COMPOUND, PHARMACEUTICALLY ACCEPTABLE SALT AND PHARMACEUTICAL COMPOSITION

专利摘要:
compounds of formulas i, ia, ib and ic, tautomeric forms thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof, combinations thereof with suitable medicament and pharmaceutical compositions containing the same, pharmaceutical composition, and methods of inhibiting mek enzymes , for treating a mek-mediated disorder, for treating or prophylaxis of a proliferative disease, for treating or prophylaxis of an inflammatory disease, for degrading, inhibiting the growth of, or killing cancer cells, and for inhibiting size increase tumor, reduce the size of a tumor, reduce tumor proliferation, or prevent tumor proliferation. the present disclosure relates to heteroaryl compounds as mek inhibitors. such compounds include heteroaryl compounds of formula (I), pharmaceutically acceptable salts thereof, combinations with suitable medicaments and pharmaceutical compositions thereof. the present disclosure also includes processes for preparing the compounds and using them in methods of treatment. compounds as disclosed herein are of formula (i).
公开号:BR112014022713B1
申请号:R112014022713-6
申请日:2013-03-11
公开日:2021-09-08
发明作者:Bhavesh Dave；Rakesh Kumar Banerjee；Samiron Phukan；Abhijit Datta Khoje；Rajkumar Hangarge；Jitendra Sambhaji Jadhav；Venkata P. Palle；Rajender Kumar Kamboj
申请人:Lupin Limited；
IPC主号:

专利说明:

FIELD OF THE INVENTION
[001] The present invention relates to anti-cancer compounds, pharmaceutically acceptable salts thereof, combinations with suitable medicine and pharmaceutical compositions thereof that contain one or more of such compounds and methods of treating various cancers. CROSS REFERENCE TO A RELATED ORDER
[002] The present application claims the benefit of Indian Provisional Patent Application no. 0288/KOL/2012 filed on March 14, 2012, the disclosure of which is incorporated herein by reference in its entirety. FUNDAMENTALS OF THE INVENTION
[003] Cancer cells have certain characteristics that allow them a growth advantage. These include six major changes in cell physiology such as self-sufficiency in growth signals, insensitivity to inhibitory growth signals, avoidance of apoptosis, undefined proliferative potential, continuous angiogenesis, tissue invasion and metastasis (Hanahan and Weinberg, Cell, 2000, Vol. 100, 57 to 70). These changes are triggered by genomic instability and inflammation that generate a conducive microenvironment for tumor growth. In addition to the tracts mentioned above, reprogramming of cellular energy metabolism and evasion of immune destruction have also been observed in most cancers.
[004] Improved survival in cancer cells is further enhanced by the presence of abnormally activated signaling pathways. The vast majority of cancers are known to have mutations in the growth factor signaling cascades that lead to a constitutive activation of these pathways. Such constitutive activations have been observed in growth factor receptors including, but not limited to, epidermal growth factor receptor - EGFR, fibroblast growth factor receptor - FGFR, hepatocyte growth factor receptor - HGFR, etc. Furthermore, activation of mutations has been reported in certain receptors as well as non-receptor tyrosine kinases which include, but are not limited to, MET receptor tyrosine kinase, EGFR tyrosine kinase, Bcr-Abl tyrosine kinase, Src tyrosine kinase, etc. Activation of Ser-Thr kinases like Ras kinases and lipid like PI3 kinases also lead to oncogenesis. Chronic activation of growth factor/cytokine/hormone-related signaling leads to activation of immediately downstream components like Src, Ras, PI3 kinase, etc. These kinases additionally activate manipulators such as MEK, ERK, AKT, which eventually lead to activation of transcription factors that favor cells with a high proliferative potential, improved survival, subversion of metabolic pathways and inhibition of apoptosis. (Hanahan and Weinberg, Cell, 2000, Vol. 100, 57 to 70; Hanahan and Weinberg Cell 2011, Vol. 144, 646 to 674).
[005] A MEK kinase (Mitogen Activated Protein Kinase (MAPKK)) is an important component of the Ras-RAF-MEK-ERK cell survival pathway. The Ras pathway is activated by the binding of growth factors, cytokines and hormones to their cognate receptors. In cancer cells, this pathway is, however, constitutively activated and leads to improved cancer cell survival, cell proliferation, angiogenesis and metastasis. Tumors that show a constitutive activation of Ras or MEK kinase include, but are not limited to those of the colon, pancreas, breast, brain, ovary, lung, and skin (Sebolt-Leopold and Herrera, Nat. Rev. Cancer 2004, 4 937 to 947; Fukazawa et al., Mol. Cancer Ther. 2002, Vol. 1, 303 to 309). Activation of Ras (due to upstream signaling or as a result of point of activation mutations in the Ras oncogene) leads to phosphorylation and activation of Raf kinase which in turn phosphorylates and activates MEK kinase. MEK1/2 kinase phosphorylates and activates the ERK1/2 kinase (also referred to as MAP Kinase) which further phosphorylates and regulates the function of proteins such as Mcl-1, Bim and Bad that are involved in cell survival and apoptosis. Therefore, activation of this phosphorylation-mediated cascade leads to improved cell proliferation, cell survival, decreased cell death that are necessary for the initiation and maintenance of the tumorigenic phenotype (Curr. Opin. Invest. Drugs, 2008, 9, 614 ).
[006] The Ras-Raf-MEK-ERK cascade plays a major role in cancer cell survival and proliferation. Thus, inhibition of this pathway at any of these levels leads to inhibition of cancer cell growth, proliferation and survival. In fact, it has been reported that Ras or Raf inhibition leads to inhibition of tumor growth in animal models as well as in cancer patients. However, success with these inhibitors has only been limited to certain types of cancers (eg Sorafenib which exhibits Raf kinase has been approved for renal cell carcinoma). Therefore, inhibiting MEK is a new approach towards controlling this pathway in cancer cells. Furthermore, the possibility of designing allosteric inhibitors also exhibits improved selectivity which is crucial for decreasing the toxic effects associated with kinase inhibitors.
[007] The MEK-ERK pathway is activated in a number of inflammatory conditions (Kyriakis and Avruch, 1996, Vol. 271, no. 40, pages 24,313 to 24,316; Hammaker et al., J. Immunol. 2004, 172, 1612 to 1618 ) which include rheumatoid arthritis, intestinal inflammatory process and COPD. MEK regulates the biosynthesis of the inflammatory cytokines TNF, IL-6 and IL-1. MEK inhibitors have been shown to interfere with the production/secretion of these cytokines. The BioPharma kit has developed a first-in-class MEK inhibitor (ARRY 438162) and has initiated clinical studies in patients with rheumatoid arthritis (RA).
International patent applications WO/2003/053960, WO/2005/023251, WO/2005/121142, WO/2005/051906, WO/2010/121646 describe MEK inhibitors. BRIEF SUMMARY OF THE INVENTION
[009] The present invention provides anticancer compounds of the general formula (I), pharmaceutically acceptable salts thereof, combinations with suitable medicine and pharmaceutical compositions thereof and uses thereof in the treatment of various cancers.

[010] where R1-R5 are described in detail below.
[011] The compounds of the present inventions are potent MEK inhibitors and show tumor regression effect with less promising side effects. DETAILED DESCRIPTION OF THE INVENTION
[012] The present invention relates to heteroaryl compounds of the formula I, pharmaceutically acceptable salts thereof, combinations thereof with suitable medicine and pharmaceutical compositions thereof. The present invention also includes processes for preparing the compounds and using them in methods of treatment. The compounds are of formula (I) below:

[013] where:
[014] R1 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl;
[015] R2 is selected from the group consisting of -(C(Rc)(Rd))mC(=O)-N(R6)R7, -C(=O)N(R8)R9 and -O- ( C(Rc)(Rd))mC(=O)-N(R6)R7;
[016] R3 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl;
[017] R4 is selected from the group consisting of hydrogen, halogen, substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl;
[018] R5 is substituted or unsubstituted aryl wherein the substituents are selected from the group consisting of Ra and Rb;
[019] R6 and R7 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; or R6 and R7 together with the nitrogen to which they are attached form a substituted or unsubstituted heterocyclyl;
[020] R8 and R9 are each independently selected from the group consisting of hydrogen, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl, or R8 and R9 joined with the nitrogen to which they are attached form a substituted heterocyclyl or not replaced;
[021] with the proviso that both R8 and R9 cannot be hydrogen at the same time; and when R8 and R9 are not a part of a heterocycle formed together with the nitrogen to which they are attached, at least one of R8 and R9 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl;
[022] Ra and Rb are each independently selected from the group consisting of hydrogen, halogen, and haloalkyl;
[023] Rc and Rd are independently selected from the group consisting of hydrogen, halogen, hydroxy and substituted or unsubstituted alkyl; or Rc and Rd together with the carbon to which they are attached form a substituted or unsubstituted cycloalkyl;
[024] m is an integer selected from the group consisting of 1, 2, 3 and 4;
[025] When the alkyl group or alkenyl group is substituted, the alkyl group or alkenyl group is substituted by 1 to 4 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, perhaloalkyl, cycloalkyl, aryl , heteroaryl, heterocyclyl, -SO2R10a, -C(=O)OR10a, -OC(=O)R10a, -C(=O)N(H)R10, -OR10b, -C(=O)N(alkyl)R10 , -N(H)C(=O)R10a, -N(H)R10, -N(alkyl)R10 -N(H)C(=O)N(H)R10, -N(H)C(= O)N(alkyl)R10, -NH-SO2-alkyl and -NH-SO2-cycloalkyl.
[026] When the cycloalkyl group or cycloalkenyl group is substituted, the cycloalkyl group or cycloalkenyl group is substituted by 1 to 3 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, alkyl, alkenyl, perhaloalkyl , hydroxyalkyl, aryl, heteroaryl, heterocyclyl, -OR10b, -SO2R10a, -C(=O)R10a, -C(=O)OR10a, - OC(=O)R10a, -C(=O)N(H)R10 , -C(=O)N(alkyl)R10, -N(H)C(=O)R10a, -N(H)R10, -N(alkyl)R10, -N(H)C(=O)N (H)R10 and -N(H)C(=O)N(alkyl)R10, -NH-SO2-alkyl and -NH-SO2-cycloalkyl.
[027] When the aryl group is substituted, the aryl group is substituted by 1 to 3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, heterocycle , -O-alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -NH2, -SO2-alkyl, -SO2-perhaloalkyl, -N(alkyl)C(=O)alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, - SO2N(alkyl)alkyl , -SO2N(H)alkyl, -SO2NH2, -NH-SO2-alkyl and -NH-SO2-cycloalkyl.
[028] When the heteroaryl group is substituted, the heteroaryl group is substituted by 1 to 3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, heterocycle , -O-alkyl, O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -NH2, -SO2-alkyl, -SO2-perhaloalkyl, -N(alkyl)C(=O)alkyl, - N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, - SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -NH-SO2-alkyl and -NH-SO2-cycloalkyl.
[029] When the heterocyclyl group is substituted, the heterocyclyl group is substituted by 1 to 3 substituents. When the substituents are on a "heterocycle" carbon ring, the substituents are independently selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, -OR10b, -C(=O)OR10a, -OC(=O)R10a, -C(=O)N(H)R10, -C(=O)N(alkyl)R10, -N(H) C(=O)R10a, -N(H)R10, -N(alkyl)R10, -N(H)C(=O)N(H)R10 and -N(H)C(=O)N(alkyl) )R10. When the heterocyclic group is substituted on a nitrogen ring of the "heterocycle", the substituents are independently selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, -SO2R10a, -C(=O )R10a, C(=O)OR10a, -C(=O)N(H)R10, -C(=O)N(alkyl)R10, -NH-SO2-alkyl and -NH-SO2-cycloalkyl. When the heterocyclic group is substituted on a "heterocycle" sulfur ring, the sulfur is substituted by 1 or 2 oxo groups.
[030] R10 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl;
[031] R10a is selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl; and
[032] R10be selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl.
[033] In certain embodiments, R1 is selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted heterocyclyl, and substituted or unsubstituted cycloalkyl.
[034] In other embodiments, R1 is selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, allyl, difluoromethyl, cyclopropyl, 3-oxetanyl, -CH2COOH, -CH2COOC2H5, -CH2CH(OH)CH2(OH) and -C2H4OH.
[035] In certain embodiments, R3 and R4 are substituted or unsubstituted alkyl.
[036] In other embodiments, R3 and R4 are methyl.
[037] In certain embodiments, R5 is substituted or unsubstituted phenyl wherein the substituents are independently selected from Ra and Rb.
[038] In certain embodiments, Ra and Rb are independently selected from the group consisting of hydrogen and halogen.
[039] In other modalities, Ra and Rb are independently fluorine or iodine.
[040] In certain embodiments, Rc and Rd are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, halogen and hydroxyl or Rc and Rd joined with the carbon to which they are attached form a ring of substituted or unsubstituted cycloalkyl.
[041] In other embodiments, Rc and Rd are independently selected from the group consisting of hydrogen, methyl, fluorine and hydroxyl; or Rc and Rd together with the carbon to which they are attached form a cyclopropyl ring.
[042] In certain modes, m is 1 or 2.
[043] In certain embodiments, R6 and R7 are independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocyclyl; or R6 and R7 together with the nitrogen atom to which they are attached form a substituted or unsubstituted heterocycle.
[044] In other embodiments, R6 and R7 are independently selected from the group consisting of hydrogen, methyl, cyclopropyl, and 3-oxetane; or R6 and R7 together with the nitrogen atom to which they are attached form azetidinyl or 3-hydroxyazetidinyl.
[045] In certain embodiments, R8 and R9 are independently selected from the group consisting of hydrogen, substituted or unsubstituted cycloalkyl and substituted or unsubstituted heterocyclyl, or R8 and R9 joined with the nitrogen to which they are attached form a substituted or unsubstituted heterocycle; with the proviso that both R8 and R9 are not hydrogen at the same time and when R8 and R9 are not a part of a heterocycle formed together with the nitrogen to which they are attached, at least one of R8 and R9 is substituted or unsubstituted cycloalkyl or substituted or unsubstituted heterocyclyl.
[046] In other embodiments, R8 and R9 are independently selected from the group consisting of hydrogen, cyclopropyl, cyclopropyl substituted by -C(=O)NH2 or -CH2OH, 3-oxetanyl, tetrahydrofuran-3-yl and tetrahydro -2H-pyranyl or R8 and R9 together with the nitrogen to which they are attached form 1,1-dioxidothiazolidinyl, 1,1-dioxidothiomorpholinyl, morpholinyl, azetidinyl, 1-pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 3-hydroxypyrrolidinyl or 4 - hydroxypiperidinyl; with the proviso that both R8 and R9 are not hydrogen at the same time and when R8 and R9 are not a part of a heterocycle formed together with the nitrogen to which they are attached, at least one of R8 and R9 is substituted cycloalkyl or unsubstituted or substituted or unsubstituted heterocyclyl.
[047] In one embodiment, the present invention is a compound of formula Ia:

[048] in which:
[049] R, R, R, R, R, R, R, R, R and m are as defined in formula (I).
[050] In another embodiment, the present invention is a compound of formula (Ib):

[051] in which:
[052] R1, R3, R4, R8, R9, Ra and Rb are as defined in formula (I); with the proviso that both R8 and R9 cannot be hydrogen at the same time and at least one of R8 and R9 is selected from the group consisting of substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl , substituted or unsubstituted heterocyclyl; or R8 and R9 together with the nitrogen to which they are attached form a substituted or unsubstituted heterocycle.
[053] In another embodiment, the present invention is a compound of formula (Ic):

[054] where: R, R, R, R, R, R, R, R, R and 'm' are as defined in formula (I).
[055] General terms used in any of the formulas in this document may be defined as follows; however, the aforementioned meaning should not be interpreted as limiting the scope of the term per se.
[056] The term "alkyl" as used herein means a straight or branched hydrocarbyl chain containing from 1 to 20 carbon atoms. Preferably, the alkyl group contains 1 to 10 carbon atoms. More preferably, the alkyl group contains up to 6 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n- hexyl.
[057] The term "alkenyl" as used herein means an "alkyl" group as defined above herein that contains 2 to 20 carbon atoms and that contains at least one double bond. Representative examples of alkenyl include, but are not limited to, pent-2-enyl, hex-3-enyl, allyl, vinyl and the like.
[058] When the alkyl and alkenyl groups are substituted alkyl or substituted alkenyl groups, the alkyl and alkenyl groups are substituted by 1 to 4 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, haloalkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, -OR10b, -SO2R10a, -C(=O)R10a, -C(=O)OR10a, -OC(=O)R10a, - C(=O)N(H)R10, -C(=O)N(alkyl)R10, -N(H)C(=O)R10a, -N(H)R10, -N(alkyl)R10, -N(H)C(=O)N( H)R10, -N(H)C(=O)N(alkyl)R10, -NH-SO2-alkyl and -NH-SO2-cycloalkyl; wherein R10 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl; R10a is selected from the group consisting of alkyl, alkenyl, haloalkyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl; R10 is selected from the group consisting of hydrogen, alkyl, alkenyl, haloalkyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl.
[059] The term "haloalkyl" means an alkyl, as the case may be, substituted by one or more halogen atoms, where alkyl groups are as defined above. The term "halo" is used interchangeably herein with the term "halogen" and means F, Cl, Br or I. Examples of "haloalkyl" include, but are not limited to, trifluoromethyl, difluoromethyl, 2.2, 2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 4,4,4-trifluorobutyl, 4,4-difluorocyclohexyl, chloromethyl, dichloromethyl, trichloromethyl, 1-bromoethyl and the like. The term "perhaloalkyl" group is defined above herein in which all hydrogen atoms of said alkyl group are replaced by halogen, exemplified by trifluoromethyl, pentafluoroethyl and the like.
[060] The term "hydroxyalkyl" means an alkyl, as the case may be, substituted by one or more hydroxyl group(s) where alkyl groups are as defined above. The term "hydroxy" as used herein means "-OH". Examples of "hydroxyalkyl" include, but are not limited to -CH2OH, -CH2CH2OH, -CH(OH)CH2OH, and the like.
[061] The term "cycloalkyl" as used herein means a non-aromatic monocyclic, bicyclic or tricyclic ring system containing from 3 to 14 carbon atoms, preferably monocyclic cycloalkyl ring containing 3 to 6 carbon atoms. of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl cyclooctyl Bicyclic ring systems include a monocyclic ring system fused through a bond to another cyclic system which may be an alicyclic ring or an aromatic ring. include spirocyclic systems in which the second ring is fused to a single carbon atom. Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent monocyclic ring carbon atoms are linked by an alkylene bridge Examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo [2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane and bicyclo[4.2.1]nonane, bicyclo[3.3.2]decane, bicyclo[3.1 .0]hexane, bicyclo[410]heptane, bicyclo[3.2.0]heptanes, octahydro-1H-indene, spiro[2.5]octane, spiro[4.5]decane, spiro[bicyclo[4.1.0]heptane-2.1 '-cyclopentane], hexahydro-2'H-spiro[cyclopropane-1,1'-pentalene]. Tricyclic ring systems are those systems in which the bicyclic systems as described above are further nullified with a third ring which may be an alicyclic ring or aromatic ring. Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non-adjacent bicyclic ring carbon atoms are linked by an alkylene bond or bridge. Examples of tricyclic ring systems include, but are not limited to, tricyclo[3.3.1.03.7]nonane and tricyclo[3.3.1.13.7]decane (adamantane).
[062] The term "cycloalkenyl" as used herein means a cycloalkyl group as defined above that contains at least one double bond.
[063] When the cycloalkyl or cycloalkenyl groups are substituted cycloalkyl or substituted cycloalkenyl groups, the cycloalkyl and cycloalkenyl groups are substituted by 1 to 3 substituents independently selected from the group consisting of oxo, halogen, nitro, cyano, hydroxyl, hydroxyalkyl, alkyl, alkenyl, perhaloalkyl, aryl, heteroaryl, heterocyclyl, -OR10b, -SO2R10a, -C(=O)R10a, -C(=O)OR10a, -OC(=O)R10a, -C(=O) N(H)R10, -C(=O)N(alkyl)R10, -N(H)C(=O)R10a, -N(H)R10, -N(alkyl)R10, -N(H)C (=O)N(H)R10, -N(H)C(=O)N(alkyl)R10, -NH-SO2-alkyl and -NH-SO2-cycloalkyl; wherein, R10 is selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl; R10a is selected from the group consisting of alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl; R10 is selected from the group consisting of hydrogen, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl and heterocyclyl.
[064] The term "aryl" refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system. Examples of aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl and the like. The aryl group also includes partially saturated bicyclic and tricyclic aromatic hydrocarbons such as tetrahydro-naphthalene.
[065] When the aryl group is a substituted aryl group, the aryl group is substituted by 1 to 3 substituents independently selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, heterocycle, -O-alkyl, -O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -NH2, -SO2-alkyl, -SO2-perhaloalkyl, -N(alkyl)C(=O )alkyl, -N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, -SO2N( alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -NH-SO2-alkyl and -NH-SO2-cycloalkyl;
[066] The term "heteroaryl" refers to a 5- to 14-membered monocyclic, bicyclic or tricyclic ring system that has 1 to 4 ring heteroatoms selected from O, N or S and the remaining ring atoms are carbon ( with appropriate hydrogen atoms unless otherwise indicated) wherein at least one ring in the ring system is aromatic. Heteroaryl Groups can optionally be substituted by one or more substituents. In one embodiment, 0, 1, 2, 3 or 4 atoms of each ring of a heteroaryl group may be replaced by a substituent. Examples of heteroaryl groups include, but are not limited to, pyridyl, 1-oxo-pyridyl, furanyl, thienyl, pyrrolyl, oxazolyl, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazolyl , thiadiazolyl, isoquinolinyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, azaindolyl, imidazopyridyl, quinazolinyl, pyroidinyl]pyrimyl[2,3]pyrimyl] (b)thienyl, 2,3-thiadiazolyl, 1H-pyrazolo[5,1-c]-1,2,4-triazolyl, pyrrolo[3,4-d]-1,2,3-triazolyl, cyclopentatriazolyl, 3H -pyrrolo[3,4-c]isoxazolyl, 2,3-dihydro-benzo[1,4]dioxin-6-yl, 2,3-dihydro-benzo[1,4]dioxin-5-yl, 2,3 -dihydro-benzofuran-5-yl, 2,3-dihydro-benzofuran-4-yl, 2,3-dihydro-benzofuran-6-yl, 2,3-dihydro-benzofuran-6-yl, 2,3-dihydro -1H-indol-5-yl, 2,3-dihydro-1H-indol-4-yl, 2,3-dihydro-1H -indol-6-yl, 2,3-dihydro-1H-indol-7-yl, benzo[1,3]dioxol-4-yl, benzo[1,3]dioxol-5-yl, 1,2,3 ,4-tetrahydroquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, 2,3-dihydrobenzothien-4-yl, 2-oxoindolin-5-yl and the like.
[067] When the heteroaryl group is a substituted heteroaryl group, the heteroaryl group is substituted by 1 to 3 substituents selected from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl, heterocycle , -O-alkyl, O-perhaloalkyl, -N(alkyl)alkyl, -N(H)alkyl, -NH2, -SO2-alkyl, -SO2-perhaloalkyl, -N(alkyl)C(=O)alkyl, - N(H)C(=O)alkyl, -C(=O)N(alkyl)alkyl, -C(=O)N(H)alkyl, -C(=O)NH2, - SO2N(alkyl)alkyl, -SO2N(H)alkyl, -SO2NH2, -NH-SO2-alkyl and -NH-SO2-cycloalkyl.
[068] The term "heterocycle" or "heterocyclic", as used herein, means a "cycloalkyl" group in which one or more of the carbon atoms is replaced by -O-, -S-, -S(O2) -, -S(O)-, -N(Rm)-, -Si(Rm)Rn-, where Rm and Rn are independently selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, cycloalkyl and heterocyclyl. The heterocycle can be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle. Examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrofuranyl, thiadiazolidinyl thiomorphothio,thio thiomorpholine sulfone), thiopyranyl and trithianyl. Examples of bicyclic heterocycle include, but are not limited to, 1,3-benzodioxolyl, 1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl, 2,3-dihydro-1-benzofuranyl, 2,3-dihydro -1-benzothienyl, 2,3-dihydro-1H-indolyl and 1,2,3,4-tetrahydroquinolinyl. The term heterocycle also includes bridged heterocyclic systems such as azabicyclo[3.2.1]octane, azabicyclo[3.3.1]nonane and the like.
[069] When the heterocyclic group is substituted, it can be substituted either on a carbon ring atom or on a ring heteroatom. When it is substituted on a carbon ring atom, it is substituted by 1 to 3 substituents independently selected from the group consisting of halogen, nitro, cyano, oxo, alkyl, alkenyl, perhaloalkyl, cycloalkyl, cycloalkenyl , aryl, heteroaryl, heterocyclyl, -OR10b, -C(=O)OR10a, -OC(=O)R10a, -C(=O)N(H)R10, -C(=O)N(alkyl)R10, -N(H)C(=O)R10a, -N(H)R10, -N(alkyl)R10, -N(H)C(=O)N(H)R10 and -N(H)C(= O)N(alkyl)R10. When the "heterocyclic" group is substituted on a nitrogen ring, it is substituted by a substituent selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, -SO2R10a, -C(=O) R10a, C(=O)OR10a, -C(=O)N(H)R10, -C(=O)N(alkyl)R10, -NH-SO2-alkyl and -NH-SO2-cycloalkyl. When the heterocyclic group is substituted on a "heterocycle" sulfur ring, it is substituted by 1 or 2 oxo groups.
[070] The term "oxo" means a divalent oxygen (=O) attached to the parent group. For example, oxo bonded to carbon forms a carbonyl, oxo substituted in cyclohexane forms a cyclohexanone, and the like.
[071] The term "annulled" means that the ring system under consideration is either annulled with another ring on a carbon atom of the cyclic system or by a bond of the cyclic system as in the case of fused or spiro ring systems.
[072] The term "bridged" means that the ring system under consideration contains an alkylene bridge that has 1 to 4 methylene units joining two non-adjacent ring atoms.
[073] It should be understood that formulas (I), (Ia), (Ib) and (Ic) structurally encompass all stereoisomers, tautomers and pharmaceutically acceptable salts that may be contemplated from the chemical structure of the genera described herein .
[074] A compound, stereoisomers thereof, racemates, tautomers and pharmaceutically acceptable salt thereof as described above herein wherein the compound of general formula I, (Ia), (Ib) and (Ic) may be selected from of the group consisting of:
[075] 3-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4, 3-d]pyrimidin-1(2H)-yl)phenyl)propanamide (Compound 1)
[076] N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4 ,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 2)
[077] 1-(3-(azetidine-1-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4 ,7(1H,3H,6H)-trione (Compound 3)
[078] N-cyclopropyl-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide (Compound 4)
[079] 2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido[4 ,3-d]pyrimidin-1(2H)-yl)phenoxy)-N-methylacetamide (Compound 5)
[080] N-cyclopropyl-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide (Compound 6)
[081] 5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(morpholine-4-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2, 4.7(1H,3H,6H)-trione (Compound 7)
[082] 1-(3-(1,1-dioxidothiomorpholine-4-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine -2,4,7(1H,3H,6H)-trione (Compound 8)
[083] 2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido[4 ,3-d]pyrimidin-1(2H)-yl)phenyl)-2-methylpropanamide (Compound 9)
[084] 2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido[4 ,3-d]pyrimidin-1(2H)-yl)phenyl)-N,N-dimethylacetamide (Compound 10)
[085] 2,2-difluoro-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,7, 8-tetrahydropyrido[2,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide (Compound 11)
[086] N-(1-carbamoylcyclopropyl)-3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7 - tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 12)
[087] 3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido [4,3-d ]pyrimidin-1(2H)-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide (Compound 13)
[088] 2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido[4 ,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide (Compound 14)
[089] 3-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido[4 ,3-d]pyrimidin-1(2H)-yl)phenyl)-N-methylpropanamide (Compound 15)
[090] 2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4, 3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide (Compound 16)
[091] 1-(3-(1,1-dioxidothiazolidine-3-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine -2,4,7(1H,3H,6H)-trione (Compound 17)
[092] 5-((2-fluoro-4-iodophenyl)amino)-1-(3-(4-hydroxypiperidine-1-carbonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2 ,4,7(1H,3H,6H)-trione (Compound 18)
[093] N-cyclopropyl-3-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide (Compound 19)
[094] 2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido[4 ,3-d]pyrimidin-1(2H)-yl)phenoxy)-2-methylpropanamide (Compound 20)
[095] 5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(4-methylpiperazine-1-carbonyl)phenyl)pyrido[4,3-d]pyrimidine- 2,4,7(1H,3H,6H)-trione (Compound 21)
[096] 5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2 ,4,7(1H,3H,6H)-trione (Compound 22)
[097] 5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(piperazine-1-carbonyl)phenyl)pyrido[4,3-d]pyrimidine-2, 4.7(1H,3H,6H)-trione (Compound 23)
[098] 1-(3-(azetidine-1-carbonyl)phenyl)-3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3-d]pyrimidine -2,4,7(1H,3H,6H)-trione (Compound 24)
[099] N-cyclopropyl-2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4, 6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide (Compound 25)
[0100] 2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide (Compound 26)
[0101] 3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(pyrrolidine-1-carbonyl)phenyl)pyrido[4,3-d] pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 27)
[0102] 2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-methylpropanamide (Compound 28)
[0103] 2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N,N-dimethylacetamide (Compound 29)
[0104] 2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,7,8- tetrahydropyrido[2,3-d]pyrimidin-1(2H)-yl)phenyl)-2,2-difluoroacetamide (Compound 30)
[0105] 2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N-(oxetan-3-yl)acetamide (Compound 31)
[0106] 2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide (Compound 32)
[0107] 3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-1-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxo ethyl)phenyl)-6, 8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 33)
[0108] 3-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide (Compound 34)
[0109] 2-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide (Compound 35)
[0110] 3-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N-methylpropanamide (Compound 36)
[0111] N-cyclopropyl-3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7 - tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 37)
[0112] 3-cyclopropyl-1-(3-(1,1-dioxidothiazolidine-3-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3 -d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 38)
[0113] 3-cyclopropyl-1-(3-(1,1-dioxidothiomorpholine-4-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4, 3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 39)
[0114] N-cyclopropyl-3-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4, 6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide (Compound 40)
[0115] N-cyclopropyl-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6, 7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide (Compound 41)
[0116] 2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[ 4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide (Compound 42)
[0117] 2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyroxide [4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-methylpropanamide (Compound 43)
[0118] 2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyroxide [4,3-d]pyrimidin-1(2H)-yl)phenyl)-N,N-dimethylacetamide (Compound 44)
[0119] 2,2-difluoro-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4, 6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide (Compound 45)
[0120] 1-(3-(2-(azetidin-1-yl)-2-oxoethyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethylpyrido[4 ,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 46)
[0121] 2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido [4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide (Compound 47)
[0122] 5-((2-fluoro-4-iodophenyl)amino)-1-(3-(2-(3-hydroxyazetidin-1-yl)-2-oxoethyl)phenyl)-3,6,8-trimethylpyrido [4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 48)
[0123] 3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4, 3-d]pyrimidin-1(2H)-yl)-N-(oxetan-3-yl)benzamide (Compound 49)
[0124] 2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido [4,3-d]pyrimidin-1(2H)-yl)phenyl)-N-(oxetan-3-yl)acetamide (Compound 50)
[0125] 3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido[4, 3-d]pyrimidin-1(2H)-yl)-N-(tetrahydrofuran-3-yl)benzamide (Compound 51)
[0126] 3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido[4, 3-d]pyrimidin-1(2H)-yl)-N-(tetrahydro-2H-pyran-4-yl)benzamide (Compound 52)
[0127] 3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido[4, 3-d]pyrimidin-1(2H)-yl)-N-(1-(hydroxymethyl)cyclopropyl)benzamide (Compound 53)
[0128] N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyroxide [4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 54)
[0129] N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-3-(2-hydroxyethyl)-6,8-dimethyl-2,4,7-trioxo-3,4 ,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 55)
[0130] 1-(3-(azetidine-1-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethylpyrido[4,3-d]pyrimidine-2 ,4,7(1H,3H,6H)-trione (Compound 56)
[0131] 2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[ 4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide (Compound 57)
[0132] N-cyclopropyl-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6, 7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide (Compound 58)
[0133] N-cyclopropyl-2-(3-(3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4, 6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide (Compound 59)
[0134] 2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[ 4,3-d]pyrimidin-1(2H)-yl)phenoxy)-N-methylacetamide (Compound 60)
[0135] 3-(3-(3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide (Compound 61)
[0136] N-cyclopropyl-3-(3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7 - tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 62)
[0137] 5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-1-(3-(morpholine-4-carbonyl)phenyl)pyrido[4,3-d]pyrimidine- 2,4,7(1H,3H,6H)-trione (Compound 63)
[0138] ethyl 2-(1-(3-(cyclopropylcarbamoyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-1,2 ,6,7-tetrahydropyrido[4,3-d]pyrimidin-3(4H)-yl)acetate (Compound 64)
[0139] 1-(3-(1,1-dioxidothiomorpholine-4-carbonyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethylpyrido[4,3-d ]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 65)
[0140] 1-(3-(1,1-dioxidothiomorpholine-4-carbonyl)phenyl)-3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3 -d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 66)
[0141] 2-(3-(3-ethyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-N,N-dimethylacetamide (Compound 67)
[0142] 3-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[ 4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide (Compound 68)
[0143] N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-3-isopropyl-6,8-dimethyl-2,4,7-trioxo-3,4,6,7 -tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 69)
[0144] 3-(3-allyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4 ,3-d]pyrimidin-1(2H)-yl)-N-cyclopropylbenzamide (Compound 70)
[0145] 2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-3-(oxetan-3-yl)-2,4,7-trioxo-3, 4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenoxy)acetamide (Compound 71)
[0146] N-cyclopropyl-3-(3-(difluoromethyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6 ,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 72)
[0147] N-cyclopropyl-3-(3-(2,3-dihydroxypropyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3 ,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 73)
[0148] 2-(1-(3-(cyclopropylcarbamoyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-1,2, 6,7-tetrahydropyrido[4,3-d]pyrimidin-3(4H)-yl)acetic acid (Compound 74)
[0149] (R)-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6, 7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide (Compound 75)
[0150] (S)-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6, 7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide (Compound 76)
[0151] 1-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl -2,4,7-trioxo-3,4,6,7-tetrahydropyrido [ 4.3-d]pyrimidin-1(2H)-yl)phenyl)cyclopropanecarboxamide (Compound 77)
[0152] 1-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7- tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)cyclopropanecarboxamide (Compound 78) and
[0153] 1-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7-tetrahydro pyrido [4,3-d]pyrimidin-1(2H)-yl)phenyl)cyclopropanecarboxamide (Compound 79)
[0154] The present disclosure provides a method for inhibiting MEK enzymes comprising contacting said MEK enzyme with a composition comprising a compound of I, Ia, Ib, Ic, tautomeric forms thereof, stereoisomers thereof or pharmaceutically acceptable salts of the even sufficient to inhibit said enzyme wherein said enzyme has inhibited MEK kinase, which occurs within a cell.
The invention also provides a method of treating a MEK-mediated disorder in an individual suffering from said disorder which comprises administering to said individual an effective amount of a composition comprising a compound of formula I, Ia, Ib, Ic , tautomeric forms thereof, stereoisomers thereof, or pharmaceutically acceptable salts thereof. The treatment method can also be combined with additional therapy such as radiation therapy, chemotherapy or a combination thereof.
[0156] MEK-mediated disorders as mentioned above include inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, heart disorder, neurological disorders, fibrogenetic disorders, proliferative disorders, hyperproliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas , metabolic diseases and malignant diseases.
The invention further provides a method for the treatment or prophylaxis of a proliferative disease in a subject comprising administering to said subject an effective amount of a composition comprising a compound of formula I, Ia, Ib, Ic, tautomeric forms of same, stereoisomers thereof or pharmaceutically acceptable salts thereof. Proliferative disease includes cancer, psoriasis, restenosis, autoimmune disease or atherosclerosis.
The invention also provides a method for the treatment or prophylaxis of an inflammatory disease in a subject comprising administering to said subject an effective amount of a composition comprising a compound of formula I, Ia, Ib, Ic, tautomeric forms of same, stereoisomers thereof or pharmaceutically acceptable salts thereof. Inflammatory disease includes rheumatoid arthritis or multiple sclerosis.
[0159] The invention also provides a method for degrading, inhibiting the growth of or killing cancer cells which comprises contacting the cells with an amount of a composition effective to degrade, inhibit the growth of or kill cancer cells, wherein the composition comprises a compound of formula I, Ia, Ib, Ic, tautomeric forms thereof, stereoisomers thereof or pharmaceutically acceptable salts thereof.
[0160] The invention also provides a method of inhibiting tumor enlargement, reducing the size of a tumor, reducing tumor proliferation or preventing tumor proliferation in an individual in need thereof which comprises administering to said individual a effective amount of a composition to inhibit tumor enlargement, reduce the size of a tumor, reduce tumor proliferation or prevent tumor proliferation, the composition comprising a compound of formula I, Ia, Ib, Ic, tautomeric forms of same, stereoisomers thereof or pharmaceutically acceptable salts thereof.
[0161] The MEK-ERK pathway is activated in a number of inflammatory conditions (Kyriakis and Avruch 1996, Vol. 271, no. 40, pages 24313 to 24316; Hammaker et al., J Immunol 2004;172;1612 to 1618) which include rheumatoid arthritis, intestinal inflammatory process and COPD.
[0162] The present invention describes MEK kinase inhibitors for treating disorders that are triggered by hyperactivation, abnormal activation, constitutive activation, MEK kinase gain-of-function mutation and/or substrate kinases thereof that include, but are not limit the ERK. Such disorders encompass hyperproliferative disorders which include but are not limited to psoriasis, keloids, skin hyperplasia, benign prostatic hyperplasia (BPH), solid tumors such as respiratory tract cancers (which include but are not limited to small cell and cell carcinomas non-small lung), brain (including but not limited to glioma, medulloblastoma, ependymoma, neuroectodermal and pineal tumors), breast (including but not limited to invasive ductal carcinoma, invasive lobular carcinoma, ductal and lobular carcinoma in situ), reproductive organs (which include but are not limited to prostate cancer, testicular cancer, ovarian cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer and sarcoma of the uterus), digestive tract (which include but not are limited to esophageal, colon, colorectal, gastric, gallbladder, pancreatic, rectal, anal, small intestine and salivary gland cancers), urinary tract (which include, but are not limited to the bladder, ureter, kidney, renal, urethral and papillary renal cancers), eye (which include, but are not limited to, intraocular melanoma and retinoblastoma), liver (which include, but are not limited to, hepatocellular carcinoma and cholangiocarcinoma), skin ( which include but are not limited to melanoma, squamous cell carcinoma, Kaposi's sarcoma, Merkel cell skin cancer, non-melanoma skin cancer), head and neck (which include but are not limited to laryngeal cancer, nasopharyngeal, hypopharyngeal, oropharyngeal, lip and oral cavity cancer and squamous cell cancer), thyroid, parathyroid and metastases thereof. Hyperproliferative disorders also include leukemias (which include but are not limited to an acute lymphoblastic leukemia, acute myeloid leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia and hairy cell leukemia), sarcomas (which include, but not limited to, a sarcoma of soft tissue, osteosarcoma, lymphosarcoma, rhabdomyosarcoma) and lymphomas (which include, but are not limited to, non-Hodgkin's lymphoma, AIDS-related lymphoma, cutaneous T-cell lymphoma, Burkitt's lymphoma, Hodgkin's disease, and central nervous system lymphoma).
[0163] The present invention describes MEK kinase inhibitors for treating certain disorders involving the abnormal regulation of extracellular mitogen kinase activity including, but not limited to, hepatomegaly, heart failure, cardiomegaly, diabetes, stroke, Alzheimer's, cystic fibrosis, septic shock or asthma.
[0164] The present invention describes MEK kinase inhibitors for treating diseases and disorders associated with abnormal, aberrant and/or excessive angiogenesis. Such disorders associated with angiogenesis include, but are not limited to, tumor growth and metastases, ischemic retinal vein occlusion, diabetic retinopathy, macular degeneration, neovascular glaucoma, psoriasis, inflammation, rheumatoid arthritis, vascular graft restenosis, restenosis and restenosis in stent.
[0165] The compounds mentioned in this invention can be used as a single (soil) therapeutic agent or in combination with other active agents which include chemotherapeutic agents and anti-inflammatory agents. Such combinations include, but are not limited to, the combination of MEK kinase inhibitors with antimitotic agents, antiangiogenic agents, alkylating agents, antihyperproliferative agents, antimetabolites, DNA intercalating agents, cell cycle inhibitors, kinase inhibitors, factor inhibitors growth, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers or anti-hormones.
[0166] The term “ambient temperature” denotes any temperature in the range from about 20°C to about 40°C, except where specifically mentioned in the specification.
[0167] The intermediates and compounds of the present invention can be obtained in pure form in a manner known per se, for example, by distilling off the solvent in vacuo and recrystallizing the obtained residue from a suitable solvent such as pentane, diethyl ether, ether of isopropyl, chloroform, dichloromethane, ethyl acetate, acetone or combinations thereof or subjecting them to one of the purification methods such as column chromatography (eg flash chromatography) on a suitable support material such as alumina or silica gel which uses eluent such as dichloromethane, ethyl acetate, hexane, methanol, acetone and combinations thereof. A preparatory LC-MS method is also used for the purification of molecules described herein.
[0168] Salts of the compound of formula I can be obtained by dissolving the compound in a suitable solvent, for example, in a chlorinated hydrocarbon such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol, which was then treated with the desired acid or base as described in Berge SM et al. “Pharmaceutical Salts, a review article in the Journal of Pharmaceutical sciences volume 66, pages 1-19 (1977)” and in the handbook of pharmaceutical salts properties, selection and use by PHEinrich Stahland Camille G.wermuth, Wiley-VCH (2002 ). Lists of suitable salts can also be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445 and Journal of Pharmaceutical Science, 66, 2 to 19 (1977). For example, the salt can be an alkali metal (eg sodium or potassium), alkaline earth metal (eg calcium) or ammonium.
[0169] The compound of the invention or a composition thereof can potentially be administered as a pharmaceutically acceptable acid addition, neutralized base or additional salt, formed by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, acid thiocyanic acid, sulfuric acid and phosphoric acid and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid and fumaric acid or by reaction with an inorganic base like sodium hydroxide, potassium hydroxide. Conversion to a salt is accomplished by treating the base compound with at least a stoichiometric amount of an appropriate acid. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol and the like, and the acid is added in a similar solvent. The mixture is kept at a suitable temperature (eg between 0 °C and 50 °C). The resulting salt spontaneously precipitates or can be removed from solution with a less polar solvent.
[0170] The stereoisomer of the compounds of formula I of the present invention can be prepared by stereospecific synthesis or resolution of racemic compound using an optically active amine, acid or complex-forming agent and which separates the diastereomeric salt/complex by fractional crystallization or by column chromatography.
[0171] The compounds of formula I of the present invention may exist in tautomeric forms as keto-enol tautomers. Such tautomeric forms are contemplated as an object of this invention and such tautomers may be in equilibrium or predominant in one of the forms.
[0172] Prodrugs can be prepared in situ during the isolation and purification of the compounds or by separately reacting the purified compound with a suitable derivatizing agent. For example, hydroxy groups can be converted to esters by treatment with a carboxylic acid in the presence of a catalyst. Examples of cleavable alcohol prodrug moieties include substituted or unsubstituted branched or unbranched lower alkyl ester moieties, e.g., ethyl esters, lower alkenyl esters, di-lower alkylamino lower alkyl esters, e.g. dimethylaminoethyl ester, acylamino lower alkyl esters, acyloxy lower alkyl esters (for example pivaloyloxymethyl ester), aryl esters, for example phenyl ester, aryl lower alkyl esters, for example benzyl ester , substituted or unsubstituted, for example, with methyl, halo or methoxy aryl substituents and aryl lower alkyl esters, amides, lower alkyl amides, di-lower alkyl amides and hydroxyamides.
[0173] The term "prodrug" denotes a derivative of a compound whose derivative, when administered to warm-blooded animals, eg, humans, is converted to the compound (drug). the enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a way that the proven drug form (parent carboxylic acid drug) is released and the split portion or portions remain non-toxic or are metabolized such that metabolic products do not toxics are produced. For example, a carboxylic acid group can be esterified, for example, with a methyl group or ethyl group to yield an ester. When an ester is administered to a subject, the ester is cleaved enzymatically or non-enzymatically, reductively, oxidatively or hydrolytically to reveal the anionic group. An anionic group can be esterified with moieties (eg, acyloxymethyl esters) that are cleaved to reveal an intermediate compound that subsequently decomposes to yield the active compound.
[0174] The inhibitors mentioned in the present invention can be combined with anti-inflammatory agents or agents that show therapeutic benefit for conditions including, but not limited to, hepatomegaly, heart failure, cardiomegaly, diabetes, stroke, Alzheimer's disease, cystic fibrosis, shock septic or asthma, diabetic retinopathy, ischemic retinal vein occlusion, macular degeneration, neovascular glaucoma, psoriasis, inflammation, rheumatoid arthritis, restenosis, stent restenosis, and vascular graft restenosis.
[0175] The term "abnormal kinase activity" refers to any abnormal expression or activity of the gene encoding the kinase or the polypeptide encoding the same. Examples of such abnormal kinase activity include, but are not limited to gene or polypeptide overexpression, gene amplification, mutations that produce constitutively active or hyperactive kinase activity, gene mutations, deletions, substitutions, additions and the like.
[0176] Therefore, the present invention further provides a pharmaceutical composition containing the compounds of general formula (I) as defined above, tautomeric forms thereof, stereoisomers thereof, pharmaceutically acceptable salts thereof in combination with normal pharmaceutically acceptable carriers, diluents, excipients and the like.
[0177] The pharmaceutically acceptable carrier or excipient is preferably one that is chemically inert to the compound of the invention and one that has no detrimental side effects or toxicity under the conditions of use. Such pharmaceutically acceptable carriers or excipients include saline (eg, 0.9% saline), Cremophor EL (which is a derivative of castor oil and ethylene oxide available from Sigma Chemical Co., St. Louis, MO, USA ) (e.g. 5% Cremophor EL/5% ethanol/90% saline, 10% Cremophor EL/90% saline or 50% Cremophor EL/50% ethanol), propylene glycol (e.g. 40% propylene glycol/10% ethanol/50% water), polyethylene glycol (eg 40% PEG 400/60% saline) and alcohol (eg 40% ethanol/60% water) . A preferred pharmaceutical carrier is polyethylene glycol such as PEG 400 and particularly a composition comprising 40% PEG 400 and 60% water or saline. The choice of vehicle will be determined in part by the particular compound chosen, as well as the particular method used to administer the composition. Consequently, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.
[0178] The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, intraperitoneal, rectal and vaginal administration are merely exemplary and are in no way limiting.
[0179] Pharmaceutical compositions can be administered parenterally, for example, intravenously, intraarterially, subcutaneously, intradermally, intratracheally, or intramuscularly. Therefore, the invention provides compositions for parenteral administration which comprise a solution of the compound of the invention dissolved or suspended in an acceptable vehicle suitable for parenteral administration which includes aqueous and non-aqueous, isotonic sterile injection solutions.
[0180] In general, the requirements for effective pharmaceutical vehicles for parenteral compositions are well known to those skilled in the art. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238 to 250 (1982) and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622 to 630 (1986). Such compositions include solutions that contain antioxidants, buffers, bacteriostatics, and solutes that make the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound can be administered in a physiologically acceptable diluent in a pharmaceutical vehicle such as a sterile liquid or mixture of liquids that include water, saline, aqueous dextrose and related sugar solutions, an alcohol such as ethanol, isopropanol (eg, in topical applications) or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, an oil, a fatty acid, an ester of fatty acid or glyceride or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant such as a soap or detergent, suspending agent such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose or carboxymethylcellulose or emulsifying agents and other pharmaceutical adjuvants.
[0181] Oils useful in parenteral formulations include petroleum, animal, vegetable and synthetic oils. Specific examples of oils useful in such formulations include peanuts, soybeans, sesame, cotton wool, corn, olive, petrolatum and mineral oil. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid and isostearic acid, ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
[0182] Soaps suitable for use in parenteral formulations include fatty alkali metal, ammonium and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium ammonium halides and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides and copolymers of polyoxyethylene-polypropylene, (d) amphoteric detergents such as, for example, alkyl-β-aminopropionates and 2-alkyl imidazoline quaternary ammonium salts and (e) mixtures thereof.
Parenteral formulations will normally contain from about 0.5% or less to about 25% or more by weight of a compound of the invention in solution. Preservatives and tampons can be used. To minimize or eliminate irritation at the injection site, such compositions may contain one or more non-ionic surfactants that have a hydrophilic-lipophilic (HLB) balance of from about 12 to about 17. The amount of surfactant in such formulations will normally remain low. in the range of about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base formed by the condensation of propylene oxide with propylene glycol. Parenteral formulations may be presented in unit dose or sealed multi-dose containers such as ampoules and vials and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of sterile excipient liquid, eg water, for injections, immediately before use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules and tablets.
[0184] Topical formulations including those that are useful for transdermal drug delivery are well known to those skilled in the art and are useful in the context of the present invention for application to the skin.
[0185] Formulations suitable for oral administration may consist of (a) liquid solutions as an effective amount of a compound of the invention dissolved in diluents such as water, saline or orange juice; (b) capsules, sachets, tablets, tablets and lozenges each containing a predetermined amount of the compound of the invention as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents such as water and alcohols, for example ethanol, benzyl alcohol and polyethylene alcohols or with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. Capsule forms can be of the hard or soft shell gelatin type which contains, for example, surfactants, lubricants and inert fillers such as lactose, sucrose, calcium phosphate and corn starch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, Croscarmellose sodium, talc, magnesium stearate , calcium stearate, zinc stearate, stearic acid and other excipients, colorants, diluents, buffering agents, disintegrating agents, wetting agents, preservatives, flavoring agents and pharmacologically compatible excipients. Tablet forms may comprise the compound ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as tablets which comprise a compound of the invention in an inert base such as gelatin and glycerin or sucrose and acacia, emulsions, gels and the like which contain, in addition to the compound of the invention, such excipients as are known in the art.
[0186] A compound of the present invention, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. A compound or epimer of the invention is preferably supplied in a finely divided form together with a surfactant and propellant. Common percentages of the compounds of the invention can be about 0.01% to about 20% by weight, preferably about 1% to about 10% by weight. The surfactant must, of course, be non-toxic and preferably soluble in the propellant. Representative of such surfactants are esters or partial esters of fatty acids containing 6 to 22 carbon atoms such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or anhydride cyclic. Mixed esters such as mixed or natural glycerides can be used. The surfactant can make up from about 0.1% to about 20% by weight of the composition, preferably from about 0.25% to about 5%. Composition balance is normally propellant. A vehicle can also be included as desired, for example lecithin, for intranasal delivery. These aerosol formulations can be placed in pressurized acceptable propellants such as dichlorodifluoromethane, propane, nitrogen and the like. They can also be formulated as pharmaceuticals for non-pressurized preparations such as in a nebulizer or an atomizer. Such spray formulations can be used to spray mucosa.
[0187] Additionally, the compound of the invention can be manufactured into suppositories by mixing with a variety of bases such as emulsifying bases or water-soluble bases. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulas which contain, in addition to the compound ingredient, such carriers as are known in the art to be appropriate.
[0188] The concentration of the compound in pharmaceutical formulations can range, for example, from less than about 1% to about 10%, to up to about 20% to about 50% or more by weight and can be selected primarily by fluid volumes and viscosities in accordance with the particular mode of administration selected.
[0189] For example, a common pharmaceutical composition for intravenous infusion can be manufactured to contain up to 250 ml of sterile Ringer's solution and 100 mg of at least one compound of the invention. Current methods for preparing parenterally administrable compounds of the invention will be known or apparent to those skilled in the art and are described in more detail in, for example, Remington's Pharmaceutical Science (17th ed., Mack Publishing Company, Easton, PA, 1985).
[0190] It will be noted by a person skilled in the art that, in addition to the pharmaceutical compositions described above, the compound of the invention can be formulated as inclusion complexes such as cyclodextrin, inclusion complexes or liposomes. Liposomes can serve to target a compound of the invention to a particular tissue such as lymphoid tissue or liver cancer cells. Liposomes can also be used to increase the half-life of a compound of the invention. Many methods are available to prepare liposomes as described in, for example, Szoka et al., Ann. Rev. Biophys. Bioeng., 9, 467 (1980) and US Patents 4,235,871, 4,501,728, 4,837,028 and 5,019,369.
[0191] The compounds of the invention can be administered in a dose sufficient to treat the disease, condition or disorder. Such doses are known in the art (see, for example, the Physicians’ Desk Reference (2004)). The compounds can be administered by using techniques such as those described in, for example, Wasserman et al., Cancer, 36, pages 1258 to 1268 (1975) and Physicians' Desk Reference, 58aed., Thomson PDR (2004).
[0192] Appropriate doses and dosing regimens can be determined by conventional range finding techniques known to those of skill in the art. Generally, treatment is initiated with lower dosages that are less than the optimal dose of the compound of the present invention. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. The present method may involve administering from about 0.1 µg to about 50 mg of at least one compound of the invention per kg of subject body weight. For a 70 kg patient, dosages of about 10 µg to about 200 mg of the compound of the invention would be used more commonly depending on the patient's physiological response.
[0193] As an example and without limiting the invention, the dose of the pharmaceutically active agent(s) described herein for methods of treating or preventing a disease or condition as described above may be from about 0.001 to about 1 mg/ kg of subject's body weight per day, for example, about 0.001mg, 0.002mg, 0.005mg, 0.010mg, 0.015mg, 0.020mg, 0.025mg, 0.050mg, 0.075mg, 0.1mg, 0.15mg , 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg or 1 mg/kg body weight per day. The dose of the pharmaceutically active agent(s) described herein for the methods described can be about 1 to about 1000 mg/kg of body weight per day of the subject being treated, for example, about 1 mg, 2 mg, 5mg, 10mg, 15mg, 0.020mg, 25mg, 50mg, 75mg, 100mg, 150mg, 200mg, 250mg, 500mg, 750mg or 1000mg/kg body weight per day.
[0194] The terms "treat", "avoid", "alleviate" and "inhibit", as well as words arising therefrom, as used herein, do not necessarily imply 100% or treatment, prevention, amelioration or complete inhibition. Rather, there are varying degrees of treatment, prevention, amelioration and inhibition which one skilled in the art recognizes as having a potential benefit or therapeutic effect. In that regard, the disclosed methods can provide any amount of any level of treatment, prevention, alleviation or inhibition of the disorder in a mammal. For example, a disorder that includes symptoms or conditions thereof can be reduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20% or 10%. Furthermore, the treatment, prevention, alleviation or inhibition provided by the inventive method may include treatment, prevention, alleviation or inhibition of one or more conditions or symptoms of the disorder, for example cancer. In addition, for the purposes of this document, “treatment,” “prevention,” “alleviating,” or “inhibition” may encompass delaying the onset of the disorder or a symptom or condition thereof.
[0195] According to the invention, the term subject includes an "animal" which in turn includes a mammal such as, without limitation, the order Rodents as mouse and the order Lagomorphs as rabbits. In one aspect, mammals are of the order Carnivora which includes Felines (cats) and Canines (dogs). In another aspect, mammals are of the order Artiodactyls which includes Bovines (cows) and Swine (pigs) or of the order Perissodactyls which includes Equines (horses). In an additional aspect, mammals are of the order Primates, Ceboids or Simoids (monkeys) or of the order Anthropoids (humans and gorillas). In yet another aspect, the mammal is human. GENERAL PREPARATION METHOD
[0196] Compounds of general formula (I) where all symbols are as defined above may be prepared by methods given in the schemes below or examples illustrated herein below.
[0197] However, the disclosure should not be construed as limiting the scope of the invention that reaches the compound of formula (I) disclosed in this document above. SCHEME 1 (R1 IS H)
[0198] The compound of formula (I) where R 1 is H can be prepared as disclosed in Scheme 1, details of which are given below.
STEP 1
[0199] Compound of formula (II) where R 1 is N protecting group can be converted to compound of formula (III) by reaction of compound of (II) (Prepared as per reference WO2005121142) (Z is any suitable leaving group as Cl, Br, I, -O(SO)2(4-MePh), -O(SO)2CH3, -O(SO)2CF3 etc.) with R2NH2 in the presence of a suitable base such as 2,6-Lutidine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), K2CO3, Cs2CO3, NaH, KH, n-BuLi, lithium bis(trimethylsilyl)amide (LiHMDS) etc. in a solvent similar to THF, DMF, DMSO etc. temperature in the range of about -78 °C to about 150 °C. STEP-2
[0200] Compound of formula (III) where R1 is N-protecting group can be converted to compound of formula-(IV) by reacting compound of formula (III) with suitable base like NaOMe, K2CO3 etc. in a solvent similar to Methanol, Ethanol, THF, DMF etc. temperature in the range of about -78 °C to about 150 °C. STEP-3
[0201] Compound of formula (IV) where R 1 is N protecting group can be converted to compound of formula (I) by reacting compound of formula (IV) with suitable N protecting agents like AlCl 3 , Pd-C /H2 etc. in a solvent similar to Anisole, Toluene, Xylene, THF, DMF, DMSO etc. temperature in the range of about -78 °C to about 150 °C. SCHEME-2:
[0202] Compound of formula (I), where R 1 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl, can be prepared as disclosed in Scheme 2, details of which are given below.
STEP 1
[0203] Compound of formula (Ia), where R1 is H, can be converted to compound of formula (I) by reacting compound of I with R1Z (Z is any suitable leaving group like Cl, Br, I, - O(SO)2(4-MePh), -O(SO)2CH3, -O(SO)2CF3 etc.) in the presence of a suitable base such as 2,6-Lutidine, 1,8-Diazabicyclo[5.4.0] undec-7-ene (DBU), K2CO3, Cs2CO3, NaH, KH, n-BuLi, lithium bis(trimethylsilyl)amide (LiHMDS) etc., in a solvent similar to THF, DMF, DMSO etc., at the temperature in the range from about -78 °C to about 150 °C. SCHEME-3:
[0204] A compound of formula (I) where R 1 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl may be prepared as disclosed in Scheme 3, details of which are given below.
STEP 1
[0205] A compound of formula (II) where R 1 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted or unsubstituted heterocyclyl, can be converted to the compound of formula (III) by the reaction of the compound of II (Z is any suitable leaving group like Cl, Br, I, -O(SO) 2(4-MePh), -OCSOhCHs, -OCSOhCFs etc.) with R2NH2 in the presence of a suitable base such as 2,6-Lutidine, 1,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), K2CO3, Cs2CO3, NaH, KH, n-BuLi, lithium bis(trimethylsilyl)amide (LiHMDS) etc., in a solvent similar to THF, DMF, DMSO and the like, at a temperature in the range of about -78 °C to about 150 °C. STEP-2
[0206] Compound of formula (III) wherein R 1 is selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and substituted or unsubstituted heterocyclyl can be converted to the compound of formula (I) by reacting the compound of formula (III) with suitable base such as NaOMe, K2 CO3 etc. in a solvent similar to Methanol, Ethanol, THF, DMF etc. temperature in the range of about -78 °C to about 150 °C.
[0207] The intermediates and compounds of the present invention are obtained in pure form in a manner known per se, for example, by distilling off the solvent in vacuo and recrystallizing the obtained residue from a suitable solvent such as pentane, diethyl ether, diethyl ether. isopropyl, chloroform, dichloromethane, ethyl acetate, acetone or combinations thereof or subjecting them to one of the purification methods such as column chromatography (eg flash chromatography) on a suitable support material such as alumina or silica gel using eluent such as dichloromethane, ethyl acetate, hexane, methanol, acetone and combinations thereof. The preparatory LC-MS method is also used for the purification of molecules described herein.
[0208] Salts of the compound of formula I are obtained by dissolving the compound in a suitable solvent, for example, in a chlorinated hydrocarbon such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol which has been then treated with the desired acid or base as described in Berge SM et al. “Pharmaceutical Salts, a review article in the Journal of Pharmaceutical sciences volume 66, pages 1-19 (1977)” and in the “Handbook of pharmaceutically salts properties, selection and use” by PHEinrich Stahland Camille G.wermuth, Wiley-VCH ( 2002).
[0209] The stereoisomer of the compounds of formula I of the present invention can be prepared by stereospecific synthesis or resolution of the achiral compound using an optically active amine, acid or complex-forming agent and which separates the diastereomeric salt/complex by fractional crystallization or by column chromatography.
[0210] The following examples are provided to further illustrate the present invention and therefore should not be construed in any way as limiting the scope of the present invention. All 1HNMR spectra were determined in the indicated solvents and chemical shifts are reported in δ units downstream of the internal tetramethylsilane (TMS) standard and interproton binding constants are reported in Hertz (Hz). EXAMPLES
[0211] Unless otherwise noted, development includes distributing the reaction mixture between the organic and aqueous phase indicated in parentheses, layer separation and drying of the organic layer over sodium sulfate, filtration and solvent evaporation. Purification, unless otherwise noted, includes purification by silica gel chromatographic techniques, which generally use a mobile phase of suitable polarity. The following abbreviations are used in the text: DMSO-d6: Hexadeuterodimethyl sulfoxide; DMSO: Dimethylsulfoxide, CDI: 1,1'-Carbonyldiimidazole, DMF: N,N-dimethyl formamide, DMA: Dimethylacetamide, HBTU: 2-(1H-Benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate, THF: Tetrahydrofuran, DCM: Dichloromethane, EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide, HATU: O-(7-Azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, DIPEA: N,N-Diisopropyl ethyl amine, HOBT: 1-Hydroxy-1H-benzotriazole, J: Binding constant in units of Hz, RT or rt: room temperature (22 to 26°C), Aq.: aqueous , AcOEt: ethyl acetate, equiv. or eq.: equivalents and hr. or h: hour(s);
[0212] The following examples demonstrate preparation of a few representative compounds incorporated into formula (I); however, it should not be construed as a limitation on the scope of the invention. INTERMEDIARIES:
[0213] Intermediate-i: Preparation of (3-aminophenyl)(azetidin-1-yl)methanone

[0214] Step a: Synthesis of 3-((tert-butoxycarbonyl)amino)benzoic acid:
[0215] To a stirred solution of 3-aminobenzoic acid (5 g, 36.5 mmol) in water (40.0 ml) was added aq. of sodium hydroxide (2.187 g, 54.7 mmol) followed by (BOC)2O (10.16 ml, 43.8 mmol) in dioxane (20.0 ml) under frozen cooling. The mixture was stirred under frozen cooling for 30 min and additionally at room temperature for 12 hours. To the reaction mixture, ethyl acetate (50.0 ml) was added and the aq. was separated. The aq layer. was acidified to pH 4 using 2N HCl and precipitated crystals were collected by filtration (7.2 g).
[0216] 1H NMR (400 MHz, DMSO-d6) δ 12.80 (brs, 1H), 9.54 (s, 1H), 8.14 (s, 1H), 7.62 (dd, 1H, J =0.8Hz, J=8Hz), 7.54 to 7.52 (m, 1H), 7.35 (t, 1H, J=7.6Hz), 1.48 (s, 9H).
[0217] Step b: Synthesis of tert-butyl (3-(azetidine-1-carbonyl)phenyl)carbamate
[0218] To a stirred solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (1.5 g, 6.32 mmol) in DMF (15 ml) was added N,N-diisopropyl ethylamine (2.208 ml, 12 .64 mmol) and o-Benzotriazol-1-yl-tetramethyluronium hexafluorophosphate (2.398 g, 6.32 mmol) followed by azetidine hydrochloride (1.183 g, 12.64 mmol) at room temperature under a nitrogen atmosphere. The reaction was stirred at room temperature for 24 h and monitored by TLC. To the reaction mixture, water (25.0 ml) was added and extracted with ethyl acetate (30 ml x 3). The aqueous layer was re-extracted with ethyl acetate. All organic layers were combined and washed with cold water (20.0 ml) and brine (20 ml); dried over sodium sulfate and solvent was evaporated under vacuum to obtain the title compound (1.1 g).
[0219] 1H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1H), 7.74 to 7.73 (m, 1H), 7.56 to 7.52 (m, 1H), 7 .31 (t, 1H, J=8 Hz), 7.19 to 7.16 (m, 1H), 4.25 (t, 2H, J=8 Hz), 4.01 (t, 2H, J= 7.6), 2.32 to 2.22 (m, 2H), 1.47 (s, 9H). ESI-MS: [m/z: 277.09 (M+1)].
[0220] Step c: Synthesis of (3-aminophenyl)(azetidin-1-yl)methanone
[0221] To a stirred solution of tert-butyl(3-(azetidine-1-carbonyl)phenyl)carbamate (600 mg, 2.171 mmol) in DCM (5.0 ml) was added trifluoroacetic acid (0.167 ml, 2.171 mmol) at 0 °C under nitrogen atmosphere. The reaction was stirred at room temperature for 1 hr. The Solvent evaporated to dryness and the residual solid was dissolved in DCM (20ml) and washed with saturated NaHCO3 solution. The DCM layer was dried over sodium sulphate and evaporated under vacuum. The resulting solid was washed with pentane and ether to furnish the title compound (310 mg).
[0222] 1H NMR (400 MHz, DMSO-d6) δ 7.04 (t, 1H, J=8 Hz), 6.80 (t, 1H, J=2Hz), 6.70 to 6.67 (m , 1H), 6.65 to 6.62 (m, 1H), 5.24 (s, 2H), 4.25 (t, 2H, J=7.6Hz), 3.98 (t, 2H, J=7.6Hz), 2.24 to 2.18 (m, 2H). GCMS: 176.13 [M+].
[0223] Intermediate-ii: Synthesis of 2-(3-aminophenyl)-N-cyclopropylacetamide

[0224] Step a: Synthesis of N-cyclopropyl-2-(3-nitrophenyl)acetamide
[0225] To a stirred solution of 2-(3-nitrophenyl)acetic acid (2.5 g, 13.80 mmol) in DMF (20 ml) was added HBTU (4.19 g, 16.56 mmol), N ,N-diisopropyl ethylamine (4.82 ml, 27.6 mmol) followed by addition of cyclopropylamine (1.946 ml, 27.6 mmol) at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 hours, the reaction mixture was diluted with water (80.0 ml) and extracted with ethyl acetate (20.0 ml x 3). Combined organic layers were washed with cold water (20.0 ml) and brine (10.0 ml); dried over sodium sulfate. The solvent was evaporated in vacuo to give the crude compound which was purified by column chromatography to give the title compound (2.41g).
[0226] 1H NMR (400 MHz, DMSO-d6) δ 8.25 (d, 1H, J= 2.4 Hz), 8.12 to 8.09 (m, 1H), 7.67 (d, 1H) , J=7.6Hz), 7.60 (t, 1H, J=7.6Hz), 3.52 (s, 2H), 2.63 to 2.58 (m, 1H), 0.63 to 0.55 (m, 2H), 0.41 to 0.37 (m, 2H), GCMS: 221.09 [M+]
[0227] Step b: Synthesis of 2-(3-aminophenyl)-N-cyclopropylacetamide
[0228] To a stirred solution of N-cyclopropyl-2-(3-nitrophenyl) acetamide (2.4 g, 10.90 mmol) in methanol (25.0 ml) was added Pd/C slurry (10%, 0.232 g). To the above reaction mixture, triethylsilane (8.70 ml, 54.5 mmol) was added dropwise slowly at room temperature (reaction was exothermic) and then the reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was filtered through a bed of celite and the filtrate was evaporated under vacuum. The residue was triturated in hexane, the solid obtained was filtered and dried under vacuum to furnish the product (1.95 g).
[0229] 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 6.90 (t, 1H, J=7.6Hz), 6.49 to 6.35 (m, 1H) ), 5.02 (s, 2H), 3.15 (s, 2H), 2.60 to 2.59 (m, 1H), 0.69 to 0.58 (m, 2H), 0.48 to 0.38(m, 2H). GCMS: 190.11 [M+].
[0230] Intermediate-iii: Synthesis of 2-(3-aminophenoxy)-N-cyclopropylacetamide

[0231] Step a: Synthesis of N-cyclopropyl-2-(3-nitrophenoxy)acetamide
[0232] A mixture of 3-nitrophenol (4 g, 28.8 mmol), 2-chloro-N-cyclopropylacetamide (4.61 g, 34.5 mmol), K2CO3 (7.95 g, 57.5 mmol) and 18-CROWN-6 (0.228 g, 0.863 mmol) in N,N-Dimethylformamide (30.0 ml) was stirred under N 2 atmosphere for 18 hours at 50 °C. After cooling to RT, the reaction mixture was partitioned between EtOAc (250 ml) and water (250 ml). The phase here it was re-extracted with EtOAc (200 ml). The combined organic layer was washed with brine (100 ml), dried over sodium sulphate and the solvent evaporated in vacuo. The crude residue was purified by flash chromatography to obtain N-cyclopropyl-2-(3-nitrophenoxy)acetamide (4.21 g).
[0233] 1H NMR(400MHz,DMSO-d6) δ 7.85 to 7.82 (m, 1H), 7.76 to 7.74(m, 1H), 7.59 (t, J = 8. 4Hz, 1H), 7.44 to 7.41 (m, 1H), 4.60 (s, 2H), 2.72 to 2.66 (m, 1H), 0.67 to 0.60 (m , 2H), 0.50 to 0.46 (m, 2H). GCMS: 236.14 [M+].
[0234] Step b: Synthesis of 2-(3-aminophenoxy)-N-cyclopropylacetamide
[0235] Triethylsilane (27.0 ml, 169 mmol) was added dropwise to a suspension of N-cyclopropyl-2-(3-nitrophenoxy)acetamide (4 g, 16.93 mmol) and Pd/C (10% , 400 mg) in MeOH (50 ml). The resulting Suspension was stirred at RT for 20 min. and filtered through celite. The filtrate was evaporated under vacuum and triturated in hexane to obtain crystals which were collected by filtration to provide 2-(3-aminophenoxy)-N-cyclopropylacetamide (2.86 g).
[0236] 1H NMR(400 MHz,DMSO-d6) δ 6.89 (t, J = 8.0 Hz, 1H), 6.18 to 6.12 (m, 2H), 6.07 to 6.04 (m, 1H), 5.21 (brs, 1H), 5.08 (s, 2H), 4.29 (s, 2H), 2.70 to 2.66 (m, 1H), 0.62 to 0.59 (m, 2H), 0.50 to 0.45 (m, 1H). GCMS: 206.11 [M+].
[0237] Intermediate-iv: Synthesis of (3-aminophenyl)(1,1-dioxidothiazolidin-3-yl)methanone

[0238] Step a: Synthesis of (3-nitrophenyl)(thiazolidin-3-yl)methanone
[0239] To a stirred solution of 3-nitrobenzoyl chloride (5.00 g, 26.9 mmol) in DCM (50 ml), thiazolidine (3.60 g, 40.4 mmol) was added at 0 °C. Triethylamine (7.51 ml, 53.9 mmol) was added dropwise into the reaction mixture over 5 min and the reaction mixture was stirred at RT for 1 hr. The reaction mixture was diluted with cold water. The organic phase was separated and the aq. was extracted using DCM (3 X 10.0 ml). The combined organic layer was washed with brine (100ml), dried over sodium sulphate and the solvent evaporated in vacuo to provide the title compound (5.0g).
[0240] 1HNMR (400 MHz, DMSO-d6), δ 8.35 to 8.31 (m, 2H), 8.01 to 7.98(m, 1H), 7.79 (t, 1H, J= 8 Hz), 4.65 to 4.52 (m, 2H), 3.84 to 3.70 (m, 2H), 3.08 to 2.97 (m, 2H). GCMS: 237.96 [M+].
[0241] Step b: Synthesis of (1,1-dioxidothiazolidin-3-yl)(3-nitrophenyl)methanone
[0242] To a stirred solution of (3-nitrophenyl)(thiazolidin-3-yl)methanone (4 g, 16.79 mmol) in acetic acid (30 ml), H2O2 (12 ml, 30% solution) was added , the resulting mixture was stirred at 100°C for 3 hours. The mixture was concentrated in vacuo and the residue treated with MeOH. The resulting solid was filtered and dried under vacuum to provide the title compound (3 g).
[0243] 1HNMR (400 MHz, DMSO-d6), δ 8.39 to 8.32 (m, 2H), 7.99 to 7.97 (m, 1H), 7.79 (t, 1H J=7 0.6Hz), 4.69 (s, 2H), 4.20 to 3.90 (m, 2H), 3.51 to 3.47(m,2H). ESI-MS: [m/z: 270.08 (M+1)].
[0244] Step c: Synthesis of (3-aminophenyl)(1,1-dioxidothiazolidin-3-yl)methanone
[0245] A solution of (1,1-dioxidothiazolidin-3-yl)(3-nitrophenyl)methanone (3 g, 11.10 mmol) in MeOH (30 ml) and 10% Pd-C (300 mg) was stirred under H2 (1 atm) overnight. The reaction mixture was filtered through a celite pad and the filtrate evaporated under vacuum to provide the title compound (2.3 g).
[0246] 1HNMR (400 MHz, DMSO-d6), δ 7.12 to 7.08 (m, 1H), 6.84 to 6.70 (m, 1H), 6.61 to 6.59(d, 1H, J=8 Hz), 5.35 (s, 2H), 4.60 (s, 2H), 4.05 to 4.00 (m, 2H), 3.45 to 3.41 (m, 2H) ). ESI-MS: [m/z = 241.71 (M+1)].
[0247] Intermediate-v: Synthesis of (3-aminophenyl)(1,1-dioxidothiomorpholino) methanone

[0248] Step a: Synthesis of (3-nitrophenyl)(thiomorpholino)methanone
[0249] To a suspension of 3-nitrobenzoic acid (6.5 g, 38.9 mmol) in DCM (50 ml) was added oxalyl chloride (5 ml, 58.1 mmol) and DMF (0.5 ml, 6.46 mmol) respectively. The resulting mixture was stirred at room temperature until a clear solution formed. The solvent was removed under vacuum. The 3-nitrobenzoyl chloride thus obtained was dissolved in DCM (50 ml), Et3N (10.13 ml, 72.7 mmol) and thiomorpholine (5 g, 48.5 mmol) was added at 0°C. The reaction mixture was allowed to gradually come to room temperature and stirred for 2 hours. The reaction mixture was concentrated under vacuum and cold water was added to the residue, the solid obtained was filtered and dried under vacuum to furnish the product (9.2 g).
[0250] 1HNMR (400 MHz, DMSO-d6), δ 8.30 to 8.28 (m, 1H), 8.26 to 8.22 (m, 1H), 7.87 to 7.84 (m, 1H), 7.74 (t, 1H, J=8 Hz), 3.88 (brs, 2H), 3.52 (brs,2H), 2.71 (brs,2H), 2.60 (brs, 2H), 2H). ESI-MS: [m/z = 252.7 (M+1)].
[0251] Step b: Synthesis of (1,1-dioxidothiomorpholino) (3-nitrophenyl) methanone
[0252] To a stirred solution of (3-nitrophenyl)(thiomorpholino)methanone (12 g, 47.6 mmol) in acetic acid (80 ml) was added H2O2 (45 ml, 30% solution), the reaction mixture. was heated to 90 °C for 3 hr. Solvents were evaporated under vacuum, the residue was dissolved in DCM:MeOH (20:20 ml) and passed through a bed of celite. The filtrate was concentrated under vacuum to obtain the crude product (7.3 g).
[0253] 1HNMR (400 MHz, DMSO-d6), δ 8.41 to 8.40 (m, 1H), 8.33 to 8.30 (m, 1H), 7.94 to 7.91 (m, 1H), 1H), 7.76 (t, 1H, J=8Hz), 4.03 (brs, 2H), 3.66 (brs,2H), 3.33 to 3.16 (m,4H). ESI-MS: [m/z = 284.6 (M+1)].
[0254] Step c: Synthesis of (3-aminophenyl) (1,1-dioxidothiomorpholino)methanone
[0255] To a stirred solution of (1,1-dioxidothiomorpholino)(3-nitrophenyl)methanone (3.5 g, 12.31 mmol) in MeOH (20 ml) was added Pd-C (10%, 350 mg) followed by slow addition of triethylsilane (8.5 ml) at RT. The reaction was stirred at RT for 1h. The reaction mixture was filtered through celite and washed with methanol (50ml). The filtrate was concentrated in vacuo and triturated in hexane to obtain the crude product (2.8 g).
[0256] 1HNMR (400 MHz, DMSO-d6), δ (t, 1H,J=7.6Hz), 6.63 to 6.56 (m, 3H), 5.28 (s, 3.73 ( m,4H), 3.16(brs,4H) GCMS: 254.09 [M+]
[0257] Intermediate-vi: Synthesis aminophenyl)-2-methylpropanamide

[0258] Step a: Synthesis of 2-methyl-2-(3-nitrophenyl)propanenitrile
[0259] To a frozen slurry of 50% NaH (6.84 g, 171 mmol) in anhydrous THF (30.0 ml) was slowly added a solution of 2-(3-nitrophenyl) acetonitrile (4.2 g, 25.9 mmol) in anhydrous THF (30 ml). After 30 min, methyl iodide (12.63 ml, 202 mmol) was slowly added. The reaction mixture was allowed to warm to room temperature and stirred overnight. It was then quenched with ice water. The reaction mixture was then extracted with ethyl acetate, the organic layer was separated and washed with water, dried over anhydrous sodium sulfate; filtered and concentrated to obtain crude oil. The crude oil purified by column chromatography on silica gel eluting with ethyl acetate/hexane (5:95) provided 2-methyl-2-(3-nitrophenyl)propanenitrile (2.1 g).
[0260] 1HNMR (400 MHz, CDCl3), δ 8.33 to 8.32 (m, 1H), 8.24 to 8.21 (m, 1H), 7.92 to 7.89 (m, 1H) , 7.63 (t, J=8.00 Hz, 1H), 1.82(s, 6H).GCMS:190.11[M+]
[0261] Step b: Synthesis of 2-methyl-2-(3-nitrophenyl)propanamide
[0262] To a solution of 2-methyl-2-(3-nitrophenyl)propanenitrile (1.5 g, 7.89 mmol) in 2-propanol was added benzyltriethyl ammonium chloride (0.054 g, 0.237 mmol) and 25% of solution aq. of KOH (5.0 ml). The resulting solution was stirred for 5 min. and H2O2 (2.5 ml, 30% aq. solution) was added (slow addition). The reaction mixture was heated to 75 °C for 4 hr. The solvent was evaporated under vacuum and the residue was suspended in water (200 ml). The precipitate was filtered and dried to obtain 2-methyl-2-(3-nitrophenyl)propanamide (0.98 g).
[0263] 1HNMR (400 MHz, DMSO-d6), δ 8.15 to 8.10 (m, 2H), 7.80 (d, J=7.6Hz, 1H), 7.64 (t, J = 8.00 Hz, 1H), 7.11 (brs., 1H), 7.05 (brs., 1H) 1.50 (s, 6H).
[0264] Step c: Synthesis of 2-(3-aminophenyl)-2-methylpropanamide
[0265] To a stirred solution of 2-methyl-2-(3-nitrophenyl)propanamide (0.9 g, 4.32 mmol) in methanol was added Pd-C (10%, 0.23 g) followed by addition triethylsilane (6.90 ml, 43.2 mmol) at RT. The reaction was stirred at the same temperature for 25 min. The reaction mixture was filtered through a bed of celite and washed with methanol (50 ml). The filtrate was collected and concentrated in vacuo to obtain 2-(3-aminophenyl)-2-methylpropanamide (0.611 g).
[0266] 1HNMR (400MHz, DMSO-d6), δ 6.93 (t, J=8.0Hz, 1H), 6.78 (brs., 1H), 6.72 (brs., 1H), 6.55 to 6.47 (m, 2H), 6.41 to 6.38 (m, 1H), 4.98 (s, 2H), 1.35 (s, 6H). GCMS:178.15 [M+].
[0267] Intermediate-vii: Synthesis of 2-(3-aminophenyl)-2,2-difluoroacetamide

[0268] Step a: Synthesis of Ethyl 2,2-difluoro-2-(3-nitrophenyl)acetate
[0269] To a solution of 1-iodo-3-nitrobenzene (1.450 g, 5.82 mmol) and ethyl 2-bromo-2,2-difluoroacetate (1.3 g, 6.40 mmol) in anhydrous DMSO (10 ml) was added copper powder (0.740 g, 11.64 mmol). The mixture was purged with N2 and heated to 70 °C in a sealed bottle for 17 h. After being cooled to room temperature, the reaction mixture was poured into 20% aqueous NH 4 Cl solution (100 ml) and extracted with EtOAc (2 x 100 ml). The organic extract was washed with brine (2 x 30 ml), dried over Na2SO4 and concentrated. The residue was purified by flash chromatography to obtain ethyl 2,2-difluoro-2-(3-nitrophenyl) acetate (0.714 g).
[0270] 1HNMR (400 MHz, DMSO-d6), δ 8.47 (d, J=6.8 Hz, 1H), 8.33 (s, 1H), 8.09 (dd, J=0.8 & 8 Hz, 1H), 7.89 (t, J=8.4 Hz, 1H), 4.3 (q, J=9.2 Hz, 2H), 1.24 (t, J=6.4 Hz, 3H). GCMS: 245.15 [M+].
[0271] Step b: Synthesis of 2,2-difluoro-2-(3-nitrophenyl) acetamide
[0272] A solution of ethyl 2,2-difluoro-2-(3-nitrophenyl) acetate (0.701 g, 2.86 mmol) in methanolic ammonia (7M, 20.0 ml) was taken up in a sealed pipette. The resulting mixture was heated at 75°C for 3 hours. The reaction mixture was concentrated in vacuo and cold water was added to obtain the precipitate. The solid was filtered to obtain 2,2-difluoro-2-(3-nitrophenyl) acetamide (0.515 g).
[0273] 1HNMR (400 MHz, DMSO-d6), δ 8.55 (brs., 1H), 8.44 to 8.37 (m, 2H), 8.18 (brs., 1H), 8.04 (d, J=7.6Hz, 1H), 7.86 (t, J=8Hz, 1H). GCMS: 215.98 [M+]
[0274] Step c: Synthesis of 2-(3-aminophenyl)-2,2-difluoroacetamide
[0275] To a stirred solution of 2,2-difluoro-2-(3-nitrophenyl)acetamide (0.5 g, 2.313 mmol) in methanol (20 ml) was added Pd-C (100 mg) followed by slow addition of triethylsilane (3.7 ml, 23.13 mmol) at RT. The reaction was stirred at the same temperature for 30 min. The reaction mixture was filtered through a bed of celite and washed with methanol (50 ml). The filtrate was collected and concentrated in vacuo to obtain 2-(3-aminophenyl)-2,2-difluoroacetamide (0.301 g).
[0276] 1HNMR (400 MHz, DMSO-d6), δ 8.21 (brs., 1H), 7.90 (brs., 1H), 7.11 (t, J=7.6Hz, 1H), 6.75 (s, 1H), 6.67 (d, J=7.6Hz, 2H), 5.42 (s, 2H). GCMS:186.01 [M+].
[0277] Intermediate-viii: Synthesis of 2-(3-aminophenyl)-N,N-dimethylacetamide

[0278] Step a: Synthesis of N,N-dimethyl-2-(3-nitrophenyl)acetamide
[0279] To a stirred solution of 2-(3-nitrophenyl)acetic acid (0.2 g, 1.104 mmol) in THF (6 ml) was added CDI (0.269 g, 1.656 mmol). The resulting mixture was heated at 50 °C for 1 hr, cooled to room temperature and then dimethyl amine hydrochloride (0.108 g, 1.325 mmol) and Et3N (0.15 ml, 1.104 mmol) were added sequentially. The resulting reaction mixture was stirred for 24 h at room temperature. Solvents were evaporated under vacuum. The residue was purified by flash chromatography to obtain N,N-dimethyl-2-(3-nitrophenyl) acetamide (0.192, 84% yield).
[0280] 1HNMR (400 MHz, DMSO-d6), δ 8.11 to 8.08 (m, 2H), 7.68 to 7.58 (m, 2H), 3.89 (s, 2H), 3 .05 (s, 3H), 2.85 (s, 3H). GCMS: 208.12 [M+].
[0281] Step b: Synthesis of 2-(3-aminophenyl)-N,N-dimethylacetamide
[0282] To a stirred solution of N,N-dimethyl-2-(3-nitrophenyl)acetamide (1.6 g, 7.68 mmol) in methanol (20 ml) was added 10% Pd-C (0.327 g ,) followed by slow addition of triethylsilane (12.3 ml, 77 mmol) at RT. The reaction was stirred at the same temperature for 30 min. The reaction mixture was filtered through a bed of celite. The filtrate was concentrated to obtain 2-(3-aminophenyl)-N,N-dimethylacetamide (1.21 g, 88% yield).
[0283] 1HNMR (400 MHz, DMSO-d6), δ 6.92 (t, J=7.6Hz, 1H), 6.43 to 6.34 (m, 3H), 5.05 (s, 2H) ), 3.49 (s, 2H), 2.95 (s, 3H), 2.81 (s, 3H). GCMS:178.15 [M+].
[0284] Intermediate-ix: Synthesis of 3-(3-aminophenyl)-N-methylpropanamide

[0285] Step a: Synthesis of N-methyl-3-(3-nitrophenyl)acrylamide
[0286] To a solution of 3-nitrocinnamic acid (5.0 g) in dry Toluene (100 ml), oxalyl chloride (11.33 ml) was carefully added followed by dry DMF (0.1 ml). The resulting yellow solution was refluxed for 3 hours and then evaporated to dryness to obtain 3-nitro cinnamoyl chloride as a solid residue. This solid residue was dissolved in THF, the resulting solution was cooled to 0 °C and 2M methylamine (13 ml) was added to the reaction mixture, the reaction mixture was stirred for 30 min. The solvents were evaporated under vacuum, the crude material was recrystallized from diethylether to provide the title compound (4g).
[0287] 1HNMR (400 MHz, DMSO-d6), δ 8.38 (s,1H), 8.26 to 8.25 (d, 1H J=4.4 Hz), 8.20 to 8.18 ( m,1H), 8.02 to 8.00 (d,1H J=7.6Hz), 7.72 to 7.68 (m,1H) 7.56 to 7.52 (d,1H J=16 Hz), 6.85 to 6.81 (d, 1H, J=15.6 Hz), 2.71 to 2.70 (d, 3H J=4.4 Hz). GCMS: 207.05 [M+].
[0288] Step b: Synthesis of 3-(3-aminophenyl)-methyl propanamide
[0289] To a stirred solution of N-methyl-3-(3-nitrophenyl)acrylamide (4 g, 19.40 mmol) and Pd-C (10%, 200 mg) in MeOH (30.0 ml) was added triethylsilane (31 ml, 194 mmol) dropwise at room temperature over a period of 1 hr. Reaction progress was monitored by TLC. After completion of the reaction, the reaction mixture was filtered through a bed of celite. The filtrate was concentrated in vacuo to furnish the title compound (2.5g).
[0290] 1HNMR (400 MHz, DMSO-d6), δ 7.76 to 7.75 (d,1H,J=4Hz), 6.96 to 6.88 (m,1H), 6.38 to 6 .32 (m,3H), 5.10 (s,2H), 2.62 to 2.58 (t,2H J=6.8 Hz), 2.55 to 2.54 (d,3H J=4 .4 Hz) 2.32 to 2.25 (t,2H J=6.9 Hz). GCMS: 177.88 [M+].
[0291] Intermediate-x: Synthesis of (3-aminophenyl)(4-hydroxypiperidin-1-yl)methanone

[0292] Step a: Synthesis of (4-hydroxypiperidin-1-yl)(3-nitrophenyl) methanone
[0293] To a stirred solution of 3-nitrobenzoyl chloride (10.0 g, 53.9 mmol) in DCM (10 ml) was added piperidin-4-one hydrochloride (10.96 g, 81.0 mmol) and triethylamine (22.53 ml, 162.0 mmol). The reaction mixture was stirred at room temperature for 30 min and evaporated to dryness. The crude material was treated with diethyl ether, the solid obtained was filtered and dried under vacuum to give the title compound (9.0 g).
[0294] 1HNMR (400 MHz,CDCl3), δ 8.35 to 8.32 (m, 2H), 7.82 (d, 1H, J=7.6Hz), 7.69 to 7.65 (m , 1H), 4.12 (bs, 2H), 3.77 (bs, 2H), 2.55 (bs, 4H). GCMS: 248.11 [M+].
[0295] Step-b: Synthesis of (4-hydroxypiperidin-1-yl)(3-nitrophenyl)methanone
[0296] To a stirred solution of 1-(3-nitrobenzoyl) piperidin-4-one (1.5 g, 6.04 mmol) in THF:Methanol (20 ml, 1:1) was added sodium borohydride ( 0.229 g, 6.04 mmol) at room temperature. The reaction mixture was stirred at room temperature for 30 min. and diluted with water (20.0 ml), extracted with ethyl acetate (3 X 30.0 ml). The combined organic layer was dried over sodium sulfate and solvents were removed under vacuum to obtain the title compound. (1 g).
[0297] 1HNMR (400 MHz, DMSO-d6), δ 8.30 to 8.27 (m,1H), 8.17 to 8.16 (m,1H), 7.85 to 7.83 (m, 1H), 7.74 (t,1H, J=7.6Hz), 4.81 (bs,1H), 3.98 (bs,1H), 3.77 to 3.72 (m,1H), 3.42 (bs,1H), 3.28 (bs,1H), 3.13 (bs,1H), 1.68 (bs, 1H), 1.53 (bs, 1H) 1.42 (bs, 1H) 1.35 (bs, 1H). GCMS: 250.19 [M+].
[0298] Step-c: Synthesis of (3-aminophenyl)(4-hydroxypiperidin-1-yl) methanone
[0299] To a stirred solution of (4-hydroxypiperidin-1-yl)(3-nitrophenyl)methanone (1 g, 4.00 mmol) and Pd-C (10%, 0.425 g,) in methanol (10 ml) triethylsilane (3.19 ml, 19.98 mmol) was added dropwise at room temperature. The reaction mixture was filtered through a bed of celite. The filtrate was concentrated in vacuo to furnish the title compound. (0.8 g)
[0300] 1HNMR (400 MHz, DMSO-d6), δ 7.03 (t, 1H, J=8 Hz), 6.58 (dd, 1H, J=8.0 and 1.6 Hz), 6, 51 to 6.50 (m, 1H), 6.42 (d, 1H, J=7.2 Hz), 5.23 (s, 1H), 4.78 (d, 1H, J=3.6 Hz ), 3.98 (bs, 1H), 3.73 to 3.69 (m, 1H), 3.50 (bs, 1H), 3.13 (bs, 2H), 1.70 (bs, 2H) , 1.30 (bs, 2H). GCMS: 220.15 [M+].
[0301] Intermediate-xi: Synthesis of 3-Amino-N-(oxetan-3-yl)benzamide

[0302] Step-a: Synthesis of 3-Nitro-N-(oxetan-3-yl) benzamide
[0303] 3-Nitrobenzoic acid (0.50 g, 2.99 mmol), oxetan-3-amine (0.219 g, 2.99 mmol) were taken up in pyridine (0.5 ml) and under an atmosphere of nitrogen and EDC HCl (0.574 g, 2.99 mmol) was added. The reaction mixture was stirred at room temperature for 10 hours. After completion of the reaction, the reaction mixture was diluted with water (5 ml) and extracted with ethyl acetate (2X5 ml). The combined organic layer was dried over sodium sulfate and concentrated in vacuo to provide the title compound (600 mg).
[0304] 1HNMR (400 MHz, CDCl3): δ 8.64 (t, 1H, J= 2 Hz), 8.43 to 8.40 (m, 1H), 8.21 to 8.18 (m, 1H) ), 7.85 (bs, 1H), 7.70 (t, 1H, J=8 Hz), 5.33 to 5.23 (m, 1H), 5.07 (t, 2H, J=7, 2 Hz), 4.66 (t, 2H, J=6.8 Hz).
[0305] Step-b: Synthesis of 3-Amino-N-(oxetan-3-yl)benzamide
[0306] To a stirred solution of 3-Nitro-N-(oxetan-3-yl)benzamide (0.06 g, 0.270 mmol) in methanol (5 ml) was added Pd/C (2.87 mg) and to Reaction mixture was stirred under hydrogen atmosphere for 20 min. The reaction mixture was diluted with methanol (10 ml) and the mixture was filtered through celite and the filtrate was concentrated in vacuo to provide the title compound (48 mg).
[0307] 1HNMR (400 MHz, CDCl3): δ 7.25 to 7.21 (m, 1H), 7.15 to 7.14 (m, 1H), 7.09 to 7.07 (m, 1H) , 6.85 to 6.82 (m, 1H), 6.55 (bs, 1H), 5.29 to 5.08 (m, 1H), 5.06 to 4.98 (m, 2H), 4 .64 to 4.60 (m, 2H), 3.95 to 3.85 (bs, 2H). GCMS: 192 (M+).
[0308] Intermediate-xii: Synthesis of 3-Amino-N-(tetrahydrofuran-3-yl) benzamide

[0309] Step-a: Synthesis of 3-Nitro-N-(tetrahydrofuran-3-yl)benzamide
[0310] Tetrahydrofuran-3-amine (0.1 g, 1.148 mmol) and 3-nitrobenzoic acid (0.192 g, 1.148 mmol) were taken up in pyridine (2 ml), the mixture EDC.HCl (0.220 g, 1.148 mmol) was added, the reaction mixture was stirred under nitrogen for 10 hours at room temperature. The reaction mixture was diluted with cold water (15 ml), extracted with ethyl acetate (2X10 ml). The combined organic layer was washed with saturated aqueous bicarbonate solution and diluted with HCl, the organic layer was dried over sodium sulfate and concentrated in vacuo to provide the title product (240 mg).
[0311] 1HNMR (400 MHz, CDCl3): δ 8.62 to 8.61 (m, 1H), 8.39 to 8.36 (m, 1H), 8.19 to 8.17 (m, 1H) , 7.67 (t, 1H, J=8Hz), 6.62 (d, 1H, J=6Hz), 4.79 to 4.75 (m, 1H), 4.08 to 4.00 ( m, 1H), 3.93 to 3.83 (m, 3H), 2.44 to 2.37 (m, 1H), 2.01 to 1.98 (m, 1H).
[0312] Step-b: Synthesis of 3-Amino-N-(tetrahydrofuran-3-yl)benzamide
[0313] 3-Nitro-N-(tetrahydrofuran-3-yl)benzamide (0.24 g, 1.016 mmol) was taken up in methanol (5 ml), Pd-C (10%, 0.108 g) added and the mixture of The reaction was stirred under a hydrogen atmosphere for 2 hr at room temperature. After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated in vacuo to provide the crude product which was purified by column chromatography, eluting with 0 to 100% ethyl acetate in hexane to obtain the title compound (180 mg).
[0314] 1HNMR (400 MHz, CDCl3): δ 7.21 (t, 1H, J=7.6Hz), 7.13 to 7.12 (m, 1H), 7.05 to 7.03 (m , 1H), 6.82 to 6.80 (m, 1H), 6.24 (bs, 1H), 4.74 to 4.71 (m, 1H), 4.04 to 3.77 (m, 6H) ), 2.39 to 2.32 (m, 1H), 1.94 to 1.91 (m, 1H). GCMS: 206 (M+).
[0315] Intermediate-xiii: Synthesis of 2-(3-aminophenyl-2-hydroxyacetamide)

[0316] Step-a: Synthesis of (Tert-butyl)-2-(3-nitrophenyl)-2-oxoacetamide
[0317] Under nitrogen atmosphere, zinc chloride (8.12 g, 59.6 mmol) and molecular cleavage (200 mg) were taken up in THF (10 ml) at room temperature. To the above mixture, 3-nitrobenzaldehyde (3.00 g, 19.85 mmol), N-methylhydroxylamine hydrochloride (2.65 g, 31.8 mmol) and sodium bicarbonate (2.67 g, 31.8 mmol) were added. mmol). The mixture was stirred at room temperature for 30 min., followed by addition of 2-isocyano-2-methylpropane (3.30 g, 39.7 mmol) and acetic acid (3.58 g, 59.6 mmol) and the Reaction mixture was stirred for 48 hours. Water (50ml) was added and the mixture was extracted with ethyl acetate (2X 50ml). The combined organic layer was washed with saturated aqueous sodium bicarbonate solution and water and dried over sodium sulfate. The mixture was concentrated in vacuo and the crude product obtained was purified by column chromatography to provide yellow oil (2.4 g).
[0318] 1HNMR (400 MHz, CDCl3): δ 9.18 (t, 1H, J=2 Hz), 8.73 to 8.70 (m, 1H), 8.49 to 8.45 (m, 1H) ), 7.69 (t, 1H, J=8.0 Hz), 7.03 (bs, 1H), 1.48 (s, 9H).
[0319] Step-b: Synthesis of 2-(3-nitrophenyl)-2-oxoacetamide
[0320] Under nitrogen atmosphere, (tert-butyl)-2-(3-nitrophenyl)-2-oxoacetamide (1.50 g, 5.99 mmol) was taken up in toluene (10 ml) at room temperature, sulfonate tert-butyldimethylsilyl trifluoromethane (1.378 ml, 5.99 mmol) was added and the reaction mixture was heated at 100°C for 8 hours. The reaction mixture was concentrated in vacuo and saturated sodium bicarbonate solution was added, the mixture was extracted with ethyl acetate (3X 20 ml). The combined organic layer was dried over sodium sulfate and the mixture was concentrated in vacuo to provide the crude product which was purified by column chromatography to provide yellow solid product (440 mg).
[0321] 1HNMR (400 MHz, CDCl3): δ 9.20 (t, 1H, J= 2 Hz), 8.74 to 8.72 (m, 1H), 8.52 to 8.49 (m, 1H) ), 7.73 (bs, 1H), 7.03 (bs, 1H), 5.78 (bs, 1H).
[0322] Step-c: Synthesis of 2-(3-aminophenyl-2-hydroxyacetamide
[0323] To a mixture of 2-(3-nitrophenyl)-2-oxoacetamide (1.00 g, 5.15 mmol), ammonium formate (0.974 g, 15.45 mmol) and methanol (20 ml) at 0 °C was added Pd/C (10%, 0.17 g) and the reaction mixture was stirred at room temperature for 18 hours. The reaction mixture filtered through celite, the filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and filtered through celite and concentrated in vacuo to provide the yellow solid product (330 mg).
[0324] 1HNMR (400 MHz, DMSO-d6): δ 7.24 (s, 1H), 7.12 (s, 1H), 6.93 (t, 1H, J=7.6Hz), 6. 6 (s, 1H), 6.55 (d, 1H, J=7.6 Hz), 6.44 (dd, 1H, J=1.2 and 5.2 Hz), 5.78 (d, 1H , J=4 Hz), 5.01 (bs, 1H), 4.64 (d, 1H, J=3.2 Hz). GCMS: 166 [M+].
[0325] Intermediate-xiv: Synthesis of 3-Amino-N-(tetrahydro-2H-pyran-4-yl)benzamide

[0326] Step-a: Synthesis of 3-Nitro-N-(tetrahydro-2H-pyran-4-yl)benzamide
[0327] Under nitrogen atmosphere, 3-nitrobenzoic acid (1.00 g, 5.98 mmol) was taken up in THF (20 ml) and the mixture was cooled to 0°C followed by addition of N-methylmorpholine (0.855 ml) , 7.78 mmol) and ethyl chloroformioate (6.58 mmol). The reaction mixture was stirred for 30 min at 0°C and tetrahydro-2H-pyran-4-amine (0.6 ml, 5.98 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated in vacuo and the residue was taken up in ethyl acetate (20 ml), washed with water and brine, dried over sodium sulfate and concentrated in vacuo to provide the solid product (1.2 g).
[0328] Step-b: Synthesis of 3-Amino-N-(tetrahydro-2H-pyran-4-yl)benzamide
[0329] To a mixture of 3-Nitro-N-(tetrahydro-2H-pyran-4-yl)benzamide (360 mg, 1.439 mmol), ammonium formate (272 mg, 4.32 mmol) in methanol (20 ml) ) at 0°C was added Pd/C (10%, 0.04 g) and the reaction mixture was stirred at 60°C for 1 hour. The reaction mixture was cooled to room temperature and filtered through celite, the filtrate was concentrated in vacuo. The residue was taken up in ethyl acetate and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo to provide the title compound (300 mg).
[0330] 1HNMR (400 MHz, DMSO -d'): δ 7.21 (t, 1H, J=8 Hz), 7.14 to 7.13 (m, 1H), 7.05 (d, 1H, J =7.6Hz), 6.82 to 6.80 (m, 1H), 5.94 (d,1H,J=6Hz), 4.22 to 4.18 (m, 1H), 4.03 to 4.00 (m, 2H), 3.98 to 3.80 (bs, 2H), 3.55 (t, 2H, J=9.6 Hz), 2.03 to 2.00 (m, 2H) ), 1.55 to 1.44 (m, 2H).
[0331] Intermediate-xv: Synthesis of 2-(3-Aminophenyl)-1-(azetidin-1-yl)ethanone

[0332] Step-a: Synthesis of 1-(Azetidin-1-yl)-2-(3-nitrophenyl)ethanone
[0333] THF (30 ml) was added to a mixture of 2-(3-Nitrophenyl)acetic acid (1 g, 5.52 mmol) and CDI (1.34 g, 8.28 mmol), the mixture was stirred for 2 hours at 0 °C followed by addition of triethylamine (2.308 ml, 16.56 mmol) and azetidine hydrochloride (1.033 g, 11.04 mmol). The reaction mixture was stirred for 12 hours at room temperature and then concentrated in vacuo. The crude residue was purified by column chromatography using 0 to 50% ethyl acetate in hexanes as eluents to provide the title product (0.53 g).
[0334] Step-b: Synthesis of 2-(3-Aminophenyl)-1-(azetidin-1-yl)ethanone
[0335] 1-(Azetidin-1-yl)-2-(3-nitrophenyl)ethanone (0.5 g, 2.27mmol) was taken up in methanol (20 ml) and at 0°C, Pd-C (10 %, 0.05g) was added. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to provide the title product (0.34 g).
[0336] Intermediate-xvi: Synthesis of 2-(3-Aminophenyl)-N-(oxetan-3-yl)acetamide

[0337] Step-a: Synthesis of 2-(3-Nitrophenyl)-N-(oxetan-3-yl)acetamide
[0338] THF (30 ml) was added to a mixture of 2-(3-Nitrophenyl)acetic acid (0.8 g, 4.42 mmol) and CDI (1.07 g, 8.28 mmol), the mixture was stirred for 2 hours at 0 °C followed by addition of triethylamine (1.8 ml, 13.25 mmol) and oxetan-3-amine (0.484 g, 6.62 mmol). The reaction mixture was stirred for 12 hours at room temperature and then concentrated in vacuo. The crude residue was purified by column chromatography using 0 to 50% ethyl acetate in hexanes as eluent to provide the title product (0.5 g).
[0339] Step-b: Synthesis of 2-(3-Aminophenyl)-N-(oxetan-3-yl)acetamide
[0340] 2-(3-Nitrophenyl)-N-(oxetan-3-yl)acetamide (0.5 g, 2.11mmol) was taken up in methanol (20 ml) and at 0°C, 10% Pd- C (0.5g) was added. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to provide the title product (0.42 g).
[0341] Intermediate-xvii: Synthesis of 2-(3-aminophenyl)-1-(3-hydroxyazetidin-1-yl)ethanone

[0342] Step-a: Synthesis of 1-(3-Hydroxyazetidin-1-yl)-2-(3-nitrophenyl)ethanone
[0343] THF (30 ml) was added to a mixture of 2-(3-Nitrophenyl)acetic acid (0.5 g, 2.76 mmol) and CDI (0.671 g, 4.14 mmol), the mixture was stirred for 2 hours at 0 °C followed by addition of triethylamine (1.2154 ml, 8.28mmol) and azetidin-3-ol hydrochloride (0.756g, 6.90mmol). The reaction mixture was stirred for 12 hours at room temperature and then concentrated in vacuo. The crude residue was purified by column chromatography using 0 to 50% ethyl acetate in hexanes as eluent to provide the title product (0.51 g).
[0344] Step-b: Synthesis of 2-(3-aminophenyl)-1-(3-hydroxyazetidin-1-yl)ethanone
[0345] 1-(3-hydroxyazetidin-1-yl)-2-(3-nitrophenyl)ethanone (0.5 g, 2.117mmol) was taken up in methanol (20 ml) and at 0°C, Pd-C ( 10%, 0.5 g) was added. The reaction mixture was stirred under a hydrogen atmosphere at room temperature for 5 hours. The reaction mixture was filtered through celite and the filtrate was concentrated in vacuo to provide the title product (0.42 g).
[0346] Intermediate xviii: Synthesis of 3-(3-aminophenyl)-N-cyclopropylpropanamide

[0347] To a stirred solution of 3-(3-aminophenyl)propanoic acid (1 g, 6.05 mmol) in 10 ml of DMF and N-ethyl-N-isopropylpropan-2-amine (1.174 g, 9.08 mmol), cyclopropanamine (0.415 g, 7.26 mmol) was added, the resulting clear solution was stirred at room temperature, HATU (3.45 g, 9.08 mmol) was added and the resulting mixture was stirred for 24 h in the room temperature. The reaction mixture was diluted with cold water and extracted with Ethyl acetate (3 X 30 ml). The combined organic layer was dried over sodium sulphate and evaporated under reduced pressure to furnish the crude compound, the crude compound was purified by column chromatography to furnish the pure title compound (500mg).
[0348] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.89 to 7.85 (m, 1H), 6.92 to 6.83 (m, 1H), 6.38 to 6. 30 (m, 3H), 4.94 (brs, 2H), 2.68 to 2.63 (m, 1H), 2.57 to 2.51 (m, 2H), 2.25 to 2.21 ( m, 2H), 0.59 to 0.55 (m, 2H), 0.35 to 0.32 (m, 2H)
[0349] ESI-MS (m/z): 205.0 [M+1]
[0350] Intermediate xix: Synthesis of 3-Amino-N-(1-carbamoylcyclopropyl)benzamide

[0351] Step-a: Synthesis of Ethyl 1-(3-nitrobenzamido)cyclopropanecarboxylate
[0352] To the suspension of 3-nitrobenzoic acid (1 g, 5.98 mmol) in pyridine (10 ml) ethyl 1-aminocyclopropanecarboxylate hydrochloride (1.090 g, 6.58 mmol) was added followed by EDC.HCl (1.721 g, 8.98 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with cold water (100 ml) and extracted with ethyl acetate (2X25 ml). The separated organic layer was washed with brine and water, dried over sodium sulfate and concentrated in vacuo to dryness to obtain the product (1.26g, 76%).
[0353] 1H NMR (400 MHz, CDCl3) δ (ppm): 8.59 (bs, 1H), 8.41 to 8.38 (m, 1H), 8.20 to 8.18(m, 1H) , 7.68 (t, 1H, J=8 Hz), 6.82 (bs, 1H), 4.19 (q, 2H, J=7.2 Hz), 1.70 to 1.34 (m, 2H), 1.37 to 1.33 (m, 2H), 1.26 (t,3H, J=7.2 Hz).
[0354] ESI-MS (m/z): 279.58 (M+1)
[0355] Step-b: Synthesis of 1-(3-Nitrobenzamido)cyclopropanecarboxylic acid
[0356] To a solution of ethyl 1-(3-nitrobenzamido)cyclopropanecarboxylate (0.5 g, 1.797 mmol) in ethanol 10 ml, sodium hydroxide (aq) (5 ml, 25.00 mmol) was added and stirred at temperature environment for 10 hr. The reaction mixture was diluted with water (20ml) and acidified by the addition of 5N HCl. The white precipitates obtained were filtered. The residue was dried by azeotrope with toluene (0.38g, 85%).
[0357] 1H NMR (400 MHz, CDCl3) δ (ppm): 12.51 (s, 1H), 9.38 (s, 1H), 8.69 (t, 1H, J=1.2 Hz), 8.41 to 8.39 (dd, 1H, J=1.2 and 8 Hz), 8.29 (d, 1H, J=7.6 Hz), 7.79 (t, 1H, J=8 Hz) ), 1.64 to 1.13 (m, 2H), 1.45 to 1.42 (m, 2H).
[0358] Step-c: Synthesis of N-(1-carbamoylcyclopropyl)-3-nitrobenzamide
[0359] To the suspension of 1-(3-Nitrobenzamido)cyclopropanecarboxylic acid (0.38 g, 1.519 mmol) in dichloromethane (5 ml), oxalyl chloride (0.199 ml, 2.278 mmol) was added followed by DMF (0.024 ml, 0.304 mmol). The reaction mixture was stirred at room temperature for 3hr. After complete dissolution of the compound, cold aqueous ammonia (5ml) was added under cooling. The content was allowed and stirred at room temperature for 1 hr. The reaction mixture concentrated to remove dichloromethane and the slurry obtained was filtered to obtain the title compound (0.28 g, 74%).
[0360] Step-d: Synthesis of 3-Amino-N-(1-carbamoylcyclopropyl)benzamide
[0361] To the suspension of N-(1-carbamoylcyclopropyl)-3-nitrobenzamide (0.28 g, 1.123 mmol) in methanol (5 ml), Pd-C (0.05 g) was added under nitrogen and the mixture of The reaction was stirred under a hydrogen atmosphere at room temperature. After 2 hr the reaction mixture was filtered and concentrated in vacuo to provide solid composite (0.2g, 81%).
[0362] ESI-MS (m/z): 220.83 (M+1)
[0363] Intermediate xx: Synthesis of 3-Amino-N-(1-(hydroxymethyl)cyclopropyl)benzamide

[0364] Step-a: Synthesis of N-(1-(Hydroxymethyl)cyclopropyl)-3-nitrobenzamide
[0365] To the suspension of ethyl 1-(3-nitrobenzamido)cyclopropanecarboxylate (0.400 g, 1.438 mmol) in 10 ml tetrahydrofuran, LiBH4 (0.063 g, 2.88 mmol) was added and the content heated to 45 °C for 15 hr. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate (2X10ml). The organic layer was dried over sodium sulfate and concentrated in vacuo which was further purified by column chromatography eluting ethyl acetate (0 to 70%) in hexane (0.05g, 14%).
[0366] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.08 (s, 1H), 8.69 (t, 1H, J=1.6 Hz), 8.38 to 8.35 (m, 1H), 8.30 to 8.27(m, 1H), 7.75 (t, 1H, J=7.6Hz), 4.80 (t, 1H, J=6Hz), 3 .53 (d, 2H, J=5.6 Hz), 0.77 to 0.72 (m, 4H).
[0367] ESI-MS (m/z): 237 (M+1)
[0368] Step-b: Synthesis of 3-Amino-N-(1-(hydroxymethyl)cyclopropyl)benzamide

[0369] To a solution of N-(1-(hydroxymethyl)cyclopropyl)-3-nitrobenzamide (0.135 g, 0.571 mmol) in methanol, Pd-C (50% wet) (0.015g) was added and stirred at room temperature under hydrogen for 2 hr. The reaction mixture was filtered through celite and concentrated to provide product (0.1 g, 85%).
[0370] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.39 (bs,1H), 7.05 to 7.00 (m,2H), 6.95 to 6.93 (m, 1H), 6.67 to 6.64 (m,1H), 5.18 (s,2H), 4.73 (t,1H,J=6Hz), 3.50 (d,2H,J=5 0.6 Hz), 0.75 to 0.64 (m,4H). GCMS: 206.98 (M+)
[0371] Intermediate xxi: of morpholino(3-nitrophenyl)methanone

[0372] Step-a Preparation of morpholino(3-nitrophenyl)methanone
[0373] To the stirred solution of 3-nitrobenzoic acid (5 g, 29.9 mmol) in DCM:DMF (30 ml, 29:1) was added oxalyl chloride (3.14 ml, 35.9 mmol) dropwise drop in RT. The resulting reaction mixture was stirred for 1 h. The mixture was concentrated and the residue was dissolved in DCM (25 ml), the reaction mixture was cooled to 0 °C and triethylamine (6.26 ml, 44.9 mmol) and morpholine (3.13 ml, 35.9 mmol) were added and the reaction mixture was stirred for 1 h. The reaction mixture was concentrated in vacuo and the residue was diluted with cold water, the solid separated was filtered and washed with n-hexanes and dried in vacuo to furnish the product (4.9 g).
[0374] 1HNMR (400 MHz, DMSO), δ (ppm): 8.32 to 8.29 (m, 1H), 8.23 to 8.22 (m, 1H), 7.89 to 7.86 ( m, 1H), 7.75 (t, J=8.00 Hz, 1H), 3.65 to 3.55 (m, 8H). GCMS-236.22 (M+).
[0375] Step-b Preparation of (3-aminophenyl)(morpholino)methanone
[0376] To a solution of morpholino(3-nitrophenyl)methanone (2 g, 8.47 mmol) in ethyl acetate (40 ml) was added dehydrated tin(II) chloride (7.64 g, 33.9 mmol) ). The resulting reaction mixture was stirred at RT for 17 h. The reaction mixture was neutralized with NaOH (2N), the mixture was filtered and the filtrate was extracted with Ethyl acetate (250 ml x 2). The combined organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo to give the title product (1.4 g).
[0377] GCMS-206.24
[0378] Intermediate xxii: Synthesis of 2-(3-aminophenoxy)-2-methylpropanamide

[0379] Step-a: Preparation of ethyl 2-methyl-2-(3-nitrophenoxy)propanoate
[0380] To a solution of 3-nitrophenol (7.5 g, 53.9 mmol) and ethyl 2-bromo-2-methylpropanoate (12.62 g, 64.7 mmol) in DMF (25 ml) was added K2CO3 (14.90 g, 108 mmol). After stirring at RT for 16 hr, the reaction mixture was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate (3 X 30 ml), the combined organic layer was washed with NaOH solution (10%, 75 ml), water (75 ml) and brine, dried over sodium sulfate. and concentrated in vacuo to provide the title product (6.7 g).
[0381] 1HNMR (400 MHz, DMSO), δ (ppm): 7.89 to 7.86 (m, 1H), 7.60 to 7.54 (m, 2H), 7.30 to 7.28 ( m, 1H), 4.18 to 4.01 (m, 2H), 1.59 (s, 6H), 1.21 to 1.14 (m, 3H). GCMS-253.25.
[0382] Step-b: Preparation of 2-methyl-2-(3-nitrophenoxy)propanoic acid
[0383] A mixture of ethyl 2-methyl-2-(3-nitrophenoxy)propanoate (3.5 g, 13.82 mmol) and LiOH·H2O (2.320 g, 55.3 mmol) in Tetrahydrofuran (7 ml) MeOH (7 ml) and Water (7 ml) was stirred at room temperature for 4 hr. The reaction mixture was concentrated in vacuo and the residue was neutralized with 1N HCl, the separated solid was filtered and treated with pentane to provide the title product (2.68 g).
[0384] 1HNMR (400 MHz, DMSO), δ (ppm): 13.40 (bs, 1H), 7.86 (dd, J=1.6 & 8.0 Hz, 1H), 7.60 to 7 .56 (m, 2H), 7.31 (dd, J=2 & 8.4 Hz, 1H), 1.57 (s, 6H). GCMS-225.19 (M+)
[0385] Step-c: Preparation of 2-methyl-2-(3-nitrophenoxy)propanamide
[0386] A mixture of 2-methyl-2-(3-nitrophenoxy)propanoic acid (1 g, 4.44 mmol) and CDI (1.080 g, 6.66 mmol) in Tetrahydrofuran (10 ml) was stirred at room temperature for 3 hr, ammonia (2.0 M in methanol, 10 ml) was added and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated in vacuo and the residue treated with pentane to provide the title product (0.914 g).
[0387] 1HNMR (400 MHz, DMSO), δ (ppm): 7.88 to 7.85 (m, 1H), 7.70 to 7.56(m, 2H), 7.40 (bs, 1H) , 7.36 to 7.32 (m, 1H), 7.01 (bs, 1H), 1.49 (s, 6H). GCMS-224.21 (M+).
[0388] Step-d: Preparation of 2-(3-aminophenoxy)-2-methylpropanamide
[0389] To a stirred solution of 2-methyl-2-(3-nitrophenoxy)propanamide (0.910 g, 4.06 mmol) in MeOH (15 ml) were added Pd-C (10%, 0.346 g) and triethylsilane ( 6.48 ml, 40.6 mmol) (slow addition) at room temperature. The reaction mixture was stirred at the same temperature for 30 min. and filtered through celite, washed with methanol (50 ml). The filtrate was concentrated under vacuum to obtain the crude compound. The crude compound was purified by flash chromatography to furnish the title product (0.516 g).
[0390] 1HNMR (400 MHz, DMSO), δ (ppm): 7.39 (bs, 1H), 7.19 (bs, 1H), 6.86 (t, J= 8.00 Hz, 1H), 6.21 to 6.18 (m, 1H), 6.14 to 6.13 (m, 1H), 6.06 to 6.04 (m, 1H), 5.03 (s, 2H), 1, 38 (s, 6H). GCMS-194.23 (M+).
[0391] Intermediate xxiii: Synthesis of (3-aminophenyl)(4-methylpiperazin-1-yl)methanone

[0392] Step-a Preparation of (4-methylpiperazin-1-yl)(3-nitrophenyl)methanone
[0393] To a solution of 3-nitrobenzoyl chloride (4.5 g, 24.25 mmol) in THF (30 ml) was added 1-methylpiperazine (8.50 g, 85 mmol). The reaction was stirred for 20 min at room temperature. The reaction mixture was diluted with 50 ml water and extracted with ethyl acetate (2x100 ml). The combined organic layer was washed with brine (50 ml). The brine was extracted again with ethyl acetate (2x50ml) and all organic layers were combined, dried over magnesium sulphate, filtered and concentrated in vacuo to provide the title product (5.2g).
[0394] 1HNMR (400 MHz, DMSO), δ (ppm): 8.32 to 8.29 (m, 1H), 8.19 to 8.18 (m, 1H), 7.86 to 7.84 ( m, 1H), 7.77 to 7.72 (m, 1H), 3.64 (bs, 2H), 3.30 (bs, 2H), 2.38 to 2.27 (m, 2H), 2 .19 (s, 3H). GCMS-249.26 (M+).
[0395] Step-b Preparation of (3-aminophenyl)(4-methylpiperazin-1-yl)methanone
[0396] To a stirred solution of (4-methylpiperazin-1-yl)(3-nitrophenyl)methanone (5.5 g, 22.06 mmol) in MeOH (50 ml) was added Pd-C (10%, 0.470 g) followed by triethylsilane (14.10 ml, 88 mmol) (slow addition) at RT. The reaction mixture was stirred at the same temperature for 25 min and filtered through celite, washed with methanol (50 ml). The filtrate was concentrated in vacuo to obtain the title product (4.11 g).
[0397] 1HNMR (400 MHz, DMSO), δ (ppm): 7.05 (t, J=8.0 Hz, 1H) 6.61 to 6.58 (m, 1H), 6.53 to 6. 52(m, 1H), 6.45 to 6.43(m, 1H), 5.25 (s, 2H), 3.55 to 3.32 (m, 4H), 2.50 to 2.28 ( m, 4H), 2.18 (s, 3H). GCMS-219.28 (M+).
[0398] The following intermediates given in table 1 were prepared according to the preparation procedures disclosed in the following related references.
[0399] Table-1:


[0400] Intermediate xxx: Synthesis of 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4, 7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzenesulfonate

[0401] Under nitrogen atmosphere, to a solution of 1-(2-fluoro-4-iodophenyl)-5-hydroxy-3-(4-methoxybenzyl)-6,8-dimethylpyrido[2,3-d]pyrimidine- 2,4,7(1H,3H,8H)-trione (41 g, 72.8mmol) (Prepared per reference WO2005121142) in acetonitrile (300ml), triethylamine (30.4ml, 218mmol) and trimethylamine hydrochloride (3.48g, 36.4mmol) was added slowly followed by addition of p-toluensulfonylchloride (27.8g, 146mmol) in acetonitrile (300ml) at 0°C and the mixture was stirred under frozen cooling for 1hr. and then at room temperature for 24 h. To the reaction mixture, methanol (220 ml) was added and the mixture was stirred at room temperature for 1h. Precipitated crystals were collected by filtration, dried under vacuum to provide the title compound (40.5 g, 78%)
[0402] 1H NMR(400 MHz,DMSO-d6) δ: 7.95 (dd, J = 1.6 and 9.6 Hz, 1H), 7.84 (d, J = 8.4 Hz, 2H) , 7.72 (dd, J = 1.2 and 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.35 (t, J = 8.4 Hz, 1H), 7.23 (d, J = 8.8 Hz, 2H), 6.86 (d, J = 8.8 Hz, 2H), 4.92 (d, J = 16Hz, 1H), 4. 77 (d, J = 16Hz, 1H), 3.71 (s, 3H), 2.76 (s, 3H), 2.42 (s, 3H), 1.53 (s, 3H).
[0403] MS (ESI): 717.9.
[0404] Intermediate xxxi: Synthesis of 1-(3-aminophenyl)cyclopropanecarboxamide
[0405] Scheme:

[0406] Step a: Synthesis of 1-(3-nitrophenyl)cyclopropanecarbonitrile
[0407] The solution of 2-(3-nitrophenyl)acetonitrile (2.5 g, 15.42 mmol) and 1,2-dibromoethane (1.329 ml, 15.42 mmol) in DMSO / Et2O (1:1, 10 ml) was added dropwise to a suspension of NaH (1.233 g, 30.8 mmol) in DMSO (Volume: 10 ml, Ratio: 1.000) keeping the temperature at 0°C. The resulting mixture was stirred at room temperature for 24 h under atm N2. The reaction mixture was quenched by adding IPA (2 ml) and water; partitioned between water (300 ml) and EtOAc (300 ml). The phase here was re-extracted with EtOAc (300 ml). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography to provide 1-(3-nitrophenyl)cyclopropanecarbonitrile (1.799 g, 9.56 mmol).
[0408] 1H NMR(400MHz,DMSO-d6) δ 8.19 to 8.16 (m, 1H), 8.07 to 8.06 (m, 1H), 7.79 to 7.75 (m, 1H), 7.58 (t, J = 8.4 Hz, 1H), 1.91 to 1.84 (m, 2H), 1.56 to 1.48 (m, 2H).
[0409] GCMS: 188.01 [M+]
[0410] Step b: Synthesis of 1-(3-nitrophenyl)cyclopropanecarboxamide:
[0411] To a solution of 1-(3-nitrophenyl)cyclopropanecarbonitrile (1.6 g, 8.50 mmol) in 2-Propanol (50 ml) was added triethylbenzylammonium chloride (0.058 g, 0.255 mmol) and 25% of aqueous KOH solution (5 ml). The resulting solution was stirred for 5 min. and H2O2 (10 ml, 98 mmol, ca. 30% solution in water) was added. The reaction mixture was heated at 50 °C for 4 h. The solvent was evaporated in vacuo and the residue suspended in water (200 ml). The precipitate was filtered and dried to obtain 1-(3-nitrophenyl)cyclopropane carboxamide (1.104 g, 5.36 mmol, 63% yield).
[0412] 1H NMR(400MHz,DMSO-d6) δ 8.31 to 8.13 (m, 2H), 7.80 to 7.78 (m, 1H), 7.64 to 7.60 (m, 1H), 7.11 (s, 1H), 6.58 (s, 1H), 1.42 to 1.35 (m, 2H), 1.08 to 1.03 (m, 2H).
[0413] GCMS: 206.04 [M+]
[0414] Step c: Synthesis of 1-(3-aminophenyl)cyclopropanecarboxamide
[0415] Triethylsilane (7.75 ml, 48.5 mmol) was added dropwise to a suspension of 1-(3-nitrophenyl)cyclopropanecarboxamide (1 g, 4.85 mmol) and Pd/C (10%, 250 mg) in MeOH (20 ml). The resulting suspension was stirred at RT for 20 min. and filtered through celite. The filtrate was evaporated and triturated in hexane to obtain crystals which were collected by filtration to provide the title compound (0.68g).
[0416] 1H NMR(400 MHz,DMSO-d6) δ 7.04 (brs, 1H), 6.98 (t, J = 8.0 Hz, 1H), 6.60 to 6.56 (m, 1H) ), 6.49 to 6.45 (m, 2H), 5.90 (brs, 1H), 5.09 (s, 2H), 1.26 to 1.23 (m, 2H), 0.88 to 0.85 (m, 2H).
[0417] GCMS: 176.07 [M+]
[0418] Example-1: Synthesis of 3-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6, 7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide (Compound 1).

[0419] Step-1: Synthesis of 3-(3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo- 1,2,3, 4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)propanamide (1b)
[0420] To a stirred solution of 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4, 7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzene sulfonate (xxx) (2 g, 2.79 mmol) in DMA (5 ml) was added 2,6-lutidine (0.597 g, 5.57 mmol) and 3-(3-aminophenyl)propanamide (intermediate xxvi) (0.915 g, 5.57 mmol). The reaction mixture was heated at 130°C for 16 h. The reaction mixture was cooled to room temperature and water added until a precipitated solid was obtained. The solid was filtered, washed with water and small amount of MeOH. The solid was purified by column chromatography over silica gel, eluting with DCM:Methanol (9:1) to provide the title compound (1b) (1.7 g) [m/z = 710.20 (M+1)] .
[0421] 1H NMR (400 MHz, DMSO-d6) δ 10.2 (s, 1H), 7.97 (dd, 2.0 and 9.6 Hz, 1H), 7.75 (dd, 1.2 and 8.4 Hz, 1H), 7.37 (t, J = 8 Hz, 1H), 7.28 (d, J = 8.8 Hz, 3H), 7.20 (t, J = 8 Hz, 1H), 6.86 (m, 3H), 6.76 (m, 3H), 5.00 (m, 2H), 3.70 (s, 3H), 2.75 (m, 5H), 2, 33 (t, J = 7.2 Hz, 2H), 1.50 (s, 3H).
[0422] Step-2: Synthesis of 3-(3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7- trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide (1c)
[0423] To a solution of 3-(3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1, 2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)propanamide (1b) (1.7gm, 2.396 mmol) in THF (8 ml) was added sodium (30% solution in MeOH) (0.431 mg, 2.396 mmol) at 0°C. The reaction mixture was stirred at room temperature for 2 hr and quenched by addition of 2N HCl solution. The resulting mixture was concentrated in vacuo and the residue was recrystallized from IPA, methanol and water to provide the title compound (1c) (1.5 g, 88%) [m/z = 710.20 (M+1)].
[0424] 1H NMR (400 MHz, DMSO-d6) δ 11.11 (s, 1H), 7.78 (dd, J = 2 Hz and 10.4 Hz, 1H), 7.52 (dd, J = 1.2 Hz and 9.6 Hz, 1H), 7.35 (t, J = 8 Hz, 2H), 7.22 (m, 5H), 6.98 (t, J = 8.8 Hz, 1H) ), 6.84 (d, J = 8.8 Hz, 2H), 6.79 (s, 1H), 4.96 (s, 2H), 3.67 (s, 3H), 3.14 (s , 3H), 2.78 (m, 2H), 2.42 (m, 2H), 1.22 (s, 3H).
[0425] Step-3: Synthesis of 3-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6, 7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide (1)
[0426] Aluminum chloride (2.82 g, 21.14 mmol) was added in small portions to a solution of 3-(3-(5-((2-fluoro-4-iodophenyl)amino)-3-( 4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)propanamide (1c) (1.500 g, 2.114 mmol) in anisole (15 ml). The resulting reaction mixture was stirred at room temperature for 24 h, then quenched by addition of MeOH (15 ml) and 2N HCl (0.5 ml). The resulting mixture was concentrated in vacuo and the residue thus obtained was purified by column chromatography with silica gel to provide the title compound (1) (0.450 g, 44%) [m/z = 590.1 (M+1)] .
[0427] 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 11.22 (s, 1H), 7.78 (dd, J = 2 & 10.4 Hz, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.31 (brs, 1H), 7.26 (brs, 1H), 7.24 to 7.21 (m, 2H), 6.94 (t, J = 8.4 Hz, 1H), 6.78 (brs, 1H), 3.06 (s, 3H), 2.82 (t, J=7.6Hz, 2H), 2.36 (t, J=6.4Hz, 2H), 1.19 (s, 3H).
[0428] The compounds given below in Table 2: were prepared by the procedure similar to that described above in Example 1 with the intermediates cited above with appropriate variations in reagents, reaction conditions and quantities of reagents.
[0429] Table-2:








[0430] Example-2: Synthesis of 5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-6,8-dimethylpyrido[4,3 -d]pyrimidine-2,4,7(1H,3H,6H)-trione (22).

[0431] Step-1: Synthesis of 3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1, acid 2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)benzoic (2b)
[0432] To a stirred solution of 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4, 7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzene sulfonate (2a) (2.0 g, 2.79 mmol) in DMA (5 ml) was added 2,6-lutidine (0 .98 ml, 8.36 mmol) and 3-aminobenzoic acid (1.147 g, 8.36 mmol). The reaction mixture was heated at 130°C for 16 h. The reaction mixture was cooled to room temperature and water was added followed by extraction with Ethyl acetate. The organic phase was dried over sodium sulphate. The solvent was evaporated in vacuo and the residual solid was purified by column chromatography over silica gel, eluting with Hexane:Ethyl acetate (1:1) to provide the title compound (2b) (1.4 g)
[0433] 1H NMR (400 MHz, DMSO-d6) δ 13.02 (s, 1H), 10.24 (s, 1H), 7.96 (dd, J=1.2 and 8.0 Hz, 1H ), 7.74 (dd, J=1.2 and 8.4 Hz, 1H), 7.57 (d, J=8.0 Hz, 1H), 7.41 to 7.38 (m, 2H) , 7.29 to 7.22 (m, 3H), 6.86 (d, J = 8.8 Hz, 2H), 5.04 to 4.94 (m, 2H), 3.69 (s, 3H) ), 2.77 (s, 3H), 1.52 (s, 3H). [m/z = 682.5 (M+1)].
[0434] Step-2: Synthesis of 1-(2-fluoro-4-iodophenyl)-5-((3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)amino)-3-(4-methoxybenzyl)-6 ,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (2c)
[0435] To a stirred solution of 3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2 acid ,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)benzoic (2b) (800 mg, 1.172 mmol) in THF (5 ml) was added EDC.HCl (494 mg) , 2.58 mmol), HOBT (395 mg, 2.58 mmol), DIPEA (0.819 ml, 4.69 mmol) and pyrrolidin-3-ol hydrochloride (290 mg, 2.35 mmol). The reaction mixture was stirred at room temperature under atm N2 for 6 h. The reaction mixture was then partitioned between water and ethyl acetate. The organic phase was removed, washed with brine and dried over sodium sulphate. The solvent was evaporated in vacuo to provide 1-(2-fluoro-4-iodophenyl)-5-((3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)amino)-3-(4-methoxybenzyl)-6. crude 8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (2c) (550 mg) which was carried on to the next step without further purification.
[0436] 1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 7.97 (dd, J=1.6 and 9.6 Hz, 1H), 7.74 (dd, J =1.2 and 8.4 Hz, 1H), 7.40 to 7.34 (m, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.11 (t, J= 6.8Hz, 1H), 7.04 (d, J=8.0Hz, 1H), 6.97 (brs, 1H), 6.86 (d, J=8.8Hz, 2H), 5 .04 to 4.93(m, 3H), 4.31 to 4.21(m, 1H), 3.70 (s, 3H), 3.55 to 3.48 (m, 2H), 3.41 to 3.35 (m, 1H), 2.76 (s, 3H), 1.94 to 1.78 (m, 2H), 1.53 (s, 3H), 1.26 to 1.23(m , 1H). [m/z = 752.0 (M+1)].
[0437] Step-3: Synthesis of 5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-3-(4-methoxybenzyl)-6 ,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (2d)
[0438] To a stirred solution of 1-(2-fluoro-4-iodophenyl)-5-((3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)amino)-3-(4-methoxybenzyl)-6, 8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione (550 mg, 0.732 mmol) in THF (2 ml) and Methanol (1 ml) was added K2CO3 ( 202 mg, 1.464 mmol) at RT. The reaction mixture was stirred at room temperature for 3 h under atm N2. Solvents were evaporated in vacuo and the residue suspended in dilute HCl (10 ml). The suspension was extracted several times with ethyl acetate. The combined organic phase was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo to provide 5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-3-(4-methoxybenzyl)-6. crude 8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (2d) (500 mg) which was carried on to the next step without further purification.
[0439] 1H NMR (400 MHz, DMSO-d6) δ 11.09 (s, 1H), 7.78 (dd, J=2.0 and 10.4 Hz, 1H), 7.58 to 7.53 (m, 5H), 7.25 (d, J=8.8 Hz, 2H), 6.99 (t, J=8.8 Hz, 1H), 6.84 (d, J=8.8 Hz) , 2H), 5.03 to 4.96 (m, 3H), 4.32 to 4.24 (m, 1H), 3.70 (s, 3H), 3.58 to 3.51 (m, 2H ), 3.13 to 3.12 (m, 1H), 3.09 (s, 3H), 1.95 to 1.91 (m, 1H), 1.83 to 1.80 (m, 1H), 1.22(s, 3H), 1.19 to 1.15(m, 1H). [m/z = 751.80 (M+1)].
[0440] Step-4: Synthesis of 5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1-carbonyl)phenyl)-6,8-dimethylpyrido[4,3 -d]pyrimidine-2,4,7(1H,3H,6H)-trione
[0441] Aluminum chloride (0.887 g, 6.65 mmol) was added in small portions to a solution of 5-((2-fluoro-4-iodophenyl)amino)-1-(3-(3-hydroxypyrrolidine-1) - carbonyl)phenyl)-3-(4-methoxybenzyl)-6,8-dimethylpyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione crude (2d) (0.500 g, 0.665 mmol) in Anisole (5 ml). The resulting reaction mixture was stirred at room temperature for 16 h which was then quenched by addition of MeOH (15 ml) and 2N HCl (0.5 ml). The resulting mixture was concentrated in vacuo and the residue thus obtained was purified by silica gel column chromatography to provide the title compound (22) (0.13 g).
[0442] 1H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 11.19 (s, 1H), 7.78 (dd, J=1.6 and 10.4 Hz, 1H ), 7.56 to 7.51 (m, 5H), 6.96 (t, J=8.4 Hz, 1H), 5.0 (brs, 1H), 4.32 to 4.24 (m, 1H), 3.60 to 3.51 (m, 2H), 3.41 to 3.37 (m, 1H), 3.06 (s, 3H), 1.95 to 1.92 (m, 1H) , 1.83 to 1.75 (m, 1H), 1.25 (s, 3H), 1.24 to 1.21 (m, 1H). [[m/z = 631.50 (M+1)]].
[0443] Example-3: Synthesis of 5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(piperazine-1-carbonyl)phenyl)pyrido[4,3- d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 23).

[0444] Step-1: Synthesis of methyl 3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1, 2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)benzoate (3b)
[0445] To a stirred solution of 1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4, 7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzene sulfonate (3a) (8.70 g, 12.13 mmol) in DMA (10 ml) was added 2,6-lutidine (3 .5 ml, 30.3 mmol) and methyl 3-aminobenzoate (5.5 g, 36.4 mmol). The reaction mixture was heated at 130°C for 16 h. The reaction mixture was cooled to room temperature and water was added followed by extraction with Ethyl acetate. The organic phase was dried over sodium sulphate. The solvent was evaporated in vacuo and the residual solid was purified by column chromatography over silica gel, eluting with Hexane:Ethyl acetate to provide the title compound (3b) (4.2g).
[0446] 1H NMR (400 MHz, DMSO-d6) δ 10.24 (s, 1H), 7.97 (d, J = 9.6 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.6 Hz, 1H), 7.48 to 7.37 (m, 3H), 7.30 to 7.23 (m, 3H), 6.85 (d, J = 8.4 Hz, 2H), 5.04 to 4.94 (m, 2H), 3.84 (s, 3H), 3.70 (s, 3H), 2.78 (s, 3H), 1.53 (s, 1H). [m/z = 630.7 (M+1)].
[0447] Step -2: Synthesis of methyl 3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoate (3c)
[0448] To a stirred solution of methyl 3-((1-(2-fluoro-4-iodophenyl)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-1,2 ,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)benzoate (3b) (3.20 g, 4.59 mmol) in THF (5 ml) and Methanol (10 ml) K2CO3 (2.54 g, 18.38 mmol) was added at RT. The reaction mixture was stirred at room temperature for 3 h under atm N2. The solvents were evaporated in vacuo and the residue was suspended in water, the precipitated product was collected by filtration and dried under high vacuum to provide the title compound (3c) , (2.1 g). The crude product was carried on to the next step without further purification.
[0449] [m/z = 697.0 (M+1)].
[0450] Step -3: Synthesis of 3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo- acid 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoic (3d)
[0451] The mixture of methyl 3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4 ,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoate (0.500 g, 0.718 mmol) and LiOH·H 2 O (0.120 g, 2.87 mmol) in THF (5.0 ml) ), MeOH (5.0 ml) and Water (5.0 ml) was stirred at room temperature for 17 h. Solvents were evaporated in vacuo and the residue was acidified with 1N HCl until solid precipitated. The product was collected by filtration and triturated in pentane, drying this solid under vacuum provided the title compound (3d), (0.312g, 63.7%); which was carried on to the next step without further purification.
[0452] 1H NMR (400 MHz, DMSO-d6) δ 13.24 (s, 1H), 11.09 (s, 1H), 7.98 to 7.96 (m, 2H), 7.79 (dd , J = 1.6 and 10.4 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.62 to 7.53 (m, 2H), 7.25 (d, J = 8.8 Hz, 2H), 7.00 (t, J = 8.4 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 3.70 (s, 3H) , 3.09 (s, 3H), 1.17 (s, 3H). [m/z = 683.0 (M+1)].
[0453] Step-4: Synthesis of tert-butyl 4-(3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4 ,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoyl)piperazine-1-carboxylate (3e)
[0454] To a stirred solution of 3-(5-((2-fluoro-4-iodophenyl)amino)-3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3 acid ,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoic (1 g, 1.465 mmol), EDC (0.421 g, 2.198 mmol), HOBT (0.337 g, 2.198 mmol) and tert-butyl piperazine-1-carboxylate (0.409 g, 2.198 mmol) in THF (5 ml) cooled to 0°C was added Hunig's base (0.512 ml, 2.93 mmol). The resulting mixture was stirred under atm N 2 for 2 h at room temperature. The solvent was evaporated in vacuo and the residue was partitioned between ethyl acetate (25ml) and water (25ml). The organic phase was separated and the aq. was re-extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated in vacuo to obtain a crude product which was carried on to the next step without further purification.
[0455] 1H NMR (400 MHz, DMSO-d6) δ 7.78 (dd, J = 2.0 and 6.0 Hz, 1H), 7.58 to 7.46 (m, 5H), 7.28 (d, J = 8.8 Hz, 2H), 7.01 (t, J = 8.4 Hz, 1H), 6.86 (d, J = 8.8 Hz, 2H), 4.96 (s , 2H), 3.72 (s, 3H), 3.58 to 3.30 (m, 6H), 3.09 (s, 3H), 1.40 (s, 9H), 1.17 (s , 3H).
[0456] Step-5: Synthesis of 5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-(piperazine-1-carbonyl)phenyl)pyrido [4,3- d]pyrimidine-2,4,7(1H,3H,6H)-trione (23).
[0457] Aluminum chloride (1.57 g, 11.76 mmol) was added in small portions to a solution of tert-butyl 4-(3-(5-((2-fluoro-4-iodophenyl)amino)- 3-(4-methoxybenzyl)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzoyl)piperazine - crude 1-carboxylate (1 g, 1.176 mmol) in Anisole (5 ml). The resulting reaction mixture was stirred at room temperature for 17 h, methanol (10 ml) was added dropwise and the resulting mixture was concentrated in vacuo. Ammonia aq. was added to the resulting residue and the reaction mixture was extracted several times with DCM. The combined organic phase was washed with brine and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on neutral alumina to provide the title compound (23) (0.113g).
[0458] 1HNMR (400 MHz, DMSO-d6), δ (ppm): 7.78 (dd, J=2 & 10.4 Hz, 1H), 7.56 to 7.39 (m, 5H), 6 .95 (t, J=8.8 Hz, 1H), 3.54 to 3.25 (m, 4H), 3.06 (s, 3H), 2.73 to 2.64 (m, 4H), 1.21 (s, 3H). [m/z = 630.4 (M+1)].
[0459] Example 4: 1-(3-(azetidine-1-carbonyl)phenyl)-3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4,3 -d]pyrimidine-2,4,7(1H,3H,6H)-trione (Compound 24)

[0460] Step-1: Synthesis of 5-((3-(azetidine-1-carbonyl)phenyl)amino)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2 ,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione.(4b)
[0461] In a sealed pipette, 3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8- hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzenesulfonate (4a) (0.5 g, 0.78 mmol), (3-aminophenyl)(azetidin-1-yl)methanone (intermediate 1) (0 .27g, 1.56mmol) were taken into the mixture, DMA (2ml) and 2,6-lutidine (0.42mg, 3.92mmol) were added and the mixture was heated to 130°C for 16 hr under nitrogen atmosphere. After completion of the reaction, the reaction mixture was poured into frozen water, the separated solid was filtered and washed with water and dried under vacuum. The crude solid was purified by column chromatography to provide the title compound (0.11 g).
[0462] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.13 (s, 1H), 7.95 (dd, J=1.6 & 9.2 Hz, 1H), 7.75 at 7.70 (m, 1H), 7.37 (t, J=8Hz, 1H), 7.27 (t, J=8Hz, 1H), 7.21 (d, J=7.6Hz , 1H), 7.12 to 7.06 (m, 2H), 4.27 (t, J=7.2 Hz, 2H), 4.02 (t, J=7.6 Hz, 2H), 2 .74 (s, 3H), 2.67 to 2.64 (m, 1H), 2.28 to 2.21 (m, 2H), 1.52 (s, 3H), 1.01 to 0.99 (m, 2H), 0.72 to 0.63 (m, 2H). [m/z = 642.1 (M+1)].
[0463] Step-2: Synthesis of 1-(3-(azetidine-1-carbonyl)phenyl)-3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethylpyrido[4 ,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione (24)
[0464] 5-((3-(azetidine-1-carbonyl)phenyl)amino)-3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6,8-dimethylpyrido[2,3-d]pyrimidine -2,4,7(1H,3H,8H)-trione (4b) (0.11 g, 0.17 mmol) was taken up in tetrahydrofuran (3 ml) at room temperature, sodium methoxide (25% in MeOH, 371 mg, 1.71 mmol) was added and the reaction mixture was stirred at the same temperature for 1 hr under nitrogen atmosphere. Reaction progress was monitored by HPLC. After complete consumption of the substrate, the reaction mixture was diluted with HCl (2 ml, 2 N) and concentrated in vacuo. To the residue, DCM (20 ml) was added, the organic layer was dried over sodium sulfate and concentrated in vacuo to furnish the crude compound which was purified by column chromatography to furnish the title product (0.09 g).
[0465] 1H NMR (400 MHz, DMSO-d6) δ (ppm): 11.05 (s, 1H), 7.80 to 7.77 (m, 1H), 7.63 to 7.59 (m, 2H), 7.58 to 7.51 (m, 3H), 6.96 to 6.92 (m, 1H), 4.27 to 4.21 (m, 2H), 4.06 to 4.02 ( m, 2H), 3.07 (s, 3H), 2.62 to 2.59 (m, 1H), 2.27 to 2.23 (m, 2H), 1.18 (s, 3H), 0 .97 to 0.95 (m, 2H), 0.72 to 0.60 (m, 2H). ESI-MS: [m/z = 642.1 (M+1)].
[0466] The compounds given below in table 3: were prepared by the procedure similar to that described above in Example 4 with the intermediates cited above and with appropriate variations in reagents, reaction conditions and quantities of reagents.
[0467] Table-3:











[0468] Example-5: N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6 ,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 54)

[0469] To a mixture of N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7 - tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (2) (110 mg, 0.183 mmol) and K2CO3 (0.51 mg, 0.37 mmol) in DMF (3 ml) was added lodomethane (9.15 µl, 0.146 mmol) in portion. The solution was heated at 60°C for 3 hours. The reaction mixture was cooled to room temperature followed by the addition of water and the mixture was extracted with ethyl acetate (3 x 10ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to obtain a crude product which was purified by column chromatography to provide the product (55) (0.06 g).
[0470] 1H NMR (400 MHz, DMSO-d6) δ 11.19 (s, 1H), 8.53 (d, 1H, J=4 Hz), 7.87 to 7.84 (m, 1H), 7.80 to 7.77 (m, 2H), 7.59 to 7.54 (m, 3H), 6.95 (t, 1H, J=8.0Hz), 3.21 (s, 3H), 3.09 (s, 3H), 2.85 to 2.83 (m, 1H), 1.18 (s, 3H), 0.70 to 0.68 (m, 2H), 0.58 to 0. 57 (m, 2H).
[0471] MS: m/z 616.1 (M+1)].
[0472] The compounds given below in Table 4: were prepared by the procedure similar to that described above in Example 5 by using the compounds prepared above as starting material and with appropriate ranges in reagents, reaction conditions and quantities of reagents.
[0473] Table-4:








[0474] Example 6: N-cyclopropyl-3-(3-(difluoromethyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3, 4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 72)

[0475] 5 ml of DMF was added to N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4, 6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 2) (200mg, 0.333mmol), Potassium Carbonate mixture (230mg, 1.663mmol) was added and the mixture was stirred at 60 °C for a period of 20 min and Sodium chlorodifluoroacetate (101 mg, 0.665 mmol) was added and the mixture was heated at 90 °C for 18 hours. The reaction mixture was cooled to room temperature followed by the addition of water and the mixture was extracted with ethyl acetate (3 x 10ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated to obtain a crude product which was purified by column chromatography to provide the product (72) as a solid (0.05 mg).
[0476] 1HNMR (400 MHz, DMSO-d6), δ 10.53 (s, 1H), 8.56 to 8.55 (d, 1H, J=4 Hz), 7.87 to 7.84 (m , 2H), 7.80 to 7.78 (m, 1H), 7.65 to 7.51 (m, 4H), 7.07 to 7.03 (t, 1H J=8 Hz), 3.09 (s, 3H), 2.85 to 2.82 (m, 1H), 1.19 (s, 3H), 0.70 to 0.68 (m, 2H), 0.59 to 0.58 (m , 2H).
[0477] MS: m/z 651.9 (M+1)].
[0478] Example 7: N-cyclopropyl-3-(3-(2,3-dihydroxypropyl)-5-((2-fluoro-4-iodophenyl)amino) -6,8-dimethyl-2,4,7- trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 73)

[0479] To a stirred solution of 3-(3-allyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6, 7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)-N-cyclopropylbenzamide (compound 70) (180 mg, 0.281 mmol) and 4-methylmorpholine N-oxide (32.9 mg, 0.281 mmol) in THF (3 ml) was added osmium tetraoxide (10% in water) (0.088 ml, 0.281 mmol) slowly. The reaction was stirred at room temperature for 3 hours. Water (20 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate (3 x 10 ml). The combined organic layers were washed with water, brine and dried over sodium sulfate. The organic layer was concentrated in vacuo to obtain a crude product which was purified by column chromatography using a gradient of hexane-90% ethyl acetate in hexane eluent to provide the product (73) (100 mg).
[0480] 1H NMR (400 MHz, DMSO-d6) δ 11.29 (s, 1H), 8.56 (d, 1H, J=4 Hz), 7.87 to 7.84 (m, 1H), 7.83 to 7.78 (m, 2H), 7.57 to 7.52 (m, 3H), 6.96 (t, 1H, J=8.8 Hz), 4.79 (d, 1H, J=5.6), 4.59 (t, 1H, J=5.6Hz), 4.01 to 3.98 (m, 1H), 3.82 to 3.76 (m, 2H), 3.40 to 3.30 (m, 2H), 3.08 (s, 3H), 2.86 to 2.81 (m, 1H), 1.18 (s, 3H), 0.70 to 0.68 (m, 2H), 0.58 to 0.57 (m, 2H).
[0481] MS: m/z 676.1 (M+1)].
[0482] Example 8: 2-(1-(3-(cyclopropylcarbamoyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- acid 1,2,6,7-tetrahydropyrido[4,3-d]pyrimidin-3(4H)-yl)acetic (Compound 74)

[0483] To a solution of ethyl 2-(1-(3-(cyclopropylcarbamoyl)phenyl)-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo -1,2,6,7-tetrahydropyrido[4,3-d]pyrimidin-3(4H)-yl)acetate (compound 64) (66 mg, 0.096 mmol) in THF:Water (2 ml, 7:3) lithium hydroxide (8.06 mg, 0.192 mmol) was added. The reaction mixture was stirred at room temperature for 3h. The reaction mixture was concentrated in vacuo and treated with 2N HCl, the precipitate was collected by filtration and purified by flash chromatography to give the pure product (74) (28 mg).
[0484] 1H NMR (400 MHz, DMSO-d6), δ 13.09 (bs, 1H), 11.03 (s, 1H), 8.57 (d, J=4Hz, 1H), 7.83 (m, 3H), 7.61 to 7.54 (m, 3H), 7.03 (t, J=8.8 Hz, 1H), 4.51 (s, 2H), 3.08 (s, 3H) , 2.86 to 2.83 (m, 1H), 1.19 (s, 3H), 0.70 to 0.68 (m, 2H), 0.58 to 0.50 (m, 2H).
[0485] MS: m/z 659.9 (M+1)].
[0486] Example 9:
[0487] Enantiomeric separation of 2-(3-(5-((2-Fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6,7 -tetrahydro pyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxy acetamide (compound 47)
[0488] Compound 47 was enantiomerically separated by using preparatory HPLC by the methods described below.
[0489] Method-1
[0490] Column: CHIRAL PAK IA, 250 mm X 4.6 µ. Flow 1.5 ml/min, Mobile phase: A= hexane: IPA (90:10% v/v, 0.1% DEA), B= MeOH:EtOH (1:1). A:B = 60:40 v/v
[0491] Method-2
[0492] Column: CHIRAL IA, 250 mm X 4.6 µ. Flow 1.5 ml/min, Mobile phase: A= n-hexane: IPA (90:10% v/v, 0.1% DEA), B= MeOH:EtOH (1:1). A:B = 85:15 v/v
[0493] (R)-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6, 7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide (Compound 75)
[0494] 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s,1H), 7.78 (dd,1H,J=2 and 8.4Hz), 7.55 (d,1H,J) =8.4 Hz), 7.48 to 7.33 (m,5H), 7.22 (s,1H), 6.93 (t,1H,J=8.4Hz), 6.15 (bs ,1H), 4.88(d,1H,J=4.8Hz), 3.21(s,3H), 3.08(s,3H), 1.17(s,3H). MS: m/z 606.1 (M+1)].
[0495] Retention time is 6.56.
[0496] (S)-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-3,6,8-trimethyl-2,4,7-trioxo-3,4,6, 7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)-2-hydroxyacetamide (Compound 76)
[0497] 1H NMR (400 MHz, DMSO-d6) δ 11.21 (s,1H), 7.78 (dd,1H,J=2 and 8.4Hz), 7.55 (dd,1H,J) =1.2 and 7.2 Hz), 7.48 to 7.33 (m,5H), 7.22 (s,1H), 6.93 (t,1H,J=8.4Hz), 6 .15 (bs,1H), 4.88 (d,1H,J=4.8Hz), 3.21(s,3H), 3.08 (s,3H), 1.17 (s,3H) .
[0498] MS: m/z 606.1 (M+1)].
[0499] Retention time is 8.93.
[0500] PHARMACOLOGICAL ACTIVITY:
[0501] In-vitro Experiments:
[0502] Example-A: Identification of compounds that inhibit MEK kinase activity
[0503] In a 25 μl reaction, MEK enzyme (final concentration 2 to 4 μg/ml) and ERK substrate (final concentration 50 to 100 μg/ml) were incubated with various concentrations of test compounds (diluted in such a way that the reaction had 1% DMSO) at 25 to 30 0C for 20 to 120 min in a shaking incubator. Reactions were initiated by the addition of ATP. Reactions were terminated by the addition of an equal volume of KinaseGlo reagent (Promega) following the manufacturer's instructions. Plates were read in a luminometer. IC50 calculations were made using a GraphPad Prism 5.
[0504] IC50 values of compounds of inventions have been provided below in table 5. Compounds that exhibit IC50 in the range of 1 nM to 499 nM have been grouped as 'a', compounds that exhibit IC50 value in the range of 0.5 μM to 1 .5 μM were grouped as 'b' and compounds exhibiting IC50 value in the range of 1.6 μM to 3.0 μM were grouped as 'c'.
[0505] Table 5: MEK kinase inhibition activity of compounds (IC50):

[0506] Example-B: ERK phosphorylation analysis
[0507] This assay was performed with human melanoma cells, mouse and human colon cancer cells. Cells were treated for 1 h with various concentrations of test compounds. ERK phosphorylation analysis was performed using the Alphascreen SureFire Phospho-ERK 1/2 Kit (Perkin Elmer) following the manufacturer's instructions. The % inhibition of ERK phosphorylation was determined as:
[0508] 100 - {(RFU test - RFU lysis buffer control) / (RFU vehicle treated control - RFU lysis buffer control)} x 100. Compounds prepared by using the above assay procedure and the results obtained are given in table 6. The percentage of inhibition at concentrations of 0.01 nM, 0.03 nM, 0.1 to 0.9 nM, 1 nM to 3 nM, 4 to 100 nM and > 100nM for the examples mentioned is defined here. The percentage of inhibition at the concentrations disclosed above for the compounds mentioned is given in the following groups.
[0509] Table-6:


[0510] Example-C: Analysis of B-Raf-mediated MEK phosphorylation
[0511] This assay was performed with human melanoma cells. Cells were treated for 1 h with various concentrations of test compounds. Phosphorylation analysis of MEK (S218 and S222) was performed using the Alphascreen SureFire Phospho-MEK Kit (Perkin Elmer) following the manufacturer's instructions. The % inhibition of ERK phosphorylation was determined as:
[0512] 100 - {(RFU Test - RFU Lysis Buffer Control) / (RFU Vehicle Treated Control - RFU Lysis Buffer Control)} x 100. The % inhibition of MEK phosphorylation at concentrations of 100 nM, 10 nM and 1 nM for some of the compounds of the present invention is shown in Table-7.
[0513] Table-7:


[0514] In-Vivo Experiments
[0515] Athymic nude mice were acclimatized in the animal experimental room for 15 days prior to cell inoculation. The mouse was inoculated subcutaneously in 5 x 106 COLO205/A375 cells (in 0.2 ml PBS) of a single cell suspension without conglomerates with 98% viability in the right flank of the mouse. Post-cell inoculation, a tumor size was measured with a digital caliper (Mitutoyo, Japan) when the tumor became palpable. Tumor volume was calculated using the formula:
[0516] Tumor volume in mm3 = (Length xWidth xWidth)/2
[0517] Mice were randomized based on tumor volume in different groups with approximately equal mean and equal variation on the day post-inoculation of desired cell. All groups were administered once/twice daily with some compounds of the invention and vehicle control for 21/22 days. Tumor measurements were taken with a caliper twice a week. Mouse body weights were recorded daily.
[0518] The percentage change in body weight was calculated according to the following formula:
[0519] (Final body weight - Initial body weight) / (Initial body weight) x 100
[0520] Percent inhibition tumor growth was calculated as:

[0521]
[0522] Where, Tf and Ti are the final and initial treatment tumor volumes and Cf and Ci are the mean final and initial control tumor volumes, respectively.
[0523] Tumor regression percentage (TR%) was calculated as:

[0524] Data were analyzed by the GraphPad Prism 5.00 software using two-output ANOVA followed by Bonferroni's post hoc test. Differences were considered significant at * p < 0.05, ** p < 0.01 and *** p < 0.001 treatment versus vehicle control group.
[0525] Compounds 2, 5, 9, and 35 were tested for tumor growth in a Colo205 xenograft nude mouse model using the assay procedure given above; % tumor growth inhibition after 20 days at 1 mg/kg dose was in the range of 60% to 100%.
[0526] The foregoing description is considered to be illustrative only of the principles of revelation. Additionally, since numerous modifications and changes will be readily apparent to those skilled in the art, it is not intended to limit disclosure to the exact construction and process shown as described herein. Accordingly, all suitable modifications and equivalents may be used so as to be within the scope of the disclosure and as defined by the following claims.
[0527] The words "understand", "comprises", "include" and "which include", when used in this descriptive report and in the following claims are intended to specify the presence of the mentioned features, integrations, components or steps, but the they do not exclude the presence or addition of one or more additional features, integrations, components or steps thereof.

权利要求:
Claims (6)
[0001]
1. COMPOUND, characterized in that it is selected from the group consisting of N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo -3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 2); N-cyclopropyl-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4 ,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide (Compound 4); and N-cyclopropyl-3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyroxide [4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 37); or a pharmaceutically acceptable salt thereof.
[0002]
A COMPOUND according to claim 1, characterized in that it is N-cyclopropyl-3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo- 3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 2).
[0003]
A COMPOUND according to claim 1, characterized in that it is N-cyclopropyl-2-(3-(5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7 -trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide (Compound 4).
[0004]
A COMPOUND according to claim 1, characterized in that it is N-cyclopropyl-3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4, 7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)benzamide (Compound 37).
[0005]
5. PHARMACEUTICALLY ACCEPTABLE SALT, characterized in that it is a compound as defined in any one of claims 2 to 4.
[0006]
6. PHARMACEUTICAL COMPOSITION, characterized in that it comprises a compound or a pharmaceutically acceptable salt, as defined in any one of claims 1 to 5, and one or more pharmaceutically acceptable carriers, diluents or excipients.

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公开号 | 公开日 | 专利标题

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BR112014022713B1|2021-09-08|COMPOUND, PHARMACEUTICALLY ACCEPTABLE SALT AND PHARMACEUTICAL COMPOSITION

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AU2016205657B2|2019-01-17|Production method of thiazole derivative

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WO2017103825A1|2017-06-22|Quinolizinone derivatives as pi3k inhibitors

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OA17133A|2016-03-28|Heterocyclyl compounds as MEK inhibitors

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OA17318A|2016-05-23|Heterocyclyl Compounds.

同族专利:

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PH12014502041A1|2014-11-24|

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EP2834236A1|2015-02-11|

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AP2014008009A0|2014-10-31|

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CR20140464A|2014-11-28|

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BR112014022713A2|2017-06-20|

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IL234559A|2017-06-29|

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EA028232B1|2017-10-31|

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GEP201706671B|2017-05-25|

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CU20140110A7|2014-11-27|

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AU2013234014A1|2014-09-25|

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JP6431770B2|2018-11-28|

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CU20140109A7|2014-11-27|

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AU2017200493B2|2018-03-29|

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DOP2014000203A|2015-02-15|

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MX366426B|2019-07-08|

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US9827247B2|2017-11-28|

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KR102241111B1|2021-04-15|

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EA201491671A1|2014-12-30|

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AP3859A|2016-10-31|

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MA37400B1|2019-11-29|

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AU2018202568B2|2019-05-09|

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AP2014008008A0|2014-10-31|

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TN2014000356A1|2015-12-21|

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NZ629432A|2017-01-27|

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CN108383836B|2021-11-12|

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KR20140138911A|2014-12-04|

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NI201400108A|2014-11-28|

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US20150133424A1|2015-05-14|

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JP6093384B2|2017-03-08|

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SG11201405007QA|2014-10-30|

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HK1202538A1|2015-10-02|

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CL2014002411A1|2015-04-06|

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UA114907C2|2017-08-28|

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US20170112840A1|2017-04-27|

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CN104271577A|2015-01-07|

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CN107698585A|2018-02-16|

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KR20140138910A|2014-12-04|

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CU24335B1|2018-04-03|

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EP2834236B1|2019-05-22|

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US20160331753A1|2016-11-17|

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CR20140463A|2014-11-28|

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CA2865167C|2019-08-06|

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PH12014502040B1|2014-11-24|

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MA37400A1|2016-05-31|

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CA2865164C|2021-06-08|

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AU2018202568A1|2018-05-10|

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PL2834237T3|2018-11-30|

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MX355526B|2018-04-20|

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DK2834236T3|2019-08-26|

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GEP201706774B|2017-11-27|

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KR20190073597A|2019-06-26|

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CA2865164A1|2013-09-19|

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IL234560A|2017-06-29|

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NI201400107A|2014-11-26|

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WO2013136249A1|2013-09-19|

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JP2018115215A|2018-07-26|

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CA2865167A1|2013-09-19|

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CN104203947A|2014-12-10|

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JP2015509975A|2015-04-02|

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GT201400196A|2017-09-28|

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IN2014MN01755A|2015-07-03|

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MX355474B|2018-04-16|

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SG11201405006PA|2014-10-30|

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PE20141974A1|2014-12-12|

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JP2015514056A|2015-05-18|

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PH12014502041B1|2014-11-24|

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US9428499B2|2016-08-30|

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EP2834237B1|2018-06-06|

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GT201400195A|2017-11-09|

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US20170101408A1|2017-04-13|

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ES2741896T3|2020-02-12|

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CO7170131A2|2015-01-28|

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AP3834A|2016-09-30|

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JP6630771B2|2020-01-15|

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PH12014502040A1|2014-11-24|

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ZA201406186B|2016-06-29|

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AU2013234009A1|2014-09-25|

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CO7160029A2|2015-01-15|

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EA201491672A1|2014-12-30|

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MX2014010925A|2015-04-10|

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EA029768B1|2018-05-31|

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HK1206020A1|2015-12-31|

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PE20141973A1|2014-12-12|

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DK2834237T3|2018-08-27|

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KR20190100472A|2019-08-28|

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IN2014MN01754A|2015-07-03|

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DOP2014000204A|2015-02-15|

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EP2834237A1|2015-02-11|

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CL2014002412A1|2015-03-06|

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MX2014010928A|2015-04-10|

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TR201811976T4|2018-09-21|

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MY174188A|2020-03-12|

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AU2013234014B2|2017-02-02|

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KR102240101B1|2021-04-14|

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UA114906C2|2017-08-28|

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法律状态:
2018-05-02| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2018-05-08| B25G| Requested change of headquarter approved|Owner name: LUPIN LIMITED (IN) |

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2019-10-08| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2020-10-06| B07E| Notification of approval relating to section 229 industrial property law [chapter 7.5 patent gazette]|

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2021-01-05| B06U| Preliminary requirement: requests with searches performed by other patent offices: procedure suspended [chapter 6.21 patent gazette]|

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2021-07-06| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-09-08| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 11/03/2013, OBSERVADAS AS CONDICOES LEGAIS. |

优先权:

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申请号 | 申请日 | 专利标题

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IN288KO2012|2012-03-14|

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IN288/KOL/2012|2012-03-14|

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PCT/IB2013/051908|WO2013136249A1|2012-03-14|2013-03-11|Heterocyclyl compounds as mek inhibitors|

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