trioxatriborinane, Pd(PPh3)4, K2C03, Toluene,
Ethanol, H20, Sealed tube, 100°C, Overnight;
To a stirred solution of intermediate-4 (0.2 g, 0.38 mmol) in toluene (2 ml): ethanol (2 ml) (1: 1), was added 2,4,6-trivinyl-l,3,5,2,4,6-trioxatriborinane (0.12 g,0. 49 mmol), Pd(Pph3)4 (0.046 g, 0.04 mmol), K2C03 (0.2 g, 1.52 mmol) and 0.5 ml of H20 and stirred for overnight at 100°C. The obtained mixture was diluted with water (15 ml) and extracted with ethyl acetate (2 X 15 ml). After brine wash, the combined organic phases were dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 3% methanol in dichloro methane to give the title compound as a yellow solid (0.048 g, 30%).1H- NMR (400 MHz, DMSO-J6) δ 7.68-7.41 (m, 7H), 7.29 (d, IH, J=8 Hz), 6.69-6.61 (m, IH), 6.36 (d, IH, J=7 Hz), 5.90-5.85 (bs, 2H), 5.51-5.46 (m, IH), 4.65-4.61 (m, IH), 2.71 (s, 3H), 2.15 (s, 3H), 1.81-1.79 (m, IH), 1.77-1.57 (m, IH), 0.63 (t, 3H, J=7 Hz). MS (ES) m/z 427 (M+l)+.
Example-XI: Synthesis of (E)-ethyl 3-(2-amino-4-methyl-6-((l-(l-methyl-4-oxo-5-phenyl- 4,5-dihydro-lH-pyrazolo[3,4-d]pyrimidin-6-yl)propyl)amino)pyrimidin-5-yl)acrylate (Compound-26)
Figure imgf000080_0002
(Intermediate-6) (Compound-26)
(i) Ethyl acrylate, Pd(OAc)2 ,ΒΙΝΛΡ, K2C03, Toluene, H20, Sealed tube, 120°C, Overnight The process of this step was adopted from step-(i) of compound- 1 from method-2 by using intermediate-6 as starting compound. 1H-NMR (400 MHz, DMSO-Je) δ 7.60-7.45 (m, 5H), 6.79 (d, 1H, J=7.8 Hz), 6.085 (d, 2H, J=l 1.8 Hz), 5.39 (bs, 1H), 4.79-4.78 (m, 1H), 4.21-4.19 (m, 2H), 3.99 (s, 3H), 2.26 (s, 3H), 1.96-1.70 (m, 2H), 0.89-0.85 (m, 3H), 0.64-0.61 (m, 3H). MS (ES) m/z 489 (M+l)+.
Example-XII: Synthesis of (Z)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3, 4-dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylate (Compound-32) and (E)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin- 2-yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylate (Compound-33)
Figure imgf000081_0001
The process of this step was adopted from step-(i) of compound- 1 from method-2 by using intermediate-4 as starting compound and separated by coloumn chromatography.
'H-NMR (400 MHz, DMSO-Je) δ 7.68-7.47 (m, 6H), 7.36 (d, 2H, J=7.8 Hz), 7.28 (d, 1H, J=7.6 Hz), 6.11 (d, 1H, J=7.6 Hz), 5.92 (bs, 2H), 4.59-4.58 (m, 1H), 4.26-4.20 (m, 2H), 2.71 (s, 3H), 2.01 (s, 3H), 1.76 (s, 3H), 1.65-1.62 (m, 2H), 0.90-0.83 (m, 3H), 0.62-0.58 (m, 3H). MS (ES) m/z 513 (M+l)+; and
'H-NMR (400 MHz, DMSO-Je) δ 7.67-7.46 (m, 6H), 7.37-7.35 (m, 2H), 7.26 (d, 1H, J=7.3 Hz), 6.22 (d, 1H, J=12.3 Hz), 5.60 (brs, 2H), 5.21 (brs, 1H), 4.48 (s, 1H), 4.23-4.18 (m, 2H), 2.70 (s, 3H), 2.00 (s, 3H), 1.76-1.62 (m, 2H), 1.30 (s, 3H), 0.59-0.55 (m, 3H). MS (ES) m/z 513 (M+l)+ respectively.
Example-XIII: Synthesis of (Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylic acid (Compound-34) and (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylicacid (Compound-35)
Figure imgf000082_0001
(Compound-32) (Compound-33) (Compound-34) (Compound-35)
(i) LiOH, THF, Ethanol, H20, Overnight, R.T;
The process of this step was adopted from step-(ii) of compound- 1 in method- 1 by using ompound-32 and compound-33 as starting compounds.'H-NMR (400 MHz, DMSO-Je) δ 7.67- 7.42 (m, 7H), 7.27 (d, IH, J=7 Hz), 7.02 (s, IH), 5.74 (bs, 2H), 4.64-4.62 (m, IH), 2.70 (s, 3H), 1.94 (s, 3H), 1.67 (m, 3H), 1.49-1.45 (m, 2H), 0.63-0.61 (m, 3H). MS (ES) m/z 485 (M+l)+; and 'H-NMR (400 MHz, DMSO-Je) δ 7.65-7.61 (m, 2H), 7.59-7.52 (m, 2H), 7.49-7.42 (m, 3H), 7.23 (d, IH, J=7.4 Hz), 5.67 (s, IH), 5.41 (bs, 2H), 4.93 (bs, IH), 4.36 (s, IH), 2.70 (s, 3H), 2.09 (s, 3H), 1.84 (s, 3H), 1.72-1.68 (m, 2H), 0.63-0.60 (m, 3H). MS (ES) m/z 485 (M+l)+.
Example-XIV:
Synthesis of (E)-2-(l-((2-amino-6-methyl-5-(3-oxo-3-(pyrrolidin-l-yl)prop-l-en-l- yl)pyrimidin-4-yl)amino ropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (Compound-36)
Figure imgf000082_0002
(Intermediate-7) (Compound-36)
(i) l-(pyrrolidin-l-yl)prop-2-en-l-one, Pd(OAC)2 ΒΓΝΑΡ, 2C03, Toluene,
H2Q, Sealed tube, 110°C,16 h;
The process of this step was adopted from step-(i) of compound- 1 in method-2 by using intermediate-7 as starting compound *H-NMR (400 MHz, DMSO-J6) δ 7.75-7.70 (m, 2H), 7.68- 7.58 (m, 3H), 7.48-7.41 (m,3H), 7.13-7.11 (m, IH), 6.57 (d, IH, J=15.6 Hz), 6.10 (d, IH, J=8.8 Hz), 5.05-5.02 (m, IH), 4.62 (brs, 2H), 3.5-3.6 (m, 4H), 2.30 (s, 3H), 2.0-1.8 (m, 6H), 0.78 (t, 3H, J=7.8 Hz). MS (ES) m/z 528 (M+l)+.
Synthesis of (E)-2-(l-((2-amino-6-methyl-5-(2-(pyridin-2-yl)vinyl)pyrimidin-4-yl)amino) propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (Compoudn-37)
(Intermediate-7) (Compound-37)
(i) 2-vinylpyridine, Pd(OAC)2 , BDSfAP, K2C03, Toluene, H20, Sealed tube, 100°C,4 h;
The process of this step was adopted from compound-36 by using intermediate-7 as starting compound !H-NMR (400 MHz, DMSO-J6) δ 8.60 (d, 1H, J=4 Hz), 7.81-7.78 (m, 2H), 7.62-7.41 (m, 8H), 7.32-7.24 (m, 2H), 6.97 (d, 2H, J=15 Hz), 6.20 (s, 2H), 4.72-4.61 (m, 1H), 2.28 (s, 3H), 1.87-1.80 (m, 1H), 1.70-1.65 (m, 1H), 0.69 (t, 3H, J=7.3 Hz). MS (ES) m/z 508(M+1)+.
Example-XV: Synthesis of (E)-2-(l-((2-amino-6-methyl-5-(2-(4-methylthiazol-2-yl)vinyl) pyrimidin-4-yl)amino ropyl)-5-fluoro-3-phenylquinazolin-4(3H)-one (Compound- 38)
Figure imgf000083_0001
(Intermediate-7) (Compound-38)
(i) 4-methyl-2-vinylthiazole, Pd(dppf )C12 Et3N, DMF, H20, Sealed tube, 100°C,16 h;
The process of this step was adopted from compound-36 by using intermediate-7 as starting compound. 1H-NMR (400 MHz, DMSO-J6) δ 7.81-7.80 (m, 1H), 7.63-7.51 (m, 8H), 7.19 (s, 1H), 6.86-6.85 (m, 1H), 6.07 (brs, 2H), 5.933 (s, 1H), 4.67 (s, 1H), 2.40 (s, 3H), 2.20 (s, 3H), 1.93-1.53 (m, 2H), 0.87-0.66 (m, 3H). MS (ES) m/z 528 (M+l)+.
The below compounds were prepared by procedure similar to the one described in Example-XV using suitable starting material with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.
Figure imgf000083_0002
1.23
m/z (s,
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Example-XVI: Synthesis of 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phi hydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)cyclopropanecarboxamide
(Compound-56)
Figure imgf000087_0002
The process of this step was adopted from step-(i) of compound-2 by using compound-8 as starting compound. !H-NMR (400 MHz, DMSO-J6) δ 7.69-7.49 (m, 9H), 6.25 (brs, 2H), 4.8- 4.75 (m, 1H), 3.64-3.45 (m, 2H), 3.5 (brs, 2H), 2.72 (s, 3H), 2.08 (s, 3H), 1.8-1.7 (m, 2H), 0.73- 0.83 (m, 2H), 0.64 (t, 3H, J=7.7 Hz). MS (ES) m/z 484 (M+l)+.
Example-XVII:
Synthesis of (E)-6-methyl-N4-(l-(2-(4-methylpiperazin-l-yl)quinolin-3-yl) propyl)-5-(2- (pyridin-2-yl)vinyl)pyrimidine-2,4-diamine (Compound-57)
Figure imgf000087_0003
,
Step-(i): (E)-2-(2.5-dimethyl-lH-pyrrol-l-yl)-6-methyl-N-(l-(2-(4-methylpiperazin-l-yl) quinolin-3-yl)propyl)-5-(2-(pyridin-2-yl)vinyl)pyrimidin-4-amine (57.1) The process of this step was adopted from compound-36 by using intermediate-2 as starting compound. MS (ES) m/z 573 (M+l)+.
Step-(ii): (E)-6-methyl-N4-(l-(2-(4-methylpiperazin-l-yl)quinolin-3-yl)propyl)-5-(2-(pyridin-2- yl)vinyl)pyrimidine-2,4-diamine (Compound-57)
The process of this step was adopted from step-(iii) of compound- l.'H-NMR (400 MHz, DMSO-Je) δ 8.56 (d, IH, J=3.9Hz), 8.13 (s,lH), 7.88-7.72 (m, 3H), 7.64-7.55 (m, 3H), 7.39-7.35 (m, IH), 7.24-7.21 (m, IH), 6.82 (d, IH, J=16.1 Hz), 6.70 (d, IH, J=7.3 Hz), 5.81 (brs, 2H), 5.32-5.27 (m, IH), 3.70 (m, 2H), 3.3-3.0 (m, 2H), 2.66-2.57 (m, 4H), 2.26 (s, 6H), 1.88-1.81 (m, 2H), 0.94 (t, 3H, J=7.3 Hz). MS (ES) m/z 495 (M+l)+.
Synthesis of (E)-5-(2-(6-methoxypyridin-3-yl)vinyl)-6-methyl-N4-(l-(2-(4-methylpiperazin- l-yl)quinolin-3-yl)propyl)pyrimidine-2,4-diamine (Compound-58)
Figure imgf000088_0001
The process for preparation of compound-58 was adopted from compound-57 by using intermediate-2 as starting compound. !H-NMR (400 MHz, DMSO-J6) δ 8.3 (d, IH, J=1.9 Hz), 8.16 (s, IH), 8.13 (d, IH, J=2.4 Hz), 8.10-8.08 (m, IH), 7.77 (d, 2H, J=8.3 Hz), 7.60 (t, IH, J=7.3 Hz), 7.40 (t, IH, J=7.3 Hz), 7.10 (d, IH, J=16.1 Hz), 6.88 (d, IH, J=8.8 Hz), 6.68 (d, IH, J=16.1 Hz), 5.9-5.75 (m, 2H), 5.35-5.29 (m, IH), 3.87 (s, 3H), 3.85-3.84 (m, 2H), 3.32-3.06 (m, 2H), 2.78-2.67 (m, 4H), 2.50 (s, 3H), 2.26 (s, 3H), 1.84-1.80 (m, IH), 1.77-1.71 (m, IH), 0.85 (t, 3H, J=7.3 Hz). MS (ES) m/z 525 (M+l)+.
Example-XVIII: Synthesis of (E)-ethyl 3-(2-amino-4-((l-(l,3-dimethyl-4-oxo-5-phenyl-4,5- dihydro-lH-pyrazolo[3,4-d]pyrimidin-6-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylate (Compound-59) and (E)-3-(2-amino-4-((l-(l,3-dimethyl-4-oxo-5-phenyl-4,5-dihydro-lH- pyrazolo[3,4-d]pyrimidin-6-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylic acid (Compound-60) (Interne diate-9) (Compound-59) (Compound-60)
(i) Ethyl acrylate, Pd(OAc)2 , BINAP, K2C03, Toluene, H20, Sealed tube, 120°C, Overnight:
(i) LiOH, THF, Ethanol, H20, Overnight, R.T;
Step-(i): (E)-ethyl 3-(2-amino-4-((l-(1 -dimethyl-4-oxo-5-phenyl-4,5-dihydro-lH-pyrazolo[3,4- dlpyrimidin-6-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylate (Compound-59)
The process of this step was adopted from step-(i) of compound- 1 in method-2 by using intermediate-9 as starting compound. !H-NMR (400 MHz, DMSO-J6) δ 7.73-7.72 (m, IH), 7.59- 7.44 (m, 5H), 6.8 (brs, IH), 6.27 (s, 2H), 6.23-6.21 (m, IH), 4.78 (m, IH), 4.15-4.12 (m, 2H), 3.84 (s, 3H), 2.47 (s, 3H), 2.39 (s, 3H), 1.81-1.62 (m, 2H), 1.27-1.23 (m, 3H), 0.64-0.60 (m, 3H). MS (ES) m/z 503 (M+l)+.
Step-(ii): (E)-3-(2-amino-4-((l-(l,3-dimethyl-4-oxo-5-phenyl-4,5-dihydro-lH-pyrazolo[3,4- dlpyrimidin-6-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylic acid (Compound-60)
The process of this step was adopted from step-(ii) of compound- 1 in method-2. 'H-NMR (400 MHz, DMSO-Je) δ 7.61-7.44 (m, 5H), 6.55 (brs, IH), 6.16 (s, 2H), 4.74 (s, IH), 3.9-3.8 (m, 2H), 2.38 (s, 3H), 2.18 (s, 3H), 1.76-1.59 (m, 2H), 1.23 (s, 3H), 0.64-0.61 (m, 3H). MS (ES) m/z 475 (M+l)+.
Compound-61 and Compound-62: Synthesis of (E)-ethyl 3-(2-amino-4-((l-(3-(4- fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)-6-methyl pyrimidin-5-yl)acrylate (Compound-61) and (E)-3-(2-amino-4-((l-(3-(4-fluorophenyl)-5- methyl-4-oxo-3,4-dihydroquinazolin-2-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylic acid (Compound-62)
(Intermediate-10) (Compound-61) (Compound-62)
(i) Ethyl acrylate, Pd(OAc)2, BINAP, K2C03, Toluene, H20, Sealed tube, 120°C, Overnight
(ii) LiOH, THF, Ethanol, H20, Overnight, R.T;
The process for preparation of compound-61 and compound-62 were adopted from compound-59 and compound-60 by using intermediate-10 as starting compound. 'H-NMR (400 MHz, DMSO-Je) δ 7.74 (d, IH, J=16.1 Hz), 7.70-7.62 (m, IH), 7.60- 7.54 (m, 3H), 7.40 (d, IH, J=1.5 Hz), 7.39-7.38 (m, IH), 7.31 (d, IH, J=7.4 Hz), 7.03 (d, IH, J=6.9 Hz), 6.38 (brs, 2H), 6.33 (d, IH, J=16.1 Hz), 4.80-4.78 (m, IH), 4.24-4.19 (m, 2H), 2.72 (s, 3H), 2.23 (s, 3H), 1.85- 1.82 (m, IH), 1.65-1.61 (m, IH), 1.33-1.28 (m, 2H), 0.66 (t, 3H, J=7.4 Hz). MS (ES) m/z 517 (M+l)+. and
'H-NMR (400 MHz, DMSO-Je) δ 12.8-11.2 (brs, IH), 7.68-7.55 (m, 5H), 7.43-7.39 (m, 2H), 7.29 (d, IH, J=7.4 Hz), 6.79 (d, IH, J=5.9 Hz), 6.26 (d, IH, J=16.7 Hz), 6.22-6.20 (brs, 2H), 4.79-4.74 (m, IH), 2.71 (s, 3H), 2.2 (s, 3H), 1.88-1.80 (m, IH), 1.75-1.58 (m, IH), 0.67 (t, 3H, J=7.3 Hz). MS (ES) m/z 489 (M+l)+.
Example-XIX: Synthesis of (E)-ethyl 3-(2-amino-4-methyl-6-((l-(8-methyl-2-(4- methylpiperazin-l-yl)quinolin-3-yl)propyl)amino)pyrimidin-5-yl)acrylate (Compound-66)
Figure imgf000090_0001
(i) Ethyl acrylate, Pd(dppf )C12, Et3N, DMP, H20, sealed tube, 100"C, Overnight; (ii) Hydroxylamine hydrochloride,
Ethanol, H20, Reflux, Overnight.
The process for preparation of compound-66 was adopted from compound-9 by using intermediate- 11 as starting compound. !H-NMR (400 MHz, DMSO-J6) δ 8.104 (s, IH), 7.77 (d, IH, J=15.7 Hz), 7.575 (d, IH, J=7.8 Hz), 7.449 (d, IH, J=6.9 Hz), 7.28-7.25 (m, IH), 6.99 (d, IH, J=7.8 Hz), 6.15 (s, 2H), 6.091 (d, IH, J=16.1 Hz), 5.33-5.28 (m, IH), 4.20-4.15 (m, 2H), 3.67 (m, 2H), 3.03 (m, 2H), 2.67 (m, 2H), 2.625 (s, 3H), 2.273 (s, 3H), 2.255 (s, 3H), 1.85-1.75 (m, 2H), 1.26 (t, 3H, J=7.4 Hz), 0.92 (t, 3H, J=7.3 Hz). MS (ES) m/z 504 (M+l)+.
Compound-67 and Compound-68: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2- (4-methylpiperazin-l-yl)quinolin-3-yl)propyl)amino)pyrimidin-5-yl)acrylic acid (Compound-67) and (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-(4-methylpiperazin-l- yl)quinolin-3-yl)propyl)amino)pyrimidin-5-yl)acrylamide (Compound-68)
Figure imgf000091_0001
The process for preparation of compound-67 and compound-68 were adopted from compound-59 and compound-60 by using compound-66 as starting compound.
Compound-67: !H-NMR (400 MHz, DMSO-J6) δ 12.19 (s, IH), 8.27 (s, IH), 7.684 (d, IH, J= 6.1 Hz), 7.647 (d, IH, J=7.3 Hz), 7.51 (d, IH, J=7.3 Hz), 7.343 (t, IH, J=7.8 Hz), 6.4 (m, 2H), 6.046 (d, IH, J=16.1 Hz), 5.37-5.36 (m, IH), 3.5-3.4 (m, 6H), 3.0-3.2 (m, 2H), 2.839 (brs, 3H), 2.650 (s, 3H), 2.261 (s, 3H), 1.824 (m, 2H), 0.897 (t, 3H, J=7.4 Hz). MS (ES) m/z 476 (M+l)+; and
Compound-68: !H-NMR (400 MHz, DMSO-J6) δ 8.12 (s, IH), 7.602 (d, IH, J=7.8 Hz), 7.467 (t, IH, J=6.9 Hz), 7.30-7.26 (m, IH), 6.9 (s, IH), 6.69-6.67 (m, IH), 6.21-6.17 (d, IH, J=15.7 Hz), 5.98 (s, 2H), 5.31-5.30 (m, IH), 3.74-3.69 (m, 4H), 3.26-3.07 (m, 4H), 2.67 (s, 3H), 2.63 (s, 3H), 2.213 (s, 3H), 1.76-1.82 (m, 2H), 0.88 (t, 3H, J=7.4 Hz). MS (ES) m/z 475 (M+l)+.
Compound-69: Synthesis of (E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2- (4-methylpiperazin-l-yl)quinolin-3-yl)propyl)pyrimidine-2,4-diamine (Compound-69) (lntermediate-11) (69.1) (Compouns-69)
(i) 5-vmyl-L -tetrazole, Pd(dppf)Cl2, Et3N, DMF, H20, Sealed tube, 100°C, 16 h; (ii) Hydroxylamine hydrochloride, Ethanol, H20, Reflux, Overnight
The process for preparation of compound-69 was adopted from compound-57 by using intermediate- 11 as starting compound. !H-NMR (400 MHz, DMSO-J6) δ 8.142 (s, IH), 7.60 (d, IH, J=7.8 Hz), 7.460 (d, IH, J=6.9 Hz), 7.40 (d, IH, J=16.7 Hz), 7.282 (t, IH, J=7.3 Hz), 6.79 (m, IH), 6.771 (d, IH, J=16.1 Hz), 5.964 (s, 2H), 5.35-5.33 (m, IH), 3.72 (brs, 2H), 3.12 (brs, 2H), 2.81-2.73 (m, 4H), 2.63 (s, 3H), 2.40 (s, 3H), 2.26 (s, 3H), 1.829-1.739 (m, 2H), 0.916 (t, IH, J=6.8 Hz). MS (ES) m/z 500 (M+l)+.
Compound-70: Synthesis of (E)-ethyl 3-(2-amino-4-methyl-6-((l-(2-thiomorpholino quinolin-3-yl)propyl)amino)pyrimidin-5-yl)acrylate (70)
Figure imgf000092_0001
The process for preparation of compound-70 was adopted from compound-9 by using intermediate-12 as starting compound. !H-NMR (400 MHz, DMSO-J6) δ 8.17 (s, IH), 7.75-7.8 (m, 3H), 7.59 (t, IH, J=6.9 Hz), 7.1 (t, IH, J=7.4 Hz), 7.04 (d, IH, J=7.8 Hz), 6.17 (brs, 2H), 6.10 (d, IH, J=16.2 Hz), 5.21-5.20 (m, IH), 4.21-4.16 (m, 2H), 3.86-3.82 (m, 2H), 2.87-2.80 (m, 4H), 2.32-2.29 (m, 2H), 2.25 (s, 3H), 1.98-1.91 (m, 2H), 1.25 (t, 3H, J=7.3 Hz), 0.95 (t, 3H, J=7.4 Hz). MS (ES) m/z 493 (M+l)+.
Compound-71 and Compound-72: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(2- thiomorpholinoquinolin-3-yl)propyl)amino)pyrimidin-5-yl)acrylic acid (Compound-71) and (E)-3-(2-amino-4-methyl-6-((l-(2-thiomorpholinoquinolin-3-yl)propyl)amino) pyrimidin-5-yl)acrylamide (Compound-72)
Figure imgf000093_0001
The process for preparation of compound-71 and compound-72 were adopted from compound-59 and compound-60 by using compound-70 as starting compound.
Compound-71 : *H-NMR (400 MHz, DMSO-J6) δ 12.02 (brs, IH), 8.19 (s, IH), 7.7-7.4 (m, 2H), 7.71 (d, IH, J=16.1 Hz), 7.59 (t, IH, J=7.4 Hz), 7.41 (t, IH, J=6.8 Hz), 6.94 (d, IH, J=7.3 Hz), 6.11 (brs, 2H), 6.05 (d, IH, J=16.2 Hz), 5.22-5.19 (m, IH), 3.87-3.82 (m, 2H), 2.90-2.81 (m, 4H), 2.24 (s, 3H), 1.90-1.71 (m, 2H), 0.95 (t, 3H, J=6.9 Hz). MS (ES) m/z 465 (M+l)+.
Compound-72: *H-NMR (400 MHz, DMSO-J6) δ 8.14 (s, IH), 7.78-7.76 (m, 2H), 7.61-7.59 (m, IH), 7.57-7.48 (m, 2H), 7.42-7.38 (m, 2H), 6.99 (brs, IH), 6.68 (d, IH, J=1.9 Hz), 6.21 (d, IH, J=15.6 Hz), 5.97 (brs, 2H), 5.20-5.19 (m, IH), 3.85-3.83 (m, 2H), 3.31 (brs, 2H), 2.9-2.79 (m, 3H), 2.21 (s, 3H), 1.82-1.74 (m, 2H), 0.94 (t, 3H, J=7.3 Hz). MS (ES) m/z 464 (M+l)+.
Compound-73: Synthesis of (E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(2-thio morpholinoquinolin-3-yl)propyl)pyrimidine-2,4-diamine (Compound-73)
Figure imgf000093_0002
(Intermediate-12) (73.1) (Compound-73)
(i) 5-vinyl-lfl-tetrazole, Pd(dppf)Cl2 Et3N, DMF, H20, Sealed tube. 100°C, 16h; (ii) Hydroxylamine hydrochloride, Ethanol, H20, Reflux, Overnight.
The process for preparation of compound-73 was adopted from compound-57 by using intermediate- 12 as starting compound. *H-NMR (400 MHz, DMSO-J6) δ 8.28 (d, IH, J=7.3 Hz), 8.19 (s, IH), 7.82-7.79 (m, 2H), 7.65-7.62 (m, IH), 7.52 (brs, 2H), 7.47-7.39 (m, 2H), 6.98 (d, IH, J=16.6 Hz), 5.375-5.363 (m, 2H), 3.66-3.62 (m, 4H), 2.89-2.78 (m, 4H), 2.396 (s, 3H), 1.98 -1.93 (m, IH), 1.86-1.80 (m, IH), 0.95 (t, 3H, J=6.4 Hz). MS (ES) m/z 489 (M+l)+. Compound-74: Synthesis of (E)-ethyl 3-(2-amino-4-methyl-6-((l-(8-methyl-2- thiomorpholinoquinolin-3-yl)propyl)amino)pyrimidin-5-yl)acrylate (Compound-74)
Figure imgf000094_0001
(Intermediate- 13 ) (74.1) (Compound-74)
(i) Ethyl aerylate, Pd(dppf )C12, Et3N, DMF, H20, sealed tube, 100°C, Overnight; (ii) Hydroxylamine hydrochloride, Ethanol, H20, Reflux, Overnight.
The process for preparation of compound-74 was adopted from compound-57 by using intermediate- 13 as starting compound. !H-NMR (400 MHz, DMSO-J6) δ 7.82 (s, IH), 7.79 (d, IH, J=7.8 Hz), 7.52 (d, IH, J=7.8 Hz), 7.44 (d, IH, J=6.9 Hz), 7.29 (d, IH, J=6.4 Hz), 6.17 (d, IH, J=16.1 Hz), 5.52 (d, IH J=6.9 Hz), 5.34-5.32 (m, IH), 4.67 (brs, 2H), 4.31-4.26 (m, 2H), 3.92-3.86 (m, 2H), 3.48-3.43 (m, 2H), 2.95-2.92 (m, 4H), 2.71 (s, 3H), 2.33 (s, 3H), 1.89-1.78 (m, 2H), 1.35 (t, 3H, J=6.8 Hz), 0.95 (t, 3H, J=7.3 Hz).MS (ES) m/z 507 (M+l)+.
Compound-75 and Compound-76: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2- thiomorpholino quinolin-3-yl)propyl)amino)pyrimidin-5-yl)acrylic acid (Compound-75) and (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-thiomorpholinoquinolin-3-yl)propyl) amino)pyrimidin-5-yl)acrylamide (Compound-76)
Figure imgf000094_0002
R.T, Overnight
The process for preparation of compound-75 and compound-76 were adopted from compound-59 and compound-60 by using compound-74 as starting compound.
Compound-75: *H-NMR (400 MHz, DMSO-J6) δ 12.6-11.6 (m, IH), 8.11 (s, IH), 7.71 (d, IH, J=16.2 Hz), 7.58 (d, IH, J=7.8 Hz), 7.45 (d, IH, J=6.9 Hz), 7.28 (t, IH, J=7.4 Hz), 6.96 (d, IH, J=7.4 Hz), 6.14 (brs, 2H), 6.04 (d, IH, J=15.6 Hz), 5.23-5.22 (m, IH), 3.88-3.34 (m, 2H), 2.92- 2.79 (m, 6H), 2.63 (s, 3H), 2.24 (s, 3H), 1.82-1.75 (m, 2H), 0.94 (t, 3H, J=7.3 Hz). MS (ES) m/z 479 (M+l)+.
Compound-76: !H-NMR (400 MHz, DMSO-J6) δ 8.10 (s, IH), 7.59 (d, IH, J=7.8 Hz), 7.52-7.45 (m, 3H), 7.28 (t, IH, J=7.8 Hz), 6.99 (brs, 2H), 6.68 (d, IH, J=7.3 Hz), 6.20 (d, IH, J=7.3 Hz), 5.99 (brs, 2H), 5.22-5.21 (m, IH), 3.90-3.85 (m, 2H), 3.35-3.32 (m, 2H), 2.93-2.97 (m, 4H), 2.63 (s, 3H), 1.82-1.75 (m, 2H), 0.93 (t, 3H, J=7.3 Hz). MS (ES) m/z 478 (M+l)+.
Compound-77: Synthesis of (E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2- thiomor holinoquinolin-3-yl)propyl)pyrimidine-2,4-diamine (Compound-77)
Figure imgf000095_0001
(i) 5-vinyl-Lf/-tetrazole, Pd(dppf)Cl2 Et3N, DMF, H20, Sealed tube, 100°C,16 h; (ii) Hydroxylamine hydrochloride, Ethanol, H20, Reflux, Overnight.
The process for preparation of compound-77 was adopted from compound-57 by using intermediate- 13 as starting compound. !H-NMR (400 MHz, DMSO-J6) δ 8.12 (s, IH), 7.59 (d, IH, J=7.9 Hz), 7.54 (d, IH, J=16.7 Hz), 7.46 (d, IH, J=6.8 Hz), 7.28 (t, IH, J=7.8 Hz), 7.04 (d, IH, J=6.8 Hz), 6.79 (d, IH, J=16.7 Hz), 6.16 (brs, 2H), 5.27-5.26 (m, IH), 3.39-3.35 (m, 2H), 3.35-3.34 (m, 2H), 2.93-2.82 (m, 4H), 2.63 (s, 3H), 2.29 (s, 3H), 1.83-1.72 (m, 2H), 0.96 (t, 3H, J=7.3 Hz). MS (ES) m/z 501 (M+l)+.
Compound-78: Synthesis of (E)-ethyl 3-(2-amino-4-methyl-6-((l-(8-methyl-2- morpholinoquinolin-3-yl)propyl)amino)pyrimidin-5-yl)acrylate (Compound-78)
Figure imgf000095_0002
(Intermediate- 14) (78.1) (Compound-78)
(i) Ethyl acrylate, Pd(dppf)Cl2, Et3N, DMF, Η,Ο, sealed tube, 100°C, Overnight; (ii) Hydroxylamine hydrochloride, Ethanol, H20, Reflux, Overnight. The process for preparation of compound-78 was adopted from compound-57 by using intermediate- 14 as starting compound. *H-NMR (400 MHz, DMSO-J6) δ 7.793 (s, IH), 7.538 (d, IH, J=16.2 Hz), 7.484 (d, IH, J=7.3 Hz), 7.417 (d, IH, J=6.9 Hz), 7.252 (t, IH, J=7.3 Hz), 6.114 (d, IH, J=16.1 Hz), 5.989 (s, IH), 5.401-5.347 (m, IH), 4.249-4.196 (m, 2H), 3.907 (m, IH), 3.886-3.806 (m, 4H), 3.542-3.501 (m, 2H), 3.412 (q, IH, J = 6.9 Hz), 3.05-3.01 (m, 2H), 2.655 (s, 3H), 2.341 (s, 3H), 1.96-1.81 (m, 2H), 1.281 (t, 3H, J=7.4 Hz), 0.881 (t, 3H, J=6.8 Hz). MS (ES) m/z 491 (M+l)+.
Compound-79: Synthesis of (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-morpholino quinolin-3-yl)propyl)amino)pyrimidin-5-yl)acrylic acid (Compound-79)
Figure imgf000096_0001
(Compound-78) (Compound-79)
(i) LiOH, THF, Ethanol, H20, Overnight, R.T
The process for preparation of compound-79 was adopted from compound-60 by using compound-78 as starting compound. *H-NMR (400 MHz, DMSO-J6) δ 12.15 (s, IH), 8.160 (s, IH), 7.694 (d, IH, J=16.2 Hz), 7.60 (d, IH, J=7.8 Hz), 7.465 (d, IH, J=6.9 Hz), 7.290 (t, IH, J=7.8 Hz), 6.15 (brs, 2H), 6.265 (d, IH, J=15.7 Hz), 5.389-5.356 (m, IH), 3.898-3.861 (m, 2H), 3.798-3.760 (m, 2H), 3.646-3.617 (m, 2H), 3.018-2.990 (m, 2H), 2.636 (s, 3H), 2.239 (s, 3H), 1.76 (m, 2H), 0.919 (t, 3H, J=6.8 Hz). MS (ES) m/z 463 (M+l)+.
Compound-80: Synthesis of (E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2- morpholinoquinolin-3-yl)propyl)pyrimidine-2,4-diamine (Com ound-80)
Figure imgf000096_0002
The process for preparation of compound-73 was adopted from compound-57 by using intermediate- 14 as starting compound1 H-NMR (400 MHz, DMSO-J6) δ 8.15 (s, 1H), 7.61-7.27 (m, 3H), 6.85-7.10 (m, 2H), 6.16 (brs, 2H), 5.52-5.02 (m, 1H), 3.88-3.67 (m, 6H), 3.02-2.98 (m, 2H), 2.63 (s, 3H), 2.28 (s, 3H), 1.86-1.75 (m, 2H), 0.93 (t, 3H, J=6.9 Hz). MS (ES) m/z 487 (M+l)+.
The below compounds were prepared by procedure similar to the one described in compound-80 by using intermediate- 14 as starting compound with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.
Figure imgf000097_0001
Compound-83: (E)-ethyl 3-(2-amino-4-((l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methyl quinolin-3-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylate (Compound-83) (i) Ethyl acrylate, Pd(dppf)Cl2, Et3N, DMF, H20, sealed tube, 100°C, Overnight; (ii) Hydroxylamine hydrochloride,
Ethanol, II2O, Reflux, Overnight.
The process for preparation of compound-83 was adopted from compound-57 by using intermediate- 15 as starting compound'H-NMR (400 MHz, DMSO-J6) δ 8.3 (s, IH), 7.64 (d, 3H, J=7.8 Hz), 7.50-7.48 (m, 3H), 6.066 (brs, 2H), 6.026 (d, IH, J=13.1 Hz), 5.6-5.5 (m, IH), 4.2- 4.19 (m, 4H), 3.39-3.37 (m, IH), 3.8-3.6 (m, IH), 2.67-2.63 (m, IH), 2.55 (s, 3H), 2.28 (s, 3H), 1.90-1.88 (m, 2H), 1.28 (t, 3H, J=7.4 Hz), 0.99-0.97 (m, 6H), 0.84-0.80 (m, 3H).MS (ES) m/z 519 (M+l)+.
Compound-84: Synthesis of (E)-3-(2-amino-4-((l-(2-((2S,6R)-2,6-dimethylmorpholino)-8- methylquinolin-3-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylic acid (Compound-84)
Figure imgf000098_0001
(i) LiOH, THF, Ethanol, H20, Overnight, R.T
The process for preparation of compound-84 was adopted from compound-60 by using compound-83 as starting compound. *H-NMR (400 MHz, DMSO-J6) δ 12.02 (brs, IH), 8.3 (s, IH), 7.64 (d, 3H, J=7.8 Hz), 7.50-7.48 (m, 3H), 6.066 (brs, 2H), 6.026 (d, IH, J=13.1 Hz), 5.6- 5.5 (m, IH), 4.2-4.19 (m, 4H), 3.39-3.37 (m, IH), 3.8-3.6 (m, IH), 2.67-2.63 (m, IH), 2.55 (s, 3H), 2.28 (s, 3H), 1.90-1.88 (m, 2H), 0.99-0.97 (m, 3H), 0.84-0.80 (m, 3H). MS (ES) m/z 491 (M+l)+.
Compound-85: Synthesis of N4-(l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methylquinolin-
3-yl)propyl)-6-methyl-5-((E)-2-(l-methyl-lH-tetrazol-5-yl)vinyl)pyrimidine-2,4-diamine
(Compound-85)
(i) l-methyl-5-vinyl-LfT-tetrazole, Pd(dppf)Cl2 Et3N, DMF, H20, Sealed tube, 100°C,16 h;
(ii) Hydroxylamine hydrochloride, Ethanol, H20, Reflux, Oveniiglit.
The process for preparation of compound-85 was adopted from compound-57 by using intermediate- 15 as starting compound. !H-NMR (400 MHz, DMSO-J6) δ 8.24 (s, IH), 7.61-7.59 (m, 2H), 7.46 (d, IH, J=6.9 Hz), 7.3 (t, IH, J=7.3 Hz), 6.84 (d, IH, J=7.8 Hz), 6.73 (d, IH, J=6.6 Hz), 5.97 (brs, 2H), 5.39-5.37 (m, IH), 4.35 (s, 3H), 3.93 (d, 2H, J=11.7 Hz), 3.89-3.78 (m, IH), 2.87-2.82 (m, IH), 2.66-2.64 (m, IH), 2.63 (s, 3H), 2.29-2.24 (m, IH), 2.27 (s, 3H), 1.85-1.81 (m, 2H), 1.18 (d, 3H, J=6.4 Hz), 1.0 (d, 3H, J=6.3 Hz), 0.84 (t, 3H, J=7.3 Hz). MS (ES) m/z 529 (M+l)+.
The below compounds were prepared by procedure similar to the one described in compound-85 by using intermediate- 15 as starting compound with appropriate variations in reactants, quantities of reagents and reaction conditions. The physiochemical characteristics of the compounds are summarized herein below table.
Figure imgf000099_0001
8.26 (s, IH), 7.62 (d, IH, J=8.3 Hz), 7.49-7.43 (m, 2H), 7.32-
87 7.28 (m, 2H), 7.05-7.03 (m, IH), 6.82-6.7 (m, 2H), 6.50 (brs,
2H), 5.50-5.45 (m, IH), 3.97-3.94 (m, IH), 3.8-3.6 (m, 5H),
2.63 (s, 3H), 2.318 (s, 3H), 1.99-1.84 (m, 2H), 1.3-1.2 (m, 5H),
Figure imgf000100_0001
0.86-0.82 (m, 3H); MS (ES) m/z 515 (M+l)+.
Compound-88: Synthesis of (E)-4-(3-(l-((2-amino-5-(2-(3-methoxypyridin-2-yl)vinyl)-6- methyl pyrimidin-4-yl)amino)propyl)-8-methylquinolin-2-yl)thiomorpholine 1,1-dioxide (Compound-88)
Figure imgf000100_0002
(i) 3-methoxy-2-vinylpyridine, Pd(dppf)Cl2 Et3N, DMF, H20, Sealed tube, 100°C,16 h; (ii) Hydroxyl
hydrochloride, Ethanol, H20, Reflux, Overnight.
The process for preparation of compound-88 was adopted from compound-57 by using intermediate- 16 as starting compound. !H-NMR (400 MHz, DMSO-J6) δ 8.236 (t, IH, J=2.9 Hz), 7.962 (s, IH), 7.628-7.491 (m, 4H), 7.474-7.274 (m, 2H), 7.208 (d, 2H, J=3Hz), 5.999 (s, IH), 5.360-5.342 (m, IH), 4.9 (m, IH), 4.160-4.112 (m, 2H), 3.968-3.855 (m, 2H), 3.827 (s, 3H), 3.49-3.47 (m, 2H), 3.260-3.206 (m, 2H), 2.698 (s, 3H), 2.382 (s, 3H), 1.896-1.798 (m, 2H), 0.880 (t, 3H, J=6.8 Hz). MS (ES) m/z 574 (M+l)+.
Example-XX: Synthesis of (E)-3-((2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)methylene)pyrrolidine-2,5-dione
(Compound-89)
Figure imgf000100_0003
(Intermediate-4) (89.1 ) (89.2) (Compound-89)
(i) CuCN, DMF, 150°C, 12 h; (ii) HCOOH, Re- i, 1 1C C, 4 h; (iii) 3-(triphenylphosphoranylidene) pyrrolidine-2, 5-dione, ethanol, 150°C, 30 min Step-(i): 2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3^-dihydroquinazolin-2-yl)propyl) amino)pyrimidine-5-carbonitrile (89.1)
To a stirred solution of intermediate-4 (8.0 g, 15.2 mmol) in DMF (100 ml) was added CuCN (5.45 g, 60.8 mmol).The reaction mixture was stirred for 12 h at 150°C. Then the obtained residue was diluted with water (15 ml) and extracted with ethyl acetate (2 x 15 ml). The combined organic phases were washed with brine, dried over sodium sulphate and concentrated. The residue was chromatographed on 100-200 mesh silica gel eluting with 2% methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (2.5 g, 38%). MS (ES) m/z 426 (M+l)+.
Step-(ii): 2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihvdroquinazolin-2-yl)propyl) amino)pyrimidine-5-carbaldehyde (89.2)
To a stirred solution of compound-89.1 (2.5 g, 5.8 mmol) in formic acid (25 ml) was added Re- Ni (1 g).The reaction mixture was stirred for 4 h at 110°C.Then reaction mixture was filtered through celite and concentrated the filterate.The residue was chromatographed on 100-200 mesh silica gel eluting with 2% methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (0.5 g, 20%). MS (ES) m/z 429 (M+l)+.
Step-(iii): (E)-3-((2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydro quinazolin-2- yl)propyl)amino)pyrimidin-5-yl)methylene)pyrrolidine-2,5-dione (89)
To a stirred solution of compound-89.2 (0.07 g,0.16 mmol) in ethanol (2 ml) was added 3- (triphenylphosphoranylidene)pyrrolidine-2,5-dione (0.11 g, 0.32 mmol). The reaction continued in microwave condition at 150°C for 30 min. After the elimination of the solvents in vacuo , the residue was chromatographed using 100-200 mesh silica gel , eluting with 4% methanol in dichloromethane to give the title compound as a yellow solid (0.03 g, 25%).1H-NMR (400 MHz, DMSO-Je) δ 12.2 (brs, 1H), 7.66-7.26 (m, 8H), 6.8 (brs, 1H), 6.52 (d, 1H, J=7.3 Hz), 6.18 (brs, 2H), 4.60-4.56 (m, 1H), 4.2-4.1 (m, 2H), 2.67 (s, 3H), 2.08 (s, 3H), 1.80-1.71 (m, 2H), 0.67 (t, 3H, J=7.3 Hz). MS (ES) m/z 510 (M+l)+.
Compound-90: Synthesis of (Z)-5-((2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrim^ (90) (89.2) (Compound-90)
(i) Thiazolidine-2,4-dione, Benzoic acid, Piperidine, Toluene, 140°C, 1 h
To a stirred solution of compound-89.2 (0.1 g, 0.23 mmol) in toluene (10 ml) was added thiazolidine-2,4-dione (0.032 g, 0.28 mmol), benzoic acid (0.0037 g, 0.03 mmol) and piperidine (0.00298 g, 0.035 mmol).The reaction was continued at 140°C for 1 h. After the elimination of the solvents in vacuo , the residue was chromatographed using 100-200 mesh silica gel , eluting with 4% methanol in dichloromethane to give the title compound as a yellow solid (0.01 g, 8%).1H-NMR (400 MHz, DMSO-J6) δ 12.2 (brs, 1H), 7.66-7.26 (m, 8H), 6.8 (brs, 1H), 6.52 (d, 1H, J=7.3 Hz), 6.18 (brs, 2H), 4.60-4.56 (m, 1H), 2.67 (s, 3H), 2.08 (s, 3H), 1.80-1.71 (m, 2H), 0.67 (t, 3H, J=7.3 Hz). MS (ES) m/z 528 (M+l)+.
Example-XXI: Synthesis of 5-(2-amino-4-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydro quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-N-(tert-butyl)pyridine-3-sulfonamide (Compound-91)
Figure imgf000102_0001
To a stirred solution of Intermediate-22 (0.2 g, 0.45 mmol) in 1,4-dioxane (6 ml) was added lntermediate-29 (0.12 g, 0.54 mmol), Pd(dppf)Cl2 (0.018 g, 0.022 mmol), K2C03 (0.18 g, 1.36 mmol) and 0.5 ml of H20. The reaction mixture was stirred for 12 h at 100°C. The progress of the reaction was monitored by TLC. After the reaction was completed, it was extracted with water (15 ml) and ethyl acetate (2x15 ml). The organic layer was collected, washed with brine, dried over sodium sulfate and concentrated under reduced pressure afforded the crude. Which was purified by column chromatography using 100-200 mesh silica gel and 3 % methanol in dichloromethane as eluent to achieve the pure product as a yellow solid (0.02 g, 10 %). IH NMR (400 MHz, DMSO-d6) δ 8.92-8.87 (m, 2H), 8.22-8.21 (m, IH), 7.83-7.81 (m, 2H), 7.79-7.46 (m, 7H), 7.29-7.27 (m, IH), 6.61-6.59 (m, IH), 6.17 (bs, 2H), 4.65-4.63 (m, IH), 2.7 (s, 3H), 1.76- 1.71 (m, IH), 1.59-1.57 (m, IH), 1.22 (s, 9H), 0.64-0.60 (m, 3H). MS (ES) m/z 599 (M+l)+.
Compounds listed in below table are prepared by following similar procedure as depicted for the preparation of Example -XXI, by using approprite intermediates in presence of suitable reagents, reactants and solvents at suitable conditions. Structure information and characterization I data for the compounds are given in below table.
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Biological Activity:
(i) PI3 Kinase TR-FRET Assay:
Compound inhibition for PI3K was determined in a homogenious TR-FRET assay using a PI3K assay kit obtained from Millipore, USA (cat # 33-016). The PI3 kinase catalyses the phosphorylation of phosphatidylinositol, 5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5- trisphosphate (PIP3) in the presence of ATP and Mg2+. The PIP3 product is detected by displacement of biotin-PIP3 from an energy transfer complex consisting of Europium labelled anti-GST monoclonal antibody, a GST-tagged pleckstrin homology (PH) domain, biotinylated PIP3 and Streptavidin-Allophycocyanin (APC). Excitation of Europium in the complex results in an energy transfer to the APC and a fluorescence emission at 665 nm.
Compounds to be tested were dissolved in DMSO and directly distributed in to 384- well plates at a volume of.0.5 ul. 14.5 ul of PI 10/P85a /PIP2 mixture was added to compound wells and incubated for 30 min at room temp for 60 min. P110/P85a was expressed in SF9 cells and purified in-house. 5 ng P110/P85a was used in the assay. The kinase reaction was started by the addition of ATP. The assay concentrations of both PIP2 and ATP were 10 μΜ. The reaction mixture was incubated for 30 minutes and was terminated by the addition of stop mix and detection mix. Fluorescence was measured at 615 and 665 nm upon excitation at 340 nm in a Victor V5 fluorimeter (Perkin Elmer, USA). The fluorescence emission ratio at 665 to 615 nm, proportional to the kinase activity, was plotted against the compound concentration to generate dose-response curves and IC50 values were determined.
(ii) mTOR kinase TR-FRET Assay:
Compound inhibition for mTOR kinase was determined in a homogenious TR-FRET assay using ULight-τρΊΟ S6K (Thr 389) peptide as substrate. mTOR enzyme was obtained from Millipore, USA. 5 μg mTOR was used in the assay. The reaction buffer was 50mM HEPES pH7.5, lmM EGTA, 3mM MnC12. Test compound was pre-incubated with mTOR for 30 min, and 50 nM Light-p70 S6K (Thr 389) Peptide was added along with 20 μΜ ATP. After incubating the reaction mixture for 30 min, 1 nM Eu- labeled anti-phospho-substrate antibody (obtained from Perkin Elmer, USA) was added. Fluorescence emission at 615 and 665 nM was measured upon excitation at 340 nM The compound dilution was carried out in 100% DMSO followed by a buffer dilution. The kinase reaction was incubated for lhr at room temperature followed by the addition of substrate- ATP mix and incubated for lhr at room temperature, the reaction was terminated by the addition of EDTA followed by the addition of detection mix. IC50 values were subsequently determined using a sigmoidal dose -response curve.
The compounds were screened at ΙμΜ concentration and the results are summarized in the table below along with the IC50 (μΜ) details for selected examples. The IC50 values of the compounds are set forth in below Table wherein "A" refers to an IC50 value of less than 0.01 μΜ, "B" refers to IC50 value in range of Ο.ΟΙμΜ to 0.1 μΜ and "C" refers to IC50 value of greater than 0.1 μΜ.
Figure imgf000111_0001
(iii) PI3 Kinase (gamma) TR-FRET Assay:
Compound inhibition for PI3K was determined in a homogenious TR-FRET assay using a PI3K assay kit obtained from Millipore, USA (cat # 33-016). The PI3 kinase catalyses the phosphorylation of phosphatidylinositol, 5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5- trisphosphate (PIP3) in the presence of ATP and Mg2+. The PIP3 product is detected by displacement of biotin-PIP3 from an energy transfer complex consisting of Europium labelled anti-GST monoclonal antibody, a GST-tagged pleckstrin homology (PH) domain, biotinylated PIP3 and Streptavidin-Allophycocyanin (APC). Excitation of Europium in the complex results in an energy transfer to the APC and a fluorescence emission at 665 nm.
Compounds to be tested were dissolved in DMSO and directly distributed into 384- well plates at a volume of 0.5 ul. 14.5 ul of PI3 kinase(pl20y) /PIP2 mixture was added to compound wells and incubated for 30 min at room temp for 60 min. PI3 kinase (ρ120γ) was procured from Millipore (cat No: 14-558). 150 ng of PI3 kinase (ρ120γ) was used in the assay. The kinase reaction was started by the addition of ATP. The assay concentrations of both PIP2 and ATP were 10 μΜ. The reaction mixture was incubated for 30 minutes and was terminated by the addition of stop mix and detection mix. Fluorescence was measured at 615 and 665 nm upon excitation at 340 nm in a Victor X5 fluorimeter (Perkin Elmer, USA). The fluorescence emission ratio at 665 to 615 nm, proportional to the kinase activity, was plotted against the compound concentration to generate dose -response curves and IC50 values were determined.
(iv) PI3 Kinase(delta) TR-FRET Assay:
Compound inhibition for PI3K was determined in a homogenious TR-FRET assay using a PI3K assay kit obtained from Millipore, USA (cat # 33-016). The PI3 kinase catalyses the phosphorylation of phosphatidylinositol, 5-bisphosphate (PIP2) to phosphatidylinositol 3,4,5- trisphosphate (PIP3) in the presence of ATP and Mg2+. The PIP3 product is detected by displacement of biotin-PIP3 from an energy transfer complex consisting of Europium labelled anti-GST monoclonal antibody, a GST-tagged pleckstrin homology (PH) domain, biotinylated PIP3 and Streptavidin-Allophycocyanin (APC). Excitation of Europium in the complex results in an energy transfer to the APC and a fluorescence emission at 665 nm.
Compounds to be tested were dissolved in DMSO and directly distributed into 384- well plates at a volume of 0.5 ul. 14.5 ul of PI3 kinase(pl l05/p85a) /PIP2 mixture was added to compound wells and incubated for 30 min at room temp for 60 min. PI3 kinase (ρ120γ) was procured from Millipore (cat No: 14-604). 5 ng of PI3 kinase (ρ110δ/ρ85α) was used in the assay. The kinase reaction was started by the addition of ATP. The assay concentrations of both PIP2 and ATP were 10 μΜ. The reaction mixture was incubated for 30 minutes and was terminated by the addition of stop mix and detection mix. Fluorescence was measured at 615 and 665 nm upon excitation at 340 nm in a Victor X5 fluorimeter (Perkin Elmer, USA). The fluorescence emission ratio at 665 to 615 nm, proportional to the kinase activity, was plotted against the compound concentration to generate dose -response curves and IC50 values were determined.
The compounds were screened for selective inhibition of ΡΒΚγ and PI3K5 at 1 nM concentration and the results are summarized in the table below along with the IC50 (nM) details for selected compounds. The IC50 values of the compounds are set forth in below Table, wherein "A" refers to an IC50 value in less than 20 nM, "B" refers to IC50 value in range of 20.01 to 100 nM and "C" refers to IC50 value in range of 100.1 nM to 1000 nM. % inhibition of ΡΙ3Κγ and PI3K5 at^M concentration of selected compounds are set forth in below table.
Figure imgf000113_0001

Claims

We claim:
1. A compound of formula
Figure imgf000114_0001
or a pharmaceutically acceptable salts or a pharmaceutically acceptable stereoisomers thereof; wherein,
Ring A is bicyclic heterocyclyl ring containing 1-5 heteroatoms/heterogroups independently selected from N and -C(O)-;
R1 is selected from hydrogen, halogen and alkyl;
R is selected from an optionally substituted heterocyclyl and optionally substituted aryl; wherein the optional substituents are selected from alkyl and halogen;
R3 is selected from hydrogen and alkyl;
R4 is selected from hydrogen, alkyl, alkoxyalkyl and heterocyclyl;
Figure imgf000114_0002
R5 is selected from -S(0)2R5a, -S(0)2NR5aR5b, -NHS(0)2R5a and -C(0)NHR5a;
R5a is selected from hydrogen and alkyl;
R5b is selected from hydrogen, alkyl, haloalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted aryl; wherein the optional substituents are independently selected from halogen and alkyl; alternatively, R a and R can be taken together with the nitrogen atom to which they are attached to form an optionally substituted 4-7 membered heterocyclyl ring; wherein the optional substituent is alkyl;
R6 is selected from hydrogen, alkyl, halo, haloalkyl, nitro and amino;
R 7' and R 8° are independently selected from hydrogen or alkyl;
se 1lec tte Hd fr from h hy Λdrogen,
Figure imgf000115_0001
, ,
Figure imgf000115_0002
optionally substituted heterocyclyl; wherein the optional substituent is selected from alkyl or alkoxy;
alternatively, R 8 and R 9 may be taken together with the carbon atom to which they are attached to form a 4-7 membered heterocyclyl ring having 1-4 heteroatoms/heterogroups independently selected from N, S and -C(O)-;
R10 is selected from
Figure imgf000115_0003
each Ra is independently selected from hydrogen and alkyl;
each Rb and Rc are independently selected from hydrogen, alkyl, cycloalkyl and optionally substituted heterocyclyl; wherein the optional substituent is alkyl;
alternatively, Rb and Rc can be taken together with the nitrogen atom to which they are attached to form a 4-7 membered heterocyclyl ring having 1-3 heteroatoms independently selected from N and O; and
'n' is an integer selected from 1 and 2.
2. The compound of claim 1, wherein the compound of formula (1) is a compound of formula (la):
Figure imgf000116_0001
wherein, Ring A is selected from
Figure imgf000116_0002
and R1, R2, R3, R4, R5, R6 and 'n' are same as defined in claim 1.
3. The compound of claim 1, wherein the compound of formula ( 1) is a compound of formula (lb)
wherein, Ring A is
Figure imgf000116_0003
; R3 is -S(0)2R3a; and R1, R2, R3, R4, R5a and 'n' are same as defined in claim 1.
4. The compound of claim 1, wherein the compound of formula ( 1) is a compound of formula (lc)
Figure imgf000117_0001
wherein, Ring A is selected from
Figure imgf000117_0002
and
R1, R2, R3, R4, R7, R8,R9 and 'n' are same as defined in claim 1.
5. The compound of claim 1, wherein the compound of formula (1) is a compound of formula (Id)
Figure imgf000117_0003
wherein, Ring A is
Figure imgf000117_0004
and R1, R2, R3, R4, R10 and "n" are same described in claim 1.
6. The compound of claim 1, wherein R is selected from
Figure imgf000118_0001
7. The co
Figure imgf000118_0002
Figure imgf000118_0003
8. The compound of claim 1, wherein R is hydrogen or amino.
9. The compound of claim 1 , wherein R 7 and R 8 are alkyl, in particular alkyl is methyl.
10. The compound of claim 1, wherein R is selected from
Figure imgf000118_0004
Figure imgf000118_0005
Figure imgf000119_0001
12. A compound selected from the group consisting of
Figure imgf000119_0002
7. tert-butyl 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydro quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)cyclopropanecarboxylate;
8. 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl)amino)pyrimidin-5-yl)cyclopropanecarboxylic acid;
9. (E)-tert-butyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydro quinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acrylate;
10. (E)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)acrylate;
11. 2-(l-((2-amino-5-((lE,3Z)-3-(hydroxyimino)but-l-en-l-yl)-6-methylpyrimidin-4-yl) amino )propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
12. (E)-ethyl 3-(2-amino-4-methyl-6-(( l-(2-(4-methylpiperazin- l-yl)quinolin-3-yl) propyl)amino)pyrimidin-5-yl)acrylate;
13. (E)-3-(2-amino-4-methyl-6-((l-(2-(4-methylpiperazin-l-yl)quinolin-3-yl)propyl) amino )pyrimidin-5-yl)acrylic acid;
14. (Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- y l)propyl) amino)pyr imidin- 5 - yl)but-2-eno ic acid;
15. (Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(tert-butyl)but-2-enamide;
16. (Z)-2-(l-((2-amino-6-methyl-5-(4-morpholino-4-oxobut-2-en-2-yl)pyrimidin-4-yl) amino )propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
17. (Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-cyclopropylbut-2-enamide;
18. (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(pyridin-2-yl)acrylamide;
19. (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(pyridin-3-yl)acrylamide;
20. (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(pyridin-4-yl)acrylamide;
21. (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(thiazol-2-yl)acrylamide;
22. (E)-2-( 1 -((2-amino-6-methyl-5-(3-oxo-3-( lH-pyrazol- 1 -yl)prop- 1 -en- 1 - yl)pyrimidin-4-yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
23. (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-methylacrylamide;
24. (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- y l)propyl) amino)pyr imidin- 5 - yl)-N-ethy lacr ylamide ;
25. 2-(l-((2-amino-6-methyl-5-vinylpyrimidin-4-yl)amino)propyl)-5-methyl-3-phenyl quinazolin-4(3H)-one;
26. (E)-ethyl 3-(2-amino-4-methyl-6-((l-(l-methyl-4-oxo-5-phenyl-4,5-dihydro-lH- pyrazolo [ 3 , 4-d] pyr imidin- 6- yl)propyl) amino)pyrimidin- 5 - yl) acr ylate ;
27. (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-(6-methylpyridin-2-yl)acrylamide;
28. (E)-2-(l-((2-amino-6-methyl-5-(3-oxo-3-(pyrrolidin-l-yl)prop-l-en-l-yl)pyrimidin- 4-yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
29. (E)-2-(l-((2-amino-6-methyl-5-(3-oxo-3-(piperidin-l-yl)prop-l-en-l-yl)pyrimidin- 4-yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
30. (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N,N-dimethylacrylamide;
31. (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)-N-ethyl-N-methylacrylamide;
32. (Z)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- di ydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylate;
33. (E)-ethyl 3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4- di ydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)-2-methylacrylate;
34. (Z)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- y l)propyl) amino)pyr imidin- 5 - yl)-2-methylacr ylic acid ;
35. (E)-3-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- y l)propyl) amino)pyr imidin- 5 - yl)-2-methylacr ylic acid ;
36. (E)-2-(l-((2-amino-6-methyl-5-(3-oxo-3-(pyrrolidin-l-yl)prop-l-en-l-yl) pyrimidin- 4-yl) amino )propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
37. (E)-2-(l-((2-amino-6-methyl-5-(2-(pyridin-2-yl)vinyl)pyrimidin-4-yl) amino )propyl) -5-fluoro-3-phenylquinazolin-4(3H)-one;
38. (E)-2-(l-((2-amino-6-methyl-5-(2-(4-methylthiazol-2-yl)vinyl)pyrimidin-4- yl)amino)
propyl) -5-fluoro-3-phenylquinazolin-4(3H)-one;
39. (E)-2-(l-((5-(2-(lH-imidazol-4-yl)vinyl)-2-amino-6-methylpyrimidin-4-yl)amino) propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
40. (E)-2-(l-((5-(2-(lH-tetrazol-5-yl)vinyl)-2-amino-6-methylpyrimidin-4-yl)amino) propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
41. (E)-2-(l-((5-(2-(lH-tetrazol-5-yl)vinyl)-2-amino-6-methylpyrimidin-4-yl) amino) propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
42. (E)-2-(l-((2-amino-6-methyl-5-(3-oxobut-l-en-l-yl)pyrimidin-4-yl) amino) propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;
43. (E)-2-(l-((5-(2-(lH-imidazol-4-yl)vinyl)-2-amino-6-methylpyrimidin-4-yl)amino) propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;
44. (E)-2-(l-((2-amino-6-methyl-5-(2-(6-methylpyridin-2-yl)vinyl)pyrimidin-4- yl)amino)
propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
45. (E)-2-(l-((2-amino-6-methyl-5-(2-(5-methylpyridin-2-yl)vinyl)pyrimidin-4-yl) amino )propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
46. (E)-2-(l-((2-amino-6-methyl-5-(2-(pyridin-2-yl)vinyl)pyrimidin-4-yl)amino)propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;
47. (E)-2-(l-((2-amino-6-methyl-5-(2-(pyridin-3-yl)vinyl)pyrimidin-4-yl) amino )propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;
48. (E)-2-(l-((2-amino-6-methyl-5-(2-(pyridin-4-yl)vinyl)pyrimidin-4-yl) amino )propyl) -5-methyl-3-phenylquinazolin-4(3H)-one;
49. (E)-2-(l-((2-amino-5-(2-(3-methoxy-6-methylpyridin-2-yl)vinyl)-6- methylpyrimidin-4-yl)amino)propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
50. (E)-2-(l-((2-amino-6-methyl-5-(2-(3-methylpyridin-2-yl)vinyl)pyrimidin-4- yl)amino)
propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
51. (E)-2-(l-((2-amino-6-methyl-5-(2-(4-methylpyridin-3-yl)vinyl)pyrimidin-4-yl) amino )propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
52. (E)-2-(l-((2-amino-5-(2-(6-methoxypyridin-3-yl)vinyl)-6-methylpyrimidin-4-yl) amino) propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
53. (E)-2-(l-((2-amino-6-methyl-5-(2-(l-methyl-lH-tetrazol-5-yl)vinyl)pyrimidin-4-yl) amino )propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
54. (E)-2-(l-((2-amino-6-methyl-5-(2-(thiazol-2-yl)vinyl)pyrimidin-4-yl) amino)
propyl)
-5-methyl-3-phenylquinazolin-4(3H)-one;
55. (E)-2-(l-((2-amino-6-methyl-5-(2-(l-methyl-lH-imidazol-2-yl)vinyl)pyrimidin-4- yi)
amino )propyl)-5-methyl-3-phenylquinazolin-4(3H)-one;
56. 2-(2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl) propyl)amino)pyrimidin-5-yl)cyclopropanecarboxamide;
57. (E)-6-methyl-N4-(l-(2-(4-methylpiperazin-l-yl)quinolin-3-yl)propyl)-5-(2-(pyridin- 2-yl)vinyl)pyrimidine-2,4-diamine;
58. (E)-5-(2-(6-methoxypyridin-3-yl)vinyl)-6-methyl-N4-(l-(2-(4-methylpiperazin-l-yl) quinolin-3-yl)propyl)pyrimidine-2,4-diamine;
59. (E)-ethyl 3-(2-amino-4-((l-(l,3-dimethyl-4-oxo-5-phenyl-4,5-dihydro-lH-pyrazolo
[3,4-d]pyrimidin-6-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylate;
60. (E)-3-(2-amino-4-((l-(l,3-dimethyl-4-oxo-5-phenyl-4,5-dihydro-lH-pyrazolo [3,4- d]
pyrimidin-6-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylic acid;
61. (E)-ethyl 3-(2-amino-4-((l-(3-(4-fluorophenyl)-5-methyl-4-oxo-3,4-dihydro
quinazolin2-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylate;
62. (E)-3-(2-amino-4-((l-(3-(4-fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylic acid;
63. (E)-3-(2-amino-4-((l-(3-(4-fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylamide;
64. (E)-3-(2-amino-4-((l-(3-(4-fluorophenyl)-5-methyl-4-oxo-3,4-dihydroquinazolin-2- yl)propyl)amino)-6-methylpyrimidin-5-yl)-N-(pyridin-3-yl)acrylamide;
65. (E)-2-(l-((5-(2-(lH-tetrazol-5-yl)vinyl)-2-amino-6-methylpyrimidin-4-yl)amino) propyl)-3-(4-fluorophenyl)-5-methylquinazolin-4(3H)-one;
66. (E)-ethyl 3-(2-amino-4-methyl-6-((l-(8-methyl-2-(4-methylpiperazin-l-yl)quinolin- 3 -yl) propyl)amino)pyrimidin-5 -yl) acrylate ;
67. (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-(4-methylpiperazin-l-yl)quinolin-3-yl) propyl)amino)pyrimidin-5-yl)acrylic acid;
68. (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-(4-methylpiperazin-l-yl)quinolin-3-yl) propyl)amino)pyrimidin-5-yl)acrylamide;
69. (E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2-(4-methylpiperazin- 1 -yl) quinolin-3-yl)propyl)pyrimidine-2,4-diamine;
70. (E)-ethyl 3-(2-amino-4-methyl-6-((l-(2-thiomorpholinoquinolin-3-yl)propyl)amino) pyrimidin-5-yl)acrylate;
71. (E)-3-(2-amino-4-methyl-6-((l-(2-thiomorpholinoquinolin-3-yl)propyl)amino) pyrimidin-5-yl)acrylic acid;
72. (E)-3-(2-amino-4-methyl-6-((l-(2-thiomorpholinoquinolin-3-yl)propyl)amino) pyrimidin-5 -yl)acrylamide ;
73. (E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(2-thiomorpholinoquinolin-3- yl)propyl)pyrimidine-2,4-diamine;
74. (E)-ethyl 3-(2-amino-4-methyl-6-((l-(8-methyl-2-thiomorpholinoquinolin-3-yl) propyl)amino)pyrimidin-5-yl)acrylate;
75. (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-thiomorpholinoquinolin-3-yl)propyl) amino )pyrimidin-5-yl)acrylic acid;
76. (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-thiomorpholinoquinolin-3-yl)propyl) amino )pyrimidin-5-yl)acrylamide;
77. (E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2-thiomorpholino quinolin-3-yl)propyl)pyrimidine-2,4-diamine;
78. (E)-ethyl 3-(2-amino-4-methyl-6-(( l-(8-methyl-2-morpholinoquinolin-3-yl) propyl) amino )pyrimidin-5-yl)acrylate;
79. (E)-3-(2-amino-4-methyl-6-((l-(8-methyl-2-morpholinoquinolin-3-yl) propyl) amino )pyrimidin-5-yl)acrylic acid;
80. (E)-5-(2-(lH-tetrazol-5-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2-morpholinoquinolin -3-yl)propyl)pyrimidine-2,4-diamine;
81. (E)-5-(2-(3-methoxypyridin-2-yl)vinyl)-6-methyl-N4-(l-(8-methyl-2-morpholino quinolin-3-yl)propyl)pyrimidine-2,4-diamine;
82. (E)-6-methyl-5-(2-(l-methyl-lH-tetrazol-5-yl)vinyl)-N4-(l-(8-methyl-2-morpholino quinolin-3-yl)propyl)pyrimidine-2,4-diamine;
83. (E)-ethyl 3-(2-amino-4-((l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methylquinolin -3-yl)propyl)amino)-6-methylpyrimidin-5-yl)acrylate;
84. (E)-3-(2-amino-4-((l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methylquinolin-3-yl) propyl)amino )- 6- methylpyr imidin- 5 - yl)acry lie acid ;
85. N4-(l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methylquinolin-3-yl)propyl)-6- methyl-5-((E)-2-(l-methyl-lH-tetrazol-5-yl)vinyl)pyrimidine-2,4-diamine;
86. N4-(l-(2-((2S,6R)-2,6-dimethylmorpholino)-8-methylquinolin-3-yl)propyl)-5-((E)- 2-(3-methoxypyridin-2-yl)vinyl)-6-methylpyrimidine-2,4-diamine;
87. 5-((E)-2-(lH-tetrazol-5-yl)vinyl)-N4-(l-(2-((2S,6R)-2,6-dimethylmorpholino)-8- methylquinolin-3-yl)propyl)-6-methylpyrimidine-2,4-diamine;
88. (E)-4-(3-(l-((2-amino-5-(2-(3-methoxypyridin-2-yl)vinyl)-6-methylpyrimidin-4-yl) amino )propyl)-8-methylquinolin-2-yl)thiomorpholine 1, 1-dioxide;
89. (E)-3-((2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin -2-yl) propyl)amino)pyrimidin-5-yl)methylene)pyrrolidine-2,5-dione; and
90. (Z)-5-((2-amino-4-methyl-6-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin -2-yl)propyl)amino)pyrimidin-5-yl)methylene)thiazolidine-2,4-dione,
or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.
13. A compound selected from the group consisting of
Compd Compound Name
No 5-(2-amino-4-((l-(5-methyl-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)
91.
amino)pyrimidin-5-yl)-N-(tert-butyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(8-methyl-2-morpholinoquinolin-3-yl)propyl)amino)pyrimidin-5-
92.
yl)-N-(tert-butyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)
93.
amino)-6-methylpyrimidin-5-yl)-N-(tert-butyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)
94.
amino)-6-methylpyrimidin-5-yl)-N-(4-fluorophenyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)
95.
amino)-6-methylpyrimidin-5-yl)pyridine-3-sulfonamide;
5-(2-amino-4-methyl-6-((l-(8-methyl-2-morpholinoquinolin-3-yl)propyl)amino)
96.
pyrimidin-5-yl)-N-(tert-butyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)
97.
amino)pyrimidin-5-yl)-N-(tert-butyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)
98.
amino)pyrimidin-5-yl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)
99.
amino)pyrimidin-5-yl)-N-(4-fluorophenyl)pyridine-3-sulfonamide;
2-amino-5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
100.
yl)propyl)amino)-6-methylpyrimidin-5-yl)-N-(tert-butyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)
101.
amino)pyrimidin-5-yl)-N-(3-chloro-4-fluorophenyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)
102.
amino)pyrimidin-5-yl)-N-(o-tolyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)
103.
amino)pyrimidin-5-yl)-N-(2,6-dimethylphenyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)
104.
propyl)amino)pyrimidin-5-yl)-N-(2-fluorophenyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)
105.
propyl)amino)pyrimidin-5-yl)-N,N-dimethylpyridine-3-sulfonamide; 2-(l-((2-amino-5-(5-(pyrrolidin-l-ylsulfonyl)pyridin-3-yl)pyrimidin-4-yl)
106.
amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
N-(tert-butyl)-5-(2-(ethylamino)-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-
107.
dihydroquinazolin-2-yl)propyl)amino)pyrimidin-5-yl)pyridine-3-sulfonamide;
5-(2-(ethylamino)-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
108.
yl)propyl)amino)pyrimidin-5-yl)pyridine-3-sulfonamide;
N-(tert-butyl)-5-(4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
109. yl)propyl)amino)-2-((2-methoxyethyl)amino)pyrimidin-5-yl)pyridine-3- sulfonamide;
2-(l-((2-amino-5-(5-((3,3-dimethylpyrrolidin-l-yl)sulfonyl)pyridin-3-yl)pyrimidin-
110.
4-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
111.
yl)propyl)amino)pyrimidin-5-yl)-N-(2-chlorophenyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
112.
yl)propyl)amino)pyrimidin-5-yl)-N-(2,2,2-trifluoroethyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
113.
yl)propyl)amino)pyrimidin-5-yl)-N-(2,3-difluorophenyl)pyridine-3-sulfonamide;
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
114.
yl)propyl)amino)pyrimidin-5-yl)-N-(2,3-dichlorophenyl)pyridine-3-sulfonamide;
5-(4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)propyl)amino)-2-
115.
(pyridin-2- ylamino)pyr imidin- 5 - yl)pyridine- 3 - sulfonamide ;
2-(l-((2-amino-5-(5-(methylsulfonyl)pyridin-3-yl)pyrimidin-4-yl)amino)propyl)-5-
116.
fluoro-3-phenylquinazolin-4(3H)-one;
2-(l-((2-amino-5-(5-(isopropylsulfonyl)pyridin-3-yl)pyrimidin-4-yl)amino)propyl)-
117.
5-fluoro-3-phenylquinazolin-4(3H)-one;
2-(l-((2-amino-5-(5-(propylsulfonyl)pyridin-3-yl)pyrimidin-4-yl)amino)propyl)-5-
118.
fluoro-3-phenylquinazolin-4(3H)-one;
N-(5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
119.
yl)propyl)amino)pyrimidin-5-yl)pyridin-3-yl)ethanesulfonamide;
120. N-(5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2- yl)propyl)amino)pyrimidin-5-yl)pyridin-3-yl)propane-2-sulfonamide;
N-(5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
121.
yl)propyl)amino)pyrimidin-5-yl)pyridin-3-yl)methanesulfonamide;
2-(l-((2-amino-5-(l-(isopropylsulfonyl)-2,3-dihydro-lH-pyrrolo[2,3-c]pyridin-4-
122.
yl)pyrimidin-4-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one;
2-(l-((2-amino-5-(l-(methylsulfonyl)-2,3-dihydro-lH-pyrrolo[2,3-c]pyridin-4-
123.
yl)pyrimidin-4-yl)amino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one; and
5-(2-amino-4-((l-(5-fluoro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-
124.
yl)propyl)amino)pyrimidin-5-yl)-N-(tert-butyl)nicotinamide,
or a pharmaceutically acceptable salts thereof or a pharmaceutically acceptable stereoisomers thereof.
14. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (1) according to any of claim 1 to 13, their pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers, in admixture with at least one pharmaceutically acceptable carrier or excipient including mixtures thereof in all ratios, for use as a medicament.
15. A method of treating cancer diseases which comprises administering to a subject in need thereof an effective amount of a compound according to any of claim 1 to 13.
16. A compound according to any of the claim 1 to 13, their pharmaceutically acceptable salts and stereoisomers, are used to inhibit one or more kinase including PI3K, AKT and m-TOR.
17. A method for inhibiting PI3K which comprises administering to a subject in need thereof an effective amount of a compound according to any of claim 1 to 13.
18. A compound according to any of the claim 1 to 13, their pharmaceutically acceptable salts and stereoisomers, are selective inhibitors of PI3K-5 isoform or selective dual inhibitors of
PI3K-5 and ΡΙ3Κ-γ isoforms.
19. A compound according to any of the claim 1 to 13, their pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers, are selective inhibitors of PI3K-5 isoform.
20. A compound of according to any of the claim 1 to 13, their pharmaceutically acceptable salts and pharmaceutically acceptable stereoisomers, are selective dual inhibitors of PI3K-5 and
ΡΙ3Κ-γ isoforms.
21. A compound according to any of claim 1 to 13, for use in the treatment of cancer and inflammatory diseases in humans.
22. Use of a compound according to any of claim 1 to 13, in the manufacture of a medicament for use in the treatment of cancer or inflammatory diseases associated with PI3 , AKT and m-TOR in humans.
PCT/IB2013/061358 2013-01-04 2013-12-27 Substituted 2-amino pyrimidine derivatives as kinase inhibitors WO2014106800A2 (en)

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