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    • 专利摘要:
    Use of a compound of formula (I), or a salt, ester, amide or prodrug thereof, in the manufacture of a medicament for the inhibition of aurora 2 kinase: (I) Wherein X is O, S, S (O) or S (O) 2 or NH or NR 12 wherein R 12 is hydrogen or C 1-6 alkyl; R 5 is NHC (O) OR 9, NHC (O) R 9, NHS (O) 2 R 9, C (O) R 9, C (O) OR 9, S (O) R 9, S (O) oR 9, S (O) 2 oR 9, C (O) NR 10 R 11, S (O) NR 10 R 11, S (O) ONR 10 R 11 ( wherein, R 9, R 10 or R 11 are different Lt; / RTI > are selected from the group consisting of R < 6 > is hydrogen, optionally substituted hydrocarbyl or optionally substituted heterocyclyl; R 7 and R 8 are various specific organic groups; R 1, R 2, R 3 , R 4 is a halogeno, cyano, nitro, C 1-3 alkyl sulfanyl, -N (OH) R 13 - ( wherein, R 13 is hydrogen or C 1-3 alkyl Or R 15 X 1 - wherein X 1 is a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, -S-, -SO 2 -, -NR 16 CO-, -CONR 16 -, -SO 2 NR 16 - , -NR 17 SO 2 - or -NR 18 - (wherein, R 16, R 17 and R 18 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C And R < 15 > is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl or optionally substituted alkoxy.
    公开号:KR20020032612A
    申请号:KR1020027003704
    申请日:2000-09-18
    公开日:2002-05-03
    发明作者:앤드류 오스텐 몰트록；니콜라스 존 킨；페더릭 헨리 중；앤드류 조지 브루스터
    申请人:다비드 에 질레스；아스트라제네카 아베；
    IPC主号:
    专利说明:

    Quinazoline Derivatives and Their Use as Medicines < RTI ID = 0.0 >
    [2] Cancer (and other hyperproliferative diseases) is characterized by uncontrolled cell proliferation. Such loss of normal regulation of cell proliferation often appears to result from genetic damage to the cell pathway that controls progression through cell cycle.
    [3] In eukaryotes, cellular circulation is largely controlled by the protein phosphorylation at an aligned stage. Several groups of protein kinases have been identified that play an important role in this step. The activity of many of these kinases increases in human tumors compared to normal tissues. This can occur by increasing the expression level of the protein (for example, as a result of gene amplification) or by altering the expression of coactivators or inhibitory proteins.
    [4] The first identified and most widely studied of these cell cycle regulators is cyclin dependent kinases (CDKs). The specific CDK activity at a specific time point is important for both initiation and coordinated progression throughout the cell cycle. For example, the CDK4 protein appears to control entry into the cell cycle by phosphorylating the retinoblastoma gene product pRb. This stimulates the release of the transcription factor E2F from pRb, which in turn acts to increase the transcription of the gene necessary to enter the S phase. The catalytic activity of CDK4 is stimulated by binding to the parent protein Cyclin D. One of the first demonstrations of a direct link between cancer and cell purification is the observation that in many human tumors the cyclin D1 gene is amplified and the level of Cyclin D protein is increased (and thus the activity of CDK4 is increased) See: [Sherr, 1996, Science 274: 1672-1677]; [Pines, 1995, Seminars in Cancer Biology 6: 63-72]). (Gemma et al., 1996, International Journal of Cancer 68 (5): 605-11); [Elledge et < RTI ID = 0.0 > al. 1996, Trends in Cell Biology 6, 388-392) have shown that CDK function negative regulators are downregulated or deleted in human tumors, which often makes the activation of these kinases inadequate.
    [5] More recently, protein kinases, which are structurally distinct from the CDK group, play an important role in regulating cell cycle, and appear important in tumorigenesis, have also been identified. This includes the newly identified Drosophila aurora and human homologues of the S. cerevisiae Ipl1 protein. Drosophila aurora and S. cerevisiae Ipl1 have high homology at amino acid sequence level and encode serine / threonine protein kinase. Both aurora and Ipl1 are known to be involved in controlling metastasis from the G2 phase of the cell cycle through mitosis, central function, formation of mitotic spindles and proper chromosome division / separation. The two human homologues of these genes are called Aurora 1 and Aurora 2, which encode a protein cycle regulated cell cycle. These represent peaks of expression and kinase activity in the G2 / M boundary (aurora 2) and mitosis itself (aurora 1). Several observations suggest that human auroral proteins, especially Aurora-2, are associated with cancer. The Aurora 2 gene maps to chromosome 20q13, and chromosome 20q13 is a region that is often amplified in human tumors, including breast and colon tumors. Aurora-2 can be the main target gene for this amplicon, because Aurora-2 DNA is amplified and over-expressed Aurora-2 mRNA in over 50% of the major human colon cancers. In these tumors, levels of Aurora 2 protein are very high compared to adjacent normal tissues. In addition, transfection of rodent fibroblasts with human Aurora-2 allows transformation to occur and to grow in soft agar and form tumors in nude mice (Bischoff et al., 1998, The EMBO Journal. (11): 3052-3065). Other studies (Zhou et al., 1998, Nature Genetics. 20 (2): 189-93) have shown that artificially over-expressing Aurora 2 increases the number of centrosomes and increases the biocompatibility.
    [6] Importantly, when a human tumor cell line is treated with an antisense oligonucleotide to terminate aurora 2 expression and function (WO 97/22702 and WO 99/3778), the cell cycle is stopped on G2 of the cell cycle and an antiproliferative effect on the tumor cell line It is proven that it exerts. This means that inhibition of the function of Aurora-2 may be useful in the treatment of human tumors and other hyperproliferative diseases.
    [7] To date, a large number of quinazoline derivatives have been proposed for inhibiting various diseases. For example, WO 96/09294, WO 96/33981 and EP 0 837 063 describe the use of certain quinazoline compounds as receptor tyrosine kinase inhibitors, which may be useful in the treatment of proliferative diseases.
    [1] The present invention relates to certain quinazoline derivatives, novel quinazoline compounds and processes for their preparation and to their use in the manufacture of medicaments for the treatment of certain diseases, in particular proliferative diseases such as cancer, and for the treatment of proliferative diseases, ≪ / RTI >
    [8] Applicants have discovered a series of compounds that inhibit the effects of Aurora 2 kinase and are therefore useful in the treatment of proliferative diseases such as cancer, particularly diseases such as colorectal cancer or breast cancer, where Aurora 2 kinase is known to have activity.
    [9] The present invention provides the use of a compound of formula (I), or a salt, ester, amide or prodrug thereof, for the manufacture of a medicament for inhibiting Aurora 2 kinase:
    [10]
    [11] Wherein X is O, S, S (O) or S (O) 2 or NH or NR 12 wherein R 12 is hydrogen or C 1-6 alkyl;
    [12] R 5 is NHC (O) OR 9, NHC (O) R 9, NHS (O) 2 R 9, C (O) R 9, C (O) OR 9, S (O) R 9, S (O) oR 9, S (O) 2 oR 9, C (O) NR 10 R 11, S (O) NR 10 R 11, S (O) ONR 10 R 11 ( wherein, R 9, R 10 or R 11 is hydrogen , Optionally substituted hydrocarbyl and optionally substituted heterocyclyl, and R 10 and R 11 , together with the nitrogen atom to which they are attached, ≪ / RTI >
    [13] R < 6 > is hydrogen, optionally substituted hydrocarbyl or optionally substituted heterocyclyl;
    [14] R 7 and R 8 are independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxymethyl, di (C 1-4 alkoxy) methyl, C 1-4 alkanoyl, trifluoromethyl A 5 to 6 membered heteroaromatic ring having 1 to 3 heteroatoms (independently selected from O, S and N), optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, C 2-5 alkenyl, C 2-5 alkynyl, phenyl, Cyclic group wherein said heterocyclic group may be aromatic or non-aromatic and may be saturated (linked through a ring carbon or nitrogen atom) or unsaturated (linked via a ring carbon atom), said phenyl, benzyl or hetero cyclic group is hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro, C 2-4 alkanoylamino, C 1 -4 alkanoylamino, C 1-4 alkoxycarbonyl, C 1-4 alkyl sulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, carbamoyl, NC 1-4 alkyl carbamoyl , N, N-di (C ( C1-4 alkyl) carbamoyl, aminosulfonyl, NC 1-4 alkylaminosulfonyl, N, N-di (C 1-4 alkyl) aminosulfonyl, C 1-4 alkylsulfonylamino, Saturated saturated heterocyclic group selected from oxo, hydroxy, halogeno, C < RTI ID = 0.0 > 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, can possess a trifluoromethyl, methyl, cyano, amino, nitro and C 1-4 alkoxy group by one or two substituents selected from carbonyl) ≪ / RTI > may be on one or more ring carbon atoms;
    [15] R 1, R 2, R 3 , R 4 is a halogeno, cyano, nitro, C 1-3 alkyl sulfanyl, -N (OH) R 13 - ( wherein, R 13 is hydrogen or C 1-3 alkyl Or R 15 X 1 - wherein X 1 is a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, -S-, -SO-, -SO 2 -, -NR 16 CO -, -CONR 16 -, -SO 2 NR 16 -, -NR 17 SO 2 - or -NR 18 -, wherein R 16 , R 17 and R 18 are each independently hydrogen, C 1-3 alkyl or C 1 -3 alkoxy C 2-3 alkyl, and R 15 is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl or optionally substituted alkoxy.
    [16] In particular, such agents are useful in the treatment of proliferative diseases such as cancer, especially those in which Aurora 2 is upregulated, such as colon or breast cancer.
    [17] As used herein, the term " alkyl " is used alone or as a prefix and includes straight chain, branched chain structures. Unless otherwise stated, this group may contain up to 10 carbon atoms, preferably up to 6, more preferably up to 4 carbon atoms. Similarly, the terms " alkenyl " and " alkynyl " refer to an unsaturated straight or branched chain structure containing, for example, from 2 to 10, preferably from 2 to 6 carbon atoms. Cyclic moieties such as cycloalkyl, cycloalkenyl, and cycloalkynyl are similar in nature but have three or more carbon atoms. The term " alkoxy " includes alkyl groups as understood in the art.
    [18] The term " halo " includes fluoro, chloro, bromo, and iodo. The aryl group includes an aromatic carbocyclic group such as phenyl and naphthyl. The term " heterocyclyl " refers to an aromatic or non-aromatic ring containing from 4 to 20, preferably from 5 to 8, ring atoms, of which at least one is a heteroatom such as oxygen, sulfur or nitrogen . Examples of such groups include furyl, thienyl, pyrrolyl, pyrrolidinyl, imidazolyl, triazolyl, thiazolyl, tetrazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, Pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, benzothienyl or benzofuryl. Examples of non-aromatic heterocyclyl groups include morpholino, piperidino, azetidine, tetrahydrofuryl, tetrahydropyridyl. In the case of a double ring, it may include aromatic and non-aromatic moieties.
    [19] &Quot; Heteroaryl " refers to such groups having aromatic character. The term " aralkyl " refers to an aryl substituted alkyl group such as benzyl.
    [20] Other expressions used in the specification include " hydrocarbyl ", which refers to any structure including carbon and hydrogen atoms. The moiety can be saturated or unsaturated. For example, it may be alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl, or combinations thereof.
    [21] Examples of such combinations include alkyl, alkenyl, or alkynyl substituted with aryl, aralkyl, cycloalkyl, cycloalkenyl, or cycloalkynyl, or aryl, heterocyclyl, or heterocyclyl substituted with alkyl, alkenyl, alkynyl, or alkoxy, Alkoxy, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl, although others are contemplated.
    [22] In particular, the hydrocarbyl group includes alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or cycloalkynyl.
    [23] The term " functional group " refers to a reactive substituent such as nitro, cyano, halo, oxo, = CR 78 R 79 , C (O) x R 77 , OR 77 , S (O) y R 77 , NR 78 R 79 (O) NR 78 R 79 , OC (O) NR 78 R 79 , -NOR 77 , -NR 77 C (O) x R 78 , -NR 77 CONR 78 R 79 , -N = CR 78 R 79 , S (O) y NR 78 R 79 or -NR 77 S (O) y R 78 wherein R 77 , R 78 and R 79 are independently selected from hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl or optionally substituted Or R 78 and R 79 together form an optionally substituted ring optionally further comprising a heteroatom such as oxygen, nitrogen, S, S (O) or S (O) 2, and x is 1 or 2, and y is 0 or an integer of 1 to 3).
    [24] Suitable optional substituents for the ring formed by hydrocarbyl, heterocyclyl or alkoxy groups R 77 , R 78 and R 79 , and R 78 and R 79 include halo, perhaloalkyl (e.g., trifluoromethyl) Alkoxy, alkoxy, alkoxy, aryloxy, wherein the aryl group is optionally substituted with one or more substituents selected from the group consisting of halo, halo, hydroxy, carboxy, alkoxy, heteroaryl, heteroaryloxy, cycloalkyl, cycloalkenyl, cycloalkynyl, Nitro, amino, mono- or di-alkylamino, oximino or S (O) y R 90 wherein y is as defined above and R 90 is selected from the group consisting of A hydrocarbyl group such as alkyl).
    [25] In particular, optional substituents for hydrocarbyl, heterocyclyl or alkoxy groups R 77 , R 78 and R 79 include halo, perhaloalkyl (e.g. trifluoromethyl), mercapto, hydroxy, carboxy, alkoxy, Alkoxy, alkoxy, alkoxy, aryloxy (wherein the aryl group may be substituted by halo, nitro or hydroxy), cyano, nitro, amino, mono-or di -Alkylamino, oximino or S (O) y R 90 , wherein y is as defined above and R 90 is a hydrocarbyl group such as alkyl.
    [26] Certain compounds of formula I may contain a chiral center and the invention includes all enantiomeric forms thereof and mixtures thereof including racemic mixtures.
    [27] In particular, R < 15 > is hydrogen or an alkyl group, optionally substituted with one or more groups selected from the above functional groups, or an alkenyl, alkynyl, aryl, heterocyclyl, cycloalkyl, cycloalkenyl or cycloalkynyl Cycloalkyl, cycloalkenyl, cycloalkynyl groups may optionally be substituted with hydrocarbyl (e.g., alkyl, alkenyl or alkynyl), which may be substituted with such functional groups, and wherein any aryl, heterocyclyl, cycloalkyl, . ≪ / RTI >
    [28] For example, R 15 is selected from one of the following 22 groups:
    [29] 1) C 1-5 alkyl which is unsubstituted or may be substituted with at least one functional group, or hydrogen;
    [30] 2) -R a X 2 C (O) R 19 wherein X 2 represents -O- or -NR 20 - (wherein R 20 represents hydrogen or alkyl optionally substituted by one functional group) R 19 is C 1-3 alkyl, -NR 21 R 22 or -OR 23 wherein R 21 , R 22 and R 23 may be the same or different and are each hydrogen or alkyl optionally substituted with one functional group );
    [31] 3) -R b X 3 R 24 { wherein, X 3 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 25 C (O) s -, -C ( O) NR 26 -, -SO 2 NR 27 -, -NR 28 SO 2 - or -NR 29 - (wherein, R 25, R 26, R 27, R 28 and R 29 Are each independently hydrogen or alkyl optionally substituted by one functional group and s is 1 or 2 and R 24 represents hydrogen, hydrocarbyl (as defined herein) or a saturated heterocyclic group, Wherein said hydrocarbyl or heterocyclic group may be optionally substituted by one or more functional groups and said heterocyclic group may be further substituted by one hydrocarbyl group;
    [32] 4) -R c X 4 R c ' X 5 R 30 wherein X 4 and X 5 may be the same or different and are each -O-, -C (O) -, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 31 C (O) s -, -C (O) x NR 32 -, -SO 2 NR 33 -, -NR 34 SO 2 - or -NR 35 - (Wherein R 31 , R 32 , R 33 , R 34 and R 35 are each independently hydrogen or alkyl optionally substituted by one functional group and s is 1 or 2), R 30 represents hydrogen , Or alkyl optionally substituted by one functional group;
    [33] 5) R 36 wherein R 36 is a C 3-6 cycloalkyl or a saturated heterocyclic ring connected via carbon or nitrogen and wherein the cycloalkyl or heterocyclic group may be substituted by one or more functional groups, Which may be substituted by one hydrocarbyl or heterocyclyl group which may be optionally substituted by one or more functional groups;
    [34] 6) -R d R 36 , wherein R 36 is as defined above;
    [35] 7) -R e R 36 wherein R 36 is as defined above;
    [36] 8) -R f R 36 wherein R 36 is as defined above;
    [37] 9) R 37 wherein R 37 represents a pyridone group, an aryl group, or an aromatic heterocyclic group having 1 to 3 hetero atoms selected from O, N and S (connected via carbon or nitrogen) The donor, aryl or aromatic heterocyclic group may be substituted by one or more functional groups, or may be substituted by one hydrocarbyl group optionally substituted by one or more functional groups or heterocyclyl groups, or may be substituted by one or more functional groups or hydrocarbons Which may be substituted by one heterocyclyl group optionally substituted by a bicyclic group;
    [38] 10) -R g R 37 wherein R 37 is as defined above;
    [39] 11) -R h R 37 wherein R 37 is as defined above;
    [40] 12) -R i R 37 wherein R 37 is as defined above;
    [41] 13) -R j X 6 R 37 wherein X 6 is -O-, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 42 C (O) NR 43 -, -SO 2 NR 44 -, -NR 45 SO 2 - or -NR 46 -, wherein R 42 , R 43 , R 44 , R 45 and R 46 are each independently hydrogen or one And R < 37 > is the same as defined above;
    [42] 14) -R k X 7 R 37 { wherein, X 7 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 47 C (O) -, -C (O ) NR 48 -, -SO 2 NR 49 -, -NR 50 SO 2 - or -NR 51 - (wherein, R 47, R 48, R 49, R 50 and R 51 is Each independently represent hydrogen or alkyl optionally substituted by one functional group, and R 37 is as defined above;
    [43] 15) -R m X 8 R 37 { wherein, X 8 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 52 C (O) -, -C (O ) NR 53 -, -SO 2 NR 54 -, -NR 55 SO 2 - or -NR 56 - (wherein, R 52, R 53, R 54, R 55 and R 56 is Each independently represent hydrogen or alkyl optionally substituted by one functional group, and R 37 is as defined above;
    [44] 16) -R n X 9 R n ' R 37 wherein X 9 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -OC NR 57 C (O) -, -C (O) NR 58 -, -SO 2 NR 59 -, -NR 60 SO 2 - or -NR 61 - (wherein, R 57, R 58, R 59, R 60 , and R 61 independently represents hydrogen or alkyl optionally substituted by one functional group, and R 37 is as defined above;
    [45] 17) -R p X 9 R p ' R 36 wherein X 9 and R 36 are as defined above;
    [46] 18) C 2-5 alkenyl which is unsubstituted or may be substituted with at least one functional group;
    [47] 19) C 2-5 alkynyl which is unsubstituted or may be substituted with at least one functional group;
    [48] 20) -R t X 9 R t ' R 36 wherein X 9 and R 36 are as defined above;
    [49] 21) -R u X 9 R u ' R 36 wherein X 9 and R 36 are as defined above; And
    [50] 22) -R v R 62 (R v ') q (X 9) r R 63 { wherein, X 9 is as defined above, q is 0 or 1, r is 0 or 1, R 62 is C 1 -3 alkylene group, a divalent cycloalkyl or a heterocyclic group (wherein the C 1-3 alkylene group may be substituted by at least one functional group, and the cyclic group may be substituted with at least one functional group Or by one hydrocarbyl group optionally substituted by at least one functional group or heterocyclyl group or by one heterocyclyl group optionally substituted by at least one functional group or hydrocarbyl group, And R 63 is hydrogen or C 1-3 alkyl or a cyclic group selected from a cycloalkyl or a heterocyclic group wherein the C 1-3 alkyl group may be substituted by at least one functional group, The cyclic group may be substituted by at least one functional group Or may be substituted by one hydrocarbyl group optionally substituted by at least one functional group or heterocyclyl group or by one heterocyclyl group optionally substituted by at least one functional group or hydrocarbyl group }
    [51] [In the above groups, R a, R b, R c, R c ', R d, R g, R j, R n, R n', R p, R p ', R t', R u ', R v and R v ' are independently selected from a C 1-8 alkylene group optionally substituted by one or more substituent functional groups,
    [52] R e , R h , R k and R t are independently selected from C 2-8 alkenylene groups optionally substituted by one or more functional groups,
    [53] R f , R i , R m and R u are independently selected from C 2-8 alkynylene groups optionally substituted by one or more functional groups.
    [54] Specific examples of the 22 groups of R 15 are:
    [55] 1) C 1-5 alkyl which is unsubstituted or substituted with one or more groups selected from hydroxy, oxiranyl, fluoro, chloro, bromo and amino (including C 1-3 alkyl and trifluoromethyl), Or hydrogen;
    [56] 2) -R a X 2 C (O) R 19 wherein X 2 is -O- or -NR 20 - wherein R 20 is hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 And R 19 represents C 1-3 alkyl, -NR 21 R 22 or -OR 23 (wherein R 21 , R 22 and R 23 may be the same or different and each represents hydrogen, C 1-5 alkyl, hydroxyC 1-5 alkyl or C 1-3 alkoxyC 2-3 alkyl;
    [57] 3) -R b X 3 R 24 { wherein, X 3 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 25 C (O) s -, -NR 25 C (O) NR 26 -, -C (O) NR 26 -, -SO 2 NR 27 -, -NR 28 SO 2 - or -NR 29 - (wherein, R 25, R 26 , R 27 , R 28 and R 29 are each independently hydrogen, C 1-3 alkyl, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl, and s is 1 or 2, And R 24 is hydrogen, C 1-6 alkyl or C 2-6 alkenyl, or is a cyclic group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or independently from O, S and N Wherein said C 1-6 alkyl group is selected from the group consisting of oxo, hydroxy, halogeno, cyclopropyl, amino, C 1-4 alkylamino, di -C 1-4 alkylamino, C 1-4 alkylthio, and can have one, two or three substituents selected from C 1-4 alkoxy, wherein the cyclic groups are oxo, hydroxy When, halogeno, cyano, C 1-4 cyanoalkyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1- 4 alkylsulfonyl C 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 aminoalkyl, C 1-4 alkylamino, di (C 1-4 alkyl) amino, C 1-4 alkylamino C 1 -4 alkyl, di (C 1-4 alkyl) amino C 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkylamino, C 1-4 alkoxy, di (C 1-4 alkyl) amino C 1- 4 alkoxy and - (- O-) f and (R b ') g D group (where, f is 0 or 1, g is 0 or 1 and ring D is a C 3-6 alkyl group or a cycloalkyl or aryl, O, S and N, wherein said cyclic group may be optionally substituted with one or more substituents selected from halo or C 1-4 alkyl, wherein said cyclic group is optionally substituted with one or more substituents selected from halo, C 1-4 alkyl, Lt; RTI ID = 0.0 > 1, < / RTI >
    [58] 4) -R c X 4 R c ' X 5 R 30 wherein X 4 and X 5 may be the same or different and are each -O-, -C (O) -, -S-, -SO-, -SO 2 -, -NR 31 C ( O) s -, -C (O) x NR 32 -, -SO 2 NR 33 -, -NR 34 SO 2 - or -NR 35 - represents a (wherein, R 31 , R 32 , R 33 , R 34 and R 35 are each independently hydrogen, C 1-3 alkyl, hydroxy C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl, s is 1 or 2 ), R 30 represents hydrogen, C 1-3 alkyl, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl;
    [59] 5) R 36 wherein R 36 is a 4 to 6 membered cycloalkyl or a saturated heterocyclic ring (linked via carbon or nitrogen) having one or two heteroatoms independently selected from O, S and N, In this case, the cycloalkyl or heterocyclic group, oxo, hydroxy, halogeno, cyano, C 1-4 alkyl, hydroxy C 1-4 alkyl, cyano C 1-4 alkyl, cyclopropyl, C 1-4 alkylsulfonyl C 1-4 alkyl, C 1-4 alkoxycarbonyl, carboxamide not shown, C 1-4 aminoalkyl, C 1-4 alkylamino, di (C 1-4 alkyl) amino, C 1-4 alkyl (C 1-4 alkyl) aminoC 1-4 alkyl, C 1-4 alkylaminoC 1-4 alkoxy, di (C 1-4 alkyl) aminoC 1-4 alkyl, aminoC 1-4 alkyl, C 1-4 alkanoyl, di C 1-4 alkoxy, nitro, amino, C 1-4 alkoxy, C 1-4 hydroxy alkoxy, carboxy, trifluoromethyl, -C (O) NR 38 R 39, -NR 40 C (O) R 41 (wherein, R 38, R 39, R 40 and R 41 may be the same or different and each Cattle, C 1-4 alkyl, hydroxy C 1-4 alkyl, or represents a C 1-3 alkoxy C 2-3 alkyl), and - (- O-) f (C 1-4 alkyl) g D group (wherein , f is 0 or 1, g is 0 or 1, and ring D is C 3-6 cycloalkyl, aryl, or a 5 or 6 membered saturated or unsaturated ring having 1 or 2 heteroatoms independently selected from O, S and N Or an unsaturated heterocyclic group, and the cyclic group may have one or more substituents selected from halo or C 1-4 alkyl;
    [60] 6) -R d R 36 , wherein R 36 is as defined above;
    [61] 7) -R e R 36 wherein R 36 is as defined above;
    [62] 8) -R f R 36 wherein R 36 is as defined above;
    [63] 9) R 37 wherein R 37 represents a pyridone group, a phenyl group, or a 5 or 6 membered aromatic heterocyclic group (connected via carbon or nitrogen) having 1 to 3 heteroatoms selected from O, N and S Wherein said pyridone, phenyl or aromatic heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, nitro, halogeno, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C C 1-4 alkyl, C 1-4 hydroxyalkoxy, oxo, cyano C 1-4 alkyl, cyclopropyl, C 1-4 alkylsulfonyl C 1-4 alkyl, C 1-4 alkoxycarbonyl, di C 1-4 alkyl) amino, C 1-4 alkylaminoC 1-4 alkyl, C 1-4 alkanoyl, di (C 1-4 alkyl) aminoC 1-4 alkyl, C 1-4 alkylaminoC 1 -4 alkoxy, di (C 1-4 alkyl) amino C 1-4 alkoxy, carboxy, carboxamide not shown, trifluoromethyl, cyano, -C (O) NR 38 R 39, -NR 40 C (O) R 41 (wherein, R 38, R 39, R 40 and R 41 may be the same or different and each Cattle, C 1-4 alkyl, hydroxy C 1-4 alkyl, or represents a C 1-3 alkoxy C 2-3 alkyl), and - (- O-) f (C 1-4 alkyl) g D group (wherein , f is 0 or 1, g is 0 or 1, ring D is a C 3-6 cycloalkyl group, aryl, or a 5 or 6 membered saturated or unsaturated ring having 1 or 2 heteroatoms independently selected from O, S and N Or an unsaturated heterocyclic group, and the cyclic group may have at least one substituent selected from halo or C 1-4 alkyl);
    [64] 10) -R g R 37 wherein R 37 is as defined above;
    [65] 11) -R h R 37 wherein R 37 is as defined above;
    [66] 12) -R i R 37 wherein R 37 is as defined above;
    [67] 13) -R j X 6 R 37 wherein X 6 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 42 C (O) -, -C (O ) NR 43 -, -SO 2 NR 44 -, -NR 45 SO 2 - or -NR 46 - (wherein, R 42, R 43, R 44, R 45 and R 46 is Each independently represents hydrogen, C 1-3 alkyl, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl, and R 37 is as defined above;
    [68] 14) -R k X 7 R 37 wherein X 7 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -NR 47 C (O) NR 48 -, -SO 2 NR 49 -, -NR 50 SO 2 - or -NR 51 - (wherein, R 47, R 48, R 49, R 50 and R 51 are independently hydrogen, C 1 each -3 alkyl, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl, and R 37 is as defined above;
    [69] 15) -R m X 8 R 37 wherein X 8 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -NR 52 C (O) NR 53 -, -SO 2 NR 54 -, -NR 55 SO 2 - or -NR 56 - wherein R 52 , R 53 , R 54 , R 55 and R 56 are each independently hydrogen, C 1 -3 alkyl, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl, and R 37 is as defined above;
    [70] 16) -R n X 9 R n ' R 37 wherein X 9 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -NR 57 C , -C (O) NR 58 - , -SO 2 NR 59 -, -NR 60 SO 2 - or -NR 61 - (wherein, R 57, are each independently hydrogen, R 58, R 59, R 60 and R 61 , C 1-3 alkyl, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl), and R 37 is as defined above;
    [71] 17) -R p X 9 R p ' R 36 wherein X 9 and R 36 are as defined above;
    [72] 18) is optionally substituted, hydroxy, fluoro, amino, C 1-4 alkylamino, carboxyl (and in particular its alkyl ester), N, N- di (C 1-4 alkyl) amino, aminosulfonyl, NC 1 -4-alkyl aminosulfonyl and N, N- di (C 1-4 alkyl) aminosulfonyl C 2-5 alkenyl which may be substituted with one or more selected from;
    [73] 19) a is optionally substituted, hydroxy, fluoro, amino, C 1-4 alkylamino, N, N- di (C 1-4 alkyl) amino, aminosulfonyl, NC 1-4 alkylamino, sulfonyl and N, C 2-5 alkynyl which may be substituted with one or more groups selected from N-di (C 1-4 alkyl) aminosulfonyl;
    [74] 20) -R t X 9 R t ' R 36 wherein X 9 and R 36 are as defined above;
    [75] 21) -R u X 9 R u ' R 36 wherein X 9 and R 36 are as defined above; And
    [76] 22) -R v R 62 (R v ') q (X 9) r R 63 { wherein, X 9 is as defined above, q is 0 or 1, r is 0 or 1, R 62 is C 1 3 alkylene group or a 5 or 6 membered saturated heterocyclic group having 1 or 2 heteroatoms independently selected from O, S and N, selected from cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, Wherein said C 1-3 alkylene group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy, said cyclic group being optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, halo C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1-4 alkyl C 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 aminoalkyl, C 1-4 alkylamino, di (C 1-4 alkyl) amino, C 1-4 alkylamino C 1-4 alkyl , Di (C 1-4 alkyl) aminoC 1-4 alkyl, C 1-4 alkyl Kill amino C 1-4 alkoxy, di (C 1-4 alkyl) amino C 1-4 alkoxy and - (- O-) f (C 1-4 alkyl) g D group (this time, and f is 0 or 1, g is 0 or 1, and ring D is selected from a C 3-6 cycloalkyl group, aryl, or a 5 or 6 membered saturated or unsaturated heterocyclic group having 1 or 2 heteroatoms independently selected from O, S and N And the cyclic group may have one or more substituents selected from halo or C 1-4 alkyl, and R 63 is hydrogen or C 1-3 alkyl, A cyclic group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a 5 or 6 membered saturated or unsaturated heterocyclic group having one or two heteroatoms independently selected from O, S and N, The C 1-3 alkyl group may be substituted by oxo, hydroxy, halogeno, C 1-4 alkoxy, And wherein said cyclic group is optionally substituted with one or two substituents selected from the group consisting of oxo, hydroxy, halogeno, cyano, C 1-4 cyanoalkyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1 -4 alkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1-4 alkylsulfonyl C 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 aminoalkyl, C 1-4 alkylamino, Di (C 1-4 alkyl) amino, C 1-4 alkylamino C 1-4 alkyl, di (C 1-4 alkyl) aminoC 1-4 alkyl, C 1-4 alkylaminoC 1-4 alkoxy, di (C 1-4 alkyl) aminoC 1-4 alkoxy and - (-O-) f (C 1-4 alkyl) g D wherein f is 0 or 1, g is 0 or 1, and ring D Is a C 3-6 cycloalkyl, aryl, or a cyclic group selected from a 5 or 6 membered saturated or unsaturated heterocyclic group having one or two heteroatoms independently selected from O, S and N, halo or C 1-4 selected from the substituents that may have more selected from alkyl), or 1 Which may have two substituents.
    [77] [In the group, R a, R b, R b ', R c, R c', R d, R g, R j, R n, R n ', R p, R p', R t ', R u ' , R v and R v' are independently selected from C 1-8 alkylene groups optionally substituted by one or more substituents selected from hydroxy, halogeno, amino,
    [78] R e , R h , R k and R t are independently selected from C 2-8 alkenylene groups optionally substituted by one or more substituents selected from hydroxy, halogeno, amino, and R t may additionally be a bond ,
    [79] R f , R i , R m and R u are independently selected from C 2-5 alkynylene groups optionally substituted by one or more substituents selected from hydroxy, halogeno, amino.
    [80] In particular, R 1 , R 2 , R 3 or R 4 are independently selected from the group consisting of halo, cyano, nitro, trifluoromethyl, C 1-3 alkyl, -NR 13 R 14 wherein R 13 and R 14 are the same or different Each represent hydrogen or C 1-3 alkyl, or is selected independently from -X 1 R 15 , wherein X 1 is a direct bond, -O-, -CH 2 -, -OCO-, carbonyl , -S-, -SO-, -SO 2 - , -NR 16 CO-, -CONR 16 -, -SO 2 NR 16 -, -NR 17 SO 2 - or -NR 18 - (wherein, R 16, R 17 and R 18 each independently represent hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl, and R 15 is selected from one of the following groups:
    [81] 1 ') C 1-5 alkyl which is unsubstituted or may be substituted with one or more groups selected from hydroxy, fluoro or amino, or hydrogen;
    [82] 2 ') C 1-5 alkyl X 2 COR 19 wherein X 2 is -O- or -NR 20 - wherein R 20 is hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl , R 19 represents C 1-3 alkyl, -NR 21 R 22 or -OR 23 wherein R 21 , R 22 and R 23 may be the same or different and each represents hydrogen, C 1 -3 alkyl or C 1-3 alkoxyC 2-3 alkyl;
    [83] 3 ') C 1-5 alkyl X 3 R 24 wherein X 3 is -O-, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 25 CO-, -C (O) NR 26 -, -SO 2 NR 27 -, -NR 28 SO 2 - or -NR 29 - wherein R 25 , R 26 , R 27 , R 28 and R 29 are each independently hydrogen, C 1 3 alkyl or C 1-3 alkoxy C 2-3 alkyl, and R 24 represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl, or one or two independently selected from O, S and N Wherein the C 1-3 alkyl group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy, and wherein the C 1-3 alkyl group may be substituted with one or two substituents selected from the group consisting of The cyclic group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy;
    [84] 4 ') C 1-5 alkyl X 4 C 1-5 alkyl X 5 R 30 wherein X 4 and X 5 may be the same or different and are each -O-, -S-, -SO-, -SO 2 -, -NR 31 CO-, -CONR 32 -, -SO 2 NR 33 -, -NR 34 SO 2 - or -NR 35 - represents a (wherein, R 31, R 32, R 33, R 34 and R 35 each independently represent hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl), and R 30 represents hydrogen or C 1-3 alkyl;
    [85] 5 ') R 36 wherein R 36 is a 5 or 6 membered saturated heterocyclic ring (linked via carbon or nitrogen) having 1 or 2 heteroatoms independently selected from O, S and N, The heterocyclic group may be optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl and C 1-4 alkylsulfonyl Lt; / RTI > alkyl optionally substituted with one or two substituents selected from C1-4 alkyl;
    [86] 6 ') C 1-5 alkyl R 36 wherein R 36 is as defined in 5'above;
    [87] 7 ') C 2-5 alkenyl R 36 wherein R 36 is as defined in 5'above;
    [88] 8 ') C 2-5 alkynyl R 36 wherein R 36 is as defined in 5'above;
    [89] 9 ') R 37 wherein R 37 is a pyridone group, a phenyl group, or a 5 or 6 membered aromatic heterocyclic group (linked via carbon or nitrogen) having 1 to 3 heteroatoms selected from O, N and S Wherein said pyridone, phenyl or aromatic heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogeno, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1 -4 alkylamino, C 1-4 hydroxy alkoxy, carboxy, trifluoromethyl, cyano, -C (O) NR 38 R 39, and -NR 40 C (O) R 41 ( wherein, R 38, R 39 , R 40 and R 41 , which may be the same or different, each represent hydrogen, C 1-4 alkyl or C 1-3 alkoxy C 2-3 alkyl) may be substituted on any possible carbon atom You can have}};
    [90] 10 ') C 1-5 alkyl R 37 wherein R 37 is as defined in 9'above;
    [91] 11 ') C 2-5 alkenyl R 37 wherein R 37 is as defined in 9'above;
    [92] 12 ') C 2-5 alkynyl R 37 wherein R 37 is as defined in 9'above;
    [93] 13 ') C 1-5 alkyl X 6 R 37 wherein X 6 is -O-, -S-, -SO-, -SO 2 -, -NR 42 CO-, -CONR 43 -, -SO 2 NR 44 -, -NR 45 SO 2 - or -NR 46 - (wherein, R 42, R 43, R 44, R 45 and R 46 are independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2 each -3 alkyl, and R 37 is the same as defined in 9 ');
    [94] 14 ') C 2-5 alkenyl X 7 R 37 wherein X 7 is -O-, -S-, -SO-, -SO 2 -, -NR 47 CO-, -CONR 48 -, -SO 2 NR 49 -, -NR 50 SO 2 - or -NR 51 -, wherein R 47 , R 48 , R 49 , R 50 and R 51 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl), and R 37 is the same as defined in 9 ');
    [95] 15 ') C 2-5 alkynyl X 8 R 37 wherein X 8 is -O-, -S-, -SO-, -SO 2 -, -NR 52 CO-, -CONR 53 -, -SO 2 NR 54 -, -NR 55 SO 2 - or -NR 56 - (wherein, R 52, R 53, R 54, R 55 and R 56 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C Gt ; and R < 37 > are as defined above;
    [96] 16 ') C 1-3 alkyl X 9 C 1-3 alkyl R 37 wherein X 9 is -O-, -S-, -SO-, -SO 2 -, -NR 57 CO-, -CONR 58 - , -SO 2 NR 59 -, -NR 60 SO 2 - or -NR 61 - (wherein, R 57, R 58, R 59, R 60 and R 61 are independently hydrogen, C 1-3 alkyl, or C 1 each -3 alkoxyC 2-3 alkyl, and R 37 is as defined above; And
    [97] 17 ') C 1-3 alkyl X 9 C 1-3 alkyl R 36 wherein X 9 and R 36 are as defined in 5' above.
    [98] R 1 is preferably hydrogen. R 4 is suitably hydrogen or a small substituent such as halo, C 1-4 alkyl or C 1-4 alkoxy such as methoxy.
    [99] It is preferable that R 1 and R 4 are both hydrogen.
    [100] In a preferred embodiment, at least one group R 2 or R 3, preferably R 3 is at least 3, preferably at least 4 optionally substituted carbon atom or a hetero atom: the chain (such as oxygen, nitrogen or sulfur) . Most preferably, the chain is substituted by a polar group which serves solubility.
    [101] R 3 is an X 1 R 15 group.
    [102] In this case, preferably, X 1 is oxygen and R 15 comprises a methylene group immediately adjacent to X 1 . Preferably, R a , R b , R b ' , R c , R c' , R d , R g , R j , R n and R n ' , which are bridging alkylene, alkenylene or alkynylene groups, When R p , R t , R u , R v , R v , R e , R h , R k , R t , R f , R i , R m and R u are present, One includes substituents, especially hydroxy substituents.
    [103] Particularly, R 15 is selected from the groups represented by the above formulas (1), (3), (6), (10) or (22), and is preferably selected from the groups of (1) or (10). The group R < 15 > is especially the group of the above (1), among which alkyl (e.g. methyl or halo substituted alkyl) or the group of the above (10). In one suitable embodiment, at least one of R 2 or R 3 is an OC 1-5 alkyl R 36 , and R 36 is a heterocyclic ring, for example an N-linked morpholine ring such as 3-morpholinopro Foxy).
    [104] Another preferred group of R 3 groups of Formula (3), in particular, X 3 is a group of NR 29.
    [105] R 2 is methyl by halo, cyano, nitro, trifluoromethyl, C 1-3 alkyl, -NR 13 R 14 (wherein, R 13 and R 14 may be the same or different and each is hydrogen or C 1-3 alkyl , Or a -X 1 R 15 group. Preferred examples of -X 1 R 15 of R 2 include those enumerated above in connection with R 3 .
    [106] Other examples of R 2 and R 3 include methoxy or 3,3,3-trifluoroethoxy.
    [107] X is preferably NH or O, and most preferably NH.
    [108] Specific examples of R < 6 > include hydrogen or a heterocyclic ring (e.g., n-morpholino). Preferably, however, R < 6 > is hydrogen.
    [109] In certain embodiments, R 5 is NHC (O) R 9 or NHS (O) 2 R 9 wherein R 9 is as defined above.
    [110] In other embodiments, R 5 is C (O) R 9, C (O) OR 9, S (O) R 9, S (O) OR 9, S (O) 2 OR 9, C (O) NR 10 R 11 , S (O) NR 10 R 11 or S (O) ONR 10 R 11, wherein R 9 , R 10 and R 11 are as defined above.
    [111] Specific examples of R 9 , R 10 or R 11 include,
    [112] Aryl optionally substituted with one or more functional groups,
    [113] C 3-6 cycloalkyl optionally substituted with one or more functional groups,
    [114] Aralkyl optionally substituted with at least one functional group, wherein the aryl moiety may further comprise at least one alkyl substituent,
    [115] A heterocyclyl optionally substituted with at least one functional alkyl, alkenyl or alkynyl group,
    [116] Alkyl optionally substituted by one functional group or cycloalkyl or heterocyclyl group wherein said cycloalkyl or heterocyclyl group itself may be optionally substituted with one or more functional groups or alkyl groups,
    [117] An alkenyl optionally substituted by one functional group or an aryl or heterocyclyl group, wherein the aryl or heterocyclyl group may be substituted with at least one functional group or an alkyl group, and
    [118] An alkynyl optionally substituted by one functional group or an aryl or heterocyclyl group, wherein the aryl or heterocyclyl group may be optionally substituted with at least one functional group or an alkyl group,
    [119] .
    [120] Specific examples of the optionally substituted aryl group R 9 , R 10 or R 11 include nitro, halo, carboxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, acetoxy, C 1-4 alkylsulfonyl, trifluoromethyl, aralkyl or aralkyloxy wherein the aryl ring itself in the substituent is optionally substituted with, for example, halo, nitro or C 1-4 alkyl Lt; / RTI > may optionally be substituted with up to five groups.
    [121] Suitable as the optionally substituted C 3-6 cycloalkyl groups R 9 , R 10 and R 11 include optionally substituted cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, any of which may be substituted by, for example, nitro, halo, carboxy , Cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthioacetoxy, acetamido, hydroxy, aminosulfonyl, C 1-4 alkylsulfonyl, trifluoromethyl, Alkyl, aralkyloxy or aryl, wherein the aryl ring in the substituent itself may be optionally substituted, for example, with halo, nitro or C 1-4 alkyl.
    [122] An optionally substituted aralkyl group R 9, R 10 and R 11 is as suitable as optionally substituted benzyl, phenylethyl or phenylpropyl [wherein the phenyl ring is a nitro, halo, carboxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, acetoxy, acetamidohydroxy, aminosulfonyl, C 1-4 alkylsulfonyl, trifluoromethyl, aralkyl or aralkoxy wherein the aryl The ring itself may be substituted, for example, with halo, carboxy, trifluoromethyl, nitro or C 1-4 alkyl, especially nitro, C 1-4 alkoxy, halo, hydroxy, trifluoromethyl or carboxy Optionally substituted with up to 5 groups selected for example).
    [123] Suitable as the optionally substituted heterocyclyl groups R 9 , R 10 and R 11 are pyridyl, pyrazine, pyrimidinyl, pyrrolidino, furyl, tetrahydrofuryl, oxazolyl, morpholino, thiadiazole, indole Thiophene, benzothiophene, all of which are optionally substituted with one or more substituents selected from the group consisting of nitro, halo, carboxy, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, acetoxy, acetamidohydroxy, aminosulfonyl, C 1-4 alkylsulfonyl, trifluoromethyl, aralkyl or aralkoxy wherein the aryl ring itself in the substituent is, for example, Optionally substituted with one or more groups selected from halo, carboxy, trifluoromethyl, nitro or C 1-4 alkyl, in particular C 1-4 alkyl, halo or nitro.
    [124] Optional substituents suitable for the alkyl group R 9 , R 10 or R 11 include amino, mono- or di-C 1-4 alkylamino, hydroxy, C 1-4 alkylamino, hydroxy, C 1-4 alkoxy, heterocyclyl (for example, thiophene, tetrahydro-thiophene-1,1-dioxide, pyrrolidino, morpholino, furyl or tetrahydrofuryl), C 1-4 alkoxy, acetamido, aryloxy (e.g., phenyloxy), alkyl, C 1-4 alkylthio, aroyl (e.g. benzoyl) wherein aryl rings themselves, for example, halo, carboxy, methyl, nitro, carboxy, methyl, cycloalkyl trifluoroacetate trifluoroacetic (e.g., cyclohexyl) or Cycloalkenyl such as cyclohexenyl).
    [125] Optional substituents suitable for the alkenyl or alkynyl group R 9 , R 10 or R 11 include nitro, halo, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, acetoxy, acetamido Hydroxy, aminosulfonyl, C 1-4 alkylsulfonyl, trifluoromethyl, aralkyl or aralkyloxy (the aryl ring in the substituent itself is, for example, halo, carboxy, trifluoromethylnitro or C 1-4 Lt; / RTI > alkyl). In particular, these groups are substituted by aryl (e.g., phenyl), wherein the aryl ring itself may be substituted, for example, with halo, nitro, carboxy, trifluoromethyl.
    [126] Suitably, R 7 and R 8 are independently selected from hydrogen, halo, C 1-4 alkoxy (e.g. methoxy or ethoxy), cyano, trifluoromethyl or phenyl.
    [127] Preferably, R 7 and R 8 are hydrogen.
    [128] X is preferably NH or O, and most preferably NH.
    [129] In certain embodiments, the present invention provides the use of a compound of formula (II), or a salt, ester, amide or prodrug thereof, for the manufacture of a medicament for use in the inhibition of aurora 2 kinase:
    [130]
    [131] Wherein X, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as defined in relation to formula (I)
    [132] Z is C (O) or S (O) 2 ,
    [133] R 64 is optionally substituted hydrocarbyl or optionally substituted heterocyclyl.
    [134] In particular, the present invention provides the use of a compound of formula (IIC), or a salt, ester or amide thereof, in the manufacture of a medicament for the inhibition of Aurora 2 kinase:
    [135]
    [136] Wherein X is O or S, S (O) or S (O) 2 , or NR 8 , wherein R 8 is hydrogen or C 1-6 alkyl;
    [137] Z is C (O) or S (O) 2 ;
    [138] R 65 is optionally substituted hydrocarbyl or optionally substituted heterocyclyl;
    [139] R 7 and R 8 are independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxymethyl, di (C 1-4 alkoxy) methyl, C 1-4 alkanoyl, trifluoromethyl A 5 to 6 membered heteroaromatic ring having 1 to 3 heteroatoms (independently selected from O, S and N), optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, C 2-5 alkenyl, C 2-5 alkynyl, phenyl, Cyclic group wherein said heterocyclic group may be aromatic or non-aromatic and may be saturated (linked through a ring carbon or nitrogen atom) or unsaturated (linked via a ring carbon atom), said phenyl, benzyl or hetero cyclic group is hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro, C 2-4 alkanoylamino, C 1 -4 alkanoylamino, C 1-4 alkoxycarbonyl, C 1-4 alkyl sulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, carbamoyl, NC 1-4 alkyl carbamoyl , N, N-di (C ( C1-4 alkyl) carbamoyl, aminosulfonyl, NC 1-4 alkylaminosulfonyl, N, N-di (C 1-4 alkyl) aminosulfonyl, C 1-4 alkylsulfonylamino, Halogen, C 1-3 alkyl, C < RTI ID = 0.0 > (Ci- 3 alkyl) < / RTI > selected from pyrrolidinyl, pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl 1-3 alkoxycarbonyl, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro and C 1-4 alkoxycarbonyl of 5 or less is selected from that can have a selected one or two substituents) from Wherein the substituents may be on one or more ring carbon atoms;
    [140] R 1, R 2, R 3 , R 4 is halo, cyano, nitro, trifluoromethyl, C 1-3 alkyl, -NR 13 R 14 (wherein, R 13 and R 14 may be the same or different , Each independently represent hydrogen or C 1-3 alkyl), or -X 1 R 15 , wherein X 1 is a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, - S-, -SO-, -SO 2, -NR 16 CO-, -CONR 16 -, -SO 2 NR 16 -, -NR 17 SO 2 - or -NR 18 - (wherein, R 16, R 17 and R 18 each independently represent hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl, and R 15 is selected from one of the following groups:
    [141] 1 ') C 1-5 alkyl which is unsubstituted or may be substituted with one or more groups selected from hydroxy, fluoro or amino, or hydrogen;
    [142] 2 ') C 1-5 alkyl X 2 COR 19 wherein X 2 is -O- or -NR 20 - wherein R 20 is hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl , R 19 represents C 1-3 alkyl, -NR 21 R 22 or -OR 23 wherein R 21 , R 22 and R 23 may be the same or different and each represents hydrogen, C 1 -3 alkyl or C 1-3 alkoxyC 2-3 alkyl;
    [143] 3 ') C 1-5 alkyl X 3 R 24 wherein X 3 is -O-, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 25 CO-, -C (O) NR 26 -, -SO 2 NR 27 -, -NR 28 SO 2 - or -NR 29 - wherein R 25 , R 26 , R 27 , R 28 and R 29 are each independently hydrogen, C 1 3 alkyl or C 1-3 alkoxy C 2-3 alkyl, and R 24 represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl, or one or two independently selected from O, S and N Wherein the C 1-3 alkyl group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy, and wherein the C 1-3 alkyl group may be substituted with one or two substituents selected from the group consisting of The cyclic group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy;
    [144] 4 ') C 1-5 alkyl X 4 C 1-5 alkyl X 5 R 30 wherein X 4 and X 5 may be the same or different and are each -O-, -S-, -SO-, -SO 2 -, -NR 31 CO-, -CONR 32 -, -SO 2 NR 33 -, -NR 34 SO 2 - or -NR 35 - represents a (wherein, R 31, R 32, R 33, R 34 and R 35 each independently represent hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl), and R 30 represents hydrogen or C 1-3 alkyl;
    [145] 5 ') R 36 wherein R 36 is a 5 or 6 membered saturated heterocyclic ring (linked via carbon or nitrogen) having 1 or 2 heteroatoms independently selected from O, S and N, The heterocyclic group may be optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl and C 1-4 alkylsulfonyl Lt; / RTI > alkyl optionally substituted with one or two substituents selected from C1-4 alkyl;
    [146] 6 ') C 1-5 alkyl R 36 wherein R 36 is as defined in 5'above;
    [147] 7 ') C 2-5 alkenyl R 36 wherein R 36 is as defined in 5'above;
    [148] 8 ') C 2-5 alkynyl R 36 wherein R 36 is as defined in 5'above;
    [149] 9 ') R 37 wherein R 37 is a pyridone group, a phenyl group, or a 5 or 6 membered aromatic heterocyclic group (linked via carbon or nitrogen) having 1 to 3 heteroatoms selected from O, N and S Wherein the pyridone, phenyl or aromatic heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogeno, amido, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl , C 1-4 alkylamino, C 1-4 hydroxy alkoxy, carboxy, trifluoromethyl, cyano, -C (O) NR 38 R 39, and -NR 40 C (O) R 41 ( wherein, R 38 , R 39 , R 40 and R 41 , which may be the same or different, each represent hydrogen, C 1-4 alkyl or C 1-3 alkoxy C 2-3 alkyl) May be on atomic};
    [150] 10 ') C 1-5 alkyl R 37 wherein R 37 is as defined in 9'above;
    [151] 11 ') C 2-5 alkenyl R 37 wherein R 37 is as defined in 9'above;
    [152] 12 ') C 2-5 alkynyl R 37 wherein R 37 is as defined in 9'above;
    [153] 13 ') C 1-5 alkyl X 6 R 37 wherein X 6 is -O-, -S-, -SO-, -SO 2 -, -NR 42 CO-, -CONR 43 -, -SO 2 NR 44 -, -NR 45 SO 2 - or -NR 46 - (wherein, R 42, R 43, R 44, R 45 and R 46 are independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2 each -3 alkyl, and R 37 is the same as defined in 9 ');
    [154] 14 ') C 2-5 alkenyl X 7 R 37 wherein X 7 is -O-, -S-, -SO-, -SO 2 -, -NR 47 CO-, -CONR 48 -, -SO 2 NR 49 -, -NR 50 SO 2 or -NR 51 -, wherein R 47 , R 48 , R 49 , R 50 and R 51 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2 -3 alkyl, and R 37 is the same as defined in 9 ');
    [155] 15 ') C 2-5 alkynyl X 8 R 37 wherein X 8 is -O-, -S-, -SO-, -SO 2 -, -NR 52 CO-, -CONR 53 -, -SO 2 NR 54 -, -NR 55 SO 2 - or -NR 56 - (wherein, R 52, R 53, R 54, R 55 and R 56 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C Gt ; and R < 37 > are as defined above;
    [156] 16 ') C 1-3 alkyl X 9 C 1-3 alkyl R 37 wherein X 9 is -O-, -S-, -SO-, -SO 2 -, -NR 57 CO-, -CONR 58 - , -SO 2 NR 59 -, -NR 60 SO 2 - or -NR 61 - (wherein, R 57, R 58, R 59, R 60 and R 61 are independently hydrogen, C 1-3 alkyl, or C 1 each -3 alkoxyC 2-3 alkyl, and R 37 is as defined above; And
    [157] 17 ') C 1-3 alkyl X 9 C 1-3 alkyl R 36 wherein X 9 and R 36 are as defined in 5' above.
    [158] Preferably, Z is C (O).
    [159] Preferably, X is NH or O, most preferably NH.
    [160] Particular examples of R < 64 > groups include groups listed for R < 9 & gt ;, especially those optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted phenyl, naphthyl or benzyl, (For example, pyridyl, furanyl).
    [161] Suitable substituents for the hydrocarbyl or heterocyclyl group R 64 include functional groups as defined above. The heterocyclyl group may be further substituted with a hydrocarbyl group such as an alkyl group, alkenyl or alkynyl.
    [162] In particular, substituents of R 64 include halo, nitro, optionally substituted C 1-6 alkoxy, C 1-4 alkoxymethyl, di (C 1-4 alkoxy) methyl, C 1-4 alkanoyl, trifluoromethyl, A 5- to 6-membered heterocyclic group having 1-3 heteroatoms independently selected from O, S and N, wherein the heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, C 2-5 alkenyl, phenyl, Aromatic, or non-aromatic, and may be saturated (linked through a ring carbon or nitrogen atom) or unsaturated (linked via a ring carbon atom), and the phenyl, benzyl or heterocyclic group may be substituted by one or more hydroxy , Halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro, C 2-4 alkanoyl, C 1-4 alkanoylamino , C 1-4 alkoxycarbonyl, C 1-4 alkyl sulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, carbamoyl, NC 1-4 Al Carbamoyl, N, N- di (C 1-4 alkyl) carbamoyl, aminosulfonyl, NC 1-4 - alkylamino-sulfonyl, N, N- di (C 1-4 alkyl) aminosulfonyl, C 1-4 alkylsulfonylamino and a saturated heterocyclic group (the saturated heterocyclic group is selected from morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl imidazolidinyl and pyrazolidinyl And is selected from the group consisting of oxo, hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro and C 1-4 alkoxycarbonyl And may have 1 or 2 substituents selected).
    [163] Further particular substituents of R < 64 > are groups of formula III:
    [164]
    [165] In this formula,
    [166] q 'is 0, 1, 2, 3, or 4;
    [167] R 70 is hydrogen, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, amino, NC 1-6 alkylamino, N, N- (C 1-6 alkyl) 2 amino, hydroxy C 2-6 alkoxy , C 1-6 alkoxy C 2-6 alkoxy, amino C 2-6 alkoxy, NC 1-6 -alkylamino C 2-6 alkoxy, N, N- (C 1-6 alkyl) 2 aminoC 2-6 alkoxy Or < RTI ID = 0.0 > C3-7 < / RTI &
    [168] -K-J
    [169] Wherein J is aryl, heteroaryl or heterocyclyl and K is a chemical bond, oxy, imino, N- (C 1-6 alkyl) imino, oxyC 1-6 alkylene, iminoC 1- 6 alkylene, N- (C 1-6 alkyl), imino C 1-6 alkylene, -NHC (O) -, -SO 2 NH-, -NHS0 2 - or -NHC (O) -C 1-6 Alkylene-
    [170] Lt; / RTI >
    [171] R any aryl, heteroaryl or heterocyclyl group is hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy, carbamoyl, formyl, sulfamoyl in the 70 group, C 1- 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, -O- (C 1-3 alkyl) -O-, C 1-6 alkyl S (O) n - (wherein , n is 0-2), NC 1-6 alkylamino, N, N- (C 1-6 alkyl) 2 amino, C 1-6 alkoxycarbonyl, NC 1-6 alkylcarbamoyl, (C 1-6 alkyl) 2 carbamoyl, C 2-6 alkanoyl, C 1-6 alkanoyloxy, C 1-6 alkanoylamino, NC 1-6 alkyl sulfamoyl, N, N- (C 1 -6 alkyl) 2 sulfamoyl, C 1-6 alkylsulfonylamino and C 1-6 alkylsulfonyl -N- (C 1-6 alkyl) amino, and suitably is optionally substituted by one or more selected from the group consisting of oxo Or,
    [172] Any aryl, heteroaryl or heterocyclyl group within the R < 70 > group may be substituted with one or more groups of the formula V:
    [173] -B 1 - (CH 2 ) p -A 1
    [174] Wherein A 1 is halo, hydroxy, C 1-6 alkoxy, cyano, amino, NC 1-6 alkylamino, N, N- (C 1-6 alkyl) 2 amino, carboxy, C 1-6 alkoxy Carbamoyl, NC 1-6 alkylcarbamoyl or N, N- (C 1-6 alkyl) 2 carbamoyl, p is 1-6, B 1 is a chemical bond, oxy, imino , - (C 1-6 alkyl) imino or -NHC (O) -, with the proviso that when B 1 is not a chemical bond or -NHC (O) -,
    [175] Lt; / RTI >
    [176] Any aryl, heteroaryl or heterocyclyl group within the R < 70 > group may be substituted with one or more groups of the formula VA:
    [177] -E 1 -D 1
    [178] Wherein E 1 is a chemical bond, C 1-6 alkylene, oxyC 1-6 alkylene, oxy, imino, N- (C 1-6 alkyl), or a pharmaceutically acceptable salt thereof, wherein: D 1 is aryl, heteroaryl or heterocyclyl; IminoC 1-6 alkylene, N- (C 1-6 alkyl) -iminoC 1-6 alkylene, C 1-6 alkylene-oxyC 1-6 alkylene, C 1-6 alkylene-imino-C 1-6 alkylene, C 1-6 alkylene -N- (C 1-6 alkyl) imino-C 1-6 alkylene, -NHC (O) -, -NHSO 2 -, -SO 2 NH- or NHC (O) -C 1-6 alkylene;
    [179] Lt; RTI ID = 0.0 >
    [180] Any substituents on the aryl in R 4, heteroaryl or heterocyclyl group is hydroxy, halo, C 1-6 alkyl, C 1-6 alkoxy, carboxy, C 1-6 alkoxycarbonyl, carbamoyl, NC 1- of 6-alkyl-carbamoyl, N- (C 1-6 alkyl) 2 carbamoyl, C 2-6 alkanoyl, amino, NC 1-6 alkylamino and N, N- (C 1-6 alkyl) 2 amino Optionally substituted with one or more groups selected,
    [181] Any C 3-7 cycloalkyl or heterocyclyl group in the R 70 group may be optionally substituted with one or two oxo or thioxo substituents,
    [182] Of the previously defined R 70 group, a 2-hydroxy-none, on each said CH 2 or CH 3 group which is attached to the included carbon atoms of the CH 2 group or a CH 3 attached to a carbon atom to the amino groups, C 1- 6 alkoxy, NC 1-6 alkylamino, N, N- (C 1-6 alkyl) 2 amino and heterocyclyl.
    [183] In yet another embodiment, R 70 is cycloalkenyl or cycloalkynyl, such as cyclohexenyl, alkenyl optionally substituted by aryl (such as styryl), or cycloalkenyl such as cyclohexyl Cyanylethyl). ≪ / RTI >
    [184] Examples of the heterocyclyl group of R 70 include pyridyl, methylenedioxyphenyl, furyl, pyrrolyl, thiophene, quinolyl, isoquinolyl, thiazolyl, thiadiazolyl, pyrazolyl, tetrahydrothiophene-1,1 -Dioxane, dioxane, tetrahydrofuryl, pyrazinyl, imidazolyl, tetrahydropyran, indolyl, indanyl, pyrrolidine, or isoxazolyl.
    [185] A specific example of the R < 70 > group in formula (III) is phenyl. Preferably, R 70 is halo substituted phenyl and 2-chloro-4-fluorophenyl is a particularly preferred example.
    [186] Particular examples of R 70 in this context include optionally substituted phenyl, especially mono- or di-halophenyl, or optionally substituted pyridyl (e.g., nitropyridyl).
    [187] Preferably, q 'is zero.
    [188] Illustrative examples of R 64 include phenyl, 2-furan, (E) -CH = CH-phenyl, 3,4,5-trimethoxyphenyl, 2,4-difluorophenyl, 2-methylbut-3-enyl, CH 2 CN n-heptyl, 2- (methylthio) ethyl, 2-ethoxy Ethyl, C (CH 3 ) ═CH 2 , 5-methyl- 2 -pyrazine 3-furyl, 3-cyanophenyl, 4-acetoxyphenyl, 2-naphthyl, 2-pyridyl, 2-quinolinyl, 1,5-dimethyl-1H-pyrazolyl, 2-fluoro-5- Pyridyl, 2-chloro-3-pyridyl, 2-fluorophenyl, 2,3-difluorophenyl, 2,5-difluorophenyl, 2,3-dimethoxyphenyl, Methoxyphenyl, 3-nitro-4-methoxyphenyl, 3-chloro-4-carboxyphenyl, (E) -CH = CH- (2-nitrophenyl), (E) -CH = CH- (3-nitrophenyl) - (4-chlorophenyl), (E) -CH = CH- (2,3,4-trifluoro-phenyl) (E) -CH = CH- (4-fluorophenyl), 2-indolyl, 5-fluoro-2-indolyl, 3-fluorophenyl, Benzyl, 3-fluorobenzyl, 4-chlorobenzyl, 4-methoxybenzyl, 4- (iso-propyl) 1-propyl, 3-phenyl-1-propyl, 3-benzoylpropyl, de-9-enyl, (3-thiophene) methyl, 2- (3-nitro-4-hydroxyphenyl) ethyl, 3,5-difluorobenzyl, 4 Benzyl, 3-methyl-1-butylpent-4-ynyl, 3-phenoxybenzyl, 2- , 3- (5-chloro-4-methoxy) thiophene, 3- (5-bromo- Benzyl 3- (2-te 2- (cyclohexyl) ethyl, 3- (cyclohexyl) ethyl, 3- (cyclohexyl) ethyl, ) propyl 1-phenoxyethyl, (E) -C (CH 3 ) = CH- , phenyl, 2-chloro-5-nitrophenyl, methyl. n-heptyl 2-furyl, 3-furyl, (2-thiophene) methyl, 2-indolyl, 2,4-difluorophenyl, 4-methoxyphenyl, 2-tetrahydrofuryl, 2-pyridyl, 3-pyridyl, (4-methylphenyl) E) -CH = CH- (4-nitrophenyl), 1,5-dimethyl-pyrazol-3-yl, cyclobutyl, 2- methoxyphenyl, 3- nitrophenyl, 4- nitrophenylcyclohexyl, 4- Nitro-4-fluorophenyl, (3-thiophene) methyl, 3-chloro-2-benzothiophene, 5-chloro-2- 3-ynyl, 3-cyanophenyl, 2- (acetamido) ethyl, 4- (trifluoromethyl) Phenyl, 3-chloro-4-fluorophenyl, 4-fluoro-3- (trifluoromethyl) -phenyl, 4-fluorophenyl, 5- Methyl-3-pyridyl, 5-nitro-2-furyl, 2-nitrophenyl, (E) -CH = CH- ( Chlorophenyl, 3-fluorophenyl, 6-chloro-3-pyridyl, 5-fluorophenyl, 2-methylphenyl, 3-chlorophenyl, 3- (tetrahydrothiophen-1-1'-dioxide) methyl, 2- methoxyethyl, 2- (methylthio) Phenyl.
    [189] Preferably, R 64 is phenyl or halosubstituted phenyl and 2-chloro-4-fluorophenyl is a particularly preferred example.
    [190] In another embodiment, the present invention provides the use of a compound of formula VI, or a salt, ester, amide or prodrug thereof, for the manufacture of a medicament for the inhibition of aurora 2 kinase:
    [191]
    [192] Wherein X, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as defined for formula I;
    [193] Y is C, S or S (O);
    [194] R 65 is R 9 , OR 9 or NR 10 R 11 , wherein R 9 , R 10 and R 11 are as defined in relation to formula (I).
    [195] For example, the compound of formula (VI) may be a compound of formula VIC, or a salt, ester or amide thereof:
    [196]
    [197] Wherein X, R 7 and R 8 are as defined in relation to formula (I);
    [198] Y is C, S or S (O);
    [199] R 65 is R 9, OR 9 or NR 10 R 11 , wherein R 9 , R 10 and R 11 are as defined for formula (I);
    [200] R 1, R 2, R 3 , R 4 is halo, cyano, nitro, trifluoromethyl, C 1-3 alkyl, -NR 13 R 14 (wherein, R 13 and R 14 may be the same or different , Each independently represent hydrogen or C 1-3 alkyl), or -X 1 R 15 , wherein X 1 is a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, - S-, -SO-, -SO 2, -NR 16 CO-, -CONR 16 -, -SO 2 NR 16 -, -NR 17 SO 2 - or -NR 18 - (wherein, R 16, R 17 and R 18 each independently represent hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl, and R 15 is selected from one of the following groups:
    [201] 1 ') C 1-5 alkyl which is unsubstituted or may be substituted with one or more groups selected from hydroxy, fluoro or amino, or hydrogen;
    [202] 2 ') C 1-5 alkyl X 2 COR 19 wherein X 2 is -O- or -NR 20 - wherein R 20 is hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl , R 19 represents C 1-3 alkyl, -NR 21 R 22 or -OR 23 wherein R 21 , R 22 and R 23 may be the same or different and each represents hydrogen, C 1 -3 alkyl or C 1-3 alkoxyC 2-3 alkyl;
    [203] 3 ') C 1-5 alkyl X 3 R 24 wherein X 3 is -O-, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 25 CO-, -C (O) NR 26 -, -SO 2 NR 27 -, -NR 28 SO 2 or -NR 29 - (wherein, R 25, R 26, R 27, R 28 and R 29 is hydrogen, C 1- each independently 3 alkyl or C 1-3 alkoxy C 2-3 alkyl, and R 24 represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl, or one or two heteroatoms independently selected from O, S, and N Wherein the C 1-3 alkyl group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy, and wherein the C 1-3 alkyl group may be substituted with one or two substituents selected from oxo, The cyclic group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy;
    [204] 4 ') C 1-5 alkyl X 4 C 1-5 alkyl X 5 R 30 wherein X 4 and X 5 may be the same or different and are each -O-, -S-, -SO-, -SO 2 -, -NR 31 CO-, -CONR 32 -, -SO 2 NR 33 -, -NR 34 SO 2 - or -NR 35 - represents a (wherein, R 31, R 32, R 33, R 34 and R 35 each independently represent hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl), and R 30 represents hydrogen or C 1-3 alkyl;
    [205] 5 ') R 36 wherein R 36 is a 5 or 6 membered saturated heterocyclic ring (linked via carbon or nitrogen) having 1 or 2 heteroatoms independently selected from O, S and N, The heterocyclic group may be optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl and C 1-4 alkylsulfonyl Lt; / RTI > alkyl optionally substituted with one or two substituents selected from C1-4 alkyl;
    [206] 6 ') C 1-5 alkyl R 36 wherein R 36 is as defined in 5'above;
    [207] 7 ') C 2-5 alkenyl R 36 wherein R 36 is as defined in 5'above;
    [208] 8 ') C 2-5 alkynyl R 36 wherein R 36 is as defined in 5'above;
    [209] 9 ') R 37 wherein R 37 is a pyridone group, a phenyl group, or a 5 or 6 membered aromatic heterocyclic group (linked via carbon or nitrogen) having 1 to 3 heteroatoms selected from O, N and S Wherein the pyridone, phenyl or aromatic heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogeno, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, C 1-4 hydroxy alkoxy, carboxy, trifluoromethyl, cyano, -C (O) NR 38 R 39, and -NR 40 C (O) R 41 ( wherein, R 38 , R 39 , R 40 and R 41 , which may be the same or different, each represent hydrogen, C 1-4 alkyl or C 1-3 alkoxy C 2-3 alkyl) May be on};
    [210] 10 ') C 1-5 alkyl R 37 wherein R 37 is as defined in 9'above;
    [211] 11 ') C 2-5 alkenyl R 37 wherein R 37 is as defined in 9'above;
    [212] 12 ') C 2-5 alkynyl R 37 wherein R 37 is as defined in 9'above;
    [213] 13 ') C 1-5 alkyl X 6 R 37 wherein X 6 is -O-, -S-, -SO-, -SO 2 -, -NR 42 CO-, -CONR 43 -, -SO 2 NR 44 -, -NR 45 SO 2 - or -NR 46 - (wherein, R 42, R 43, R 44, R 45 and R 46 are independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2 each -3 alkyl, and R 37 is the same as defined in 9 ');
    [214] 14 ') C 2-5 alkenyl X 7 R 37 wherein X 7 is -O-, -S-, -SO-, -SO 2 , -NR 47 CO-, -CONR 48 -, -SO 2 NR 49 -, -NR 50 SO 2 - or -NR 51 - (wherein, R 47, R 48, R 49, R 50 and R 51 are independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2 each -3 alkyl, and R 37 is the same as defined in 9 ');
    [215] 15 ') C 2-5 alkynyl X 8 R 37 wherein X 8 is -O-, -S-, -SO-, -SO 2 -, -NR 52 CO-, -CONR 53 -, -SO 2 NR 54 -, -NR 55 SO 2 - or -NR 56 - (wherein, R 52, R 53, R 54, R 55 and R 56 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C Gt ; and R < 37 > are as defined above;
    [216] 16 ') C 1-3 alkyl X 9 C 1-3 alkyl R 37 wherein X 9 is -O-, -S-, -SO-, -SO 2 -, -NR 57 CO-, -CONR 58 - , -SO 2 NR 59 -, -NR 60 SO 2 - or -NR 61 - (wherein, R 57, R 58, R 59, R 60 and R 61 are independently hydrogen, C 1-3 alkyl, or C 1 each -3 alkoxyC 2-3 alkyl, and R 37 is as defined above; And
    [217] 17 ') C 1-3 alkyl X 9 C 1-3 alkyl R 36 wherein X 9 and R 36 are as defined in 5' above.
    [218] Preferably, Y is a carbon atom or an S (O) group, and is most preferably carbon.
    [219] Examples of R 65 include R 9 or OR 9 , wherein R 9 is hydrogen, optionally substituted C 1-6 alkyl or optionally substituted aryl, such as optionally substituted phenyl. Suitable substituents for the alkyl or aryl group R 9 include functional groups as defined above, but in particular nitro, halo (e.g. fluoro), or cyano.
    [220] Further examples of R 65 groups include NR 10 R 11 wherein at least one of R 10 or R 11 is hydrogen and the other is hydrogen, optionally substituted C 1-6 alkyl, optionally substituted aryl or optionally substituted the heterocyclyl is selected from the reel R 10 or but optionally substituents suitable for R 11 includes a functional group as defined above, in particular nitro, halo (e.g. fluoro): trifluoromethyl, or cyano, haloalkyl (e.g. Alkyl), alkoxy (for example methoxy). The alkyl group R 10 or R 11 is an aryl, cycloalkyl, cycloalkenyl, cycloalkynyl or heterocyclic group (any of which is itself a functional group, May be substituted with an alkyl group such as methyl. The aryl and heterocyclic groups R 10 and R 11 may be substituted with an alkyl group (e.g., methyl).
    [221] In certain embodiments, the group Y (O) R 65 is a group of formula VII:
    [222]
    [223] Wherein R 66 and R 67 are independently selected from hydrogen, optionally substituted hydrocarbyl or optionally substituted heterocyclyl, or R 66 and R 67 together with the nitrogen atom to which they are attached are optionally substituted hetero To form cyclic rings.
    [224] Examples of R 66 and R 67 groups include - (CH 2 ) q ' R 70 groups wherein q' and R 70 are as defined in relation to Formula III above.
    [225] Suitably, one of R 66 or R 67 is hydrogen, or methyl, ethyl or propyl, optionally substituted with hydroxy, preferably one of R 66 or R 67 is hydrogen. In this case, the other is suitably a larger substituent, for example a substituent having at least 4 carbon or hetero atoms, and is optionally substituted hydrocarbyl or optionally substituted heterocyclyl. The optionally substituted hydrocarbyl groups of R 66 or R 67 include, in particular, alkyl, cycloalkyl, alkenyl or aryl, either of which is optionally substituted by a functional group as defined above, or, in the case of an aryl group, In the case of alkyl groups, substituted by aryl or heterocyclic groups, which themselves may optionally be substituted with alkyl or functional groups. Examples of optionally substituted aryl groups R 66 or R 67 include C 1-6 alkyl groups such as methyl or ethyl, which may optionally be substituted with functional groups such as hydroxy, or functional groups as defined above [e.g., For example, halo (for example fluoro, chloro or bromo), hydroxy, alkoxy (for example methoxy), trifluoromethyl, nitro, cyano, trifluoromethoxy, CONH 2 , C 3 , amino, or dimethylamino].
    [226] R 66 or, when R 67 is optionally substituted alkyl, Suitably, at least one functional group [for example, cyano, hydroxy, alkoxy (especially methoxy), COO alkyl (for example: COOCH 3)] to An optionally substituted C 1-6 alkyl group, or aryl optionally substituted with a functional group as defined above (particularly with respect to R 66 or R 67 itself), or an optionally substituted heterocyclic group such as N- Methylpyrrole).
    [227] When R 66 or R 67 is optionally substituted cycloalkyl, cyclohexyl optionally substituted with a functional group such as hydroxy is suitable.
    [228] When R 66 or R 67 is optionally substituted alkenyl, prop-2-enyl is suitable.
    [229] When R 66 or R 67 is optionally substituted heterocyclyl, or R 66 and R 67 together form a heterocyclic group, they may be aromatic or non-aromatic and may in particular be piperidine, piperazine, morpholinyl, Any of which may optionally be substituted with a functional group such as hydroxy, alkoxy (e.g. methoxy), or alkyl (e.g. methyl) (which may itself be substituted, for example, with hydroxy) Which may be substituted with < RTI ID = 0.0 >
    [230] Suitable prodrugs of the compounds of formula I are those which promote solubility, including phosphates and sulphates, in particular phosphates and alkyl, aryl or aralkyl derivatives thereof, such as dibenzylphosphate. The prodrug moiety is a suitable location for the random molecules, for example, be attached as a derivative of a hydroxy group, but, in particular, to advantageously R 1, R 2, R 3 or at least one of R 4, preferably R 2 Or R < 3 >.
    [231] Suitable pharmaceutically acceptable salts of the compounds of formula I include acid addition salts such as methanesulfonate, fumarate, hydrochloride, hydrobromide, citrate, maleate, and salts formed with phosphoric and sulfuric acid do. Depending on the number of charged functional groups and the valence of the cation or anion, there can be one or more cations or anions. When the compound of formula (I) comprises an acid functionality, the salt can be a base salt, such as an alkali metal (e.g. sodium) salt, an alkaline earth metal (e.g. calcium or magnesium) Amine, morpholine, N-methylpiperidine, N-ethylpiperidine, procaine, dibenzylamine, N, N-dibenzylethylamine or an amino acid such as lysine) salt. Sodium salts are preferred as pharmaceutically acceptable salts.
    [232] The in vivo hydrolysable esters of compounds of formula (I) containing a carboxy or hydroxy group can be prepared, for example, by hydrolysis in a human or animal body to produce the parent acid or parent alcohol, Ester.
    [233] Suitable pharmaceutically acceptable esters for carboxy include C 1-6 alkyl (e.g., methyl or ethyl) esters, C 1-6 alkoxymethyl (e.g. methoxymethyl) esters, C 1-6 alkanoyloxymethyl pivaloyloxymethyl, phthalidyl) esters, C 3-8 cycloalkoxy-carbonyl oxy-C 1-6 alkyl (such as 1-cyclohexyl-carbonyloxy-ethyl) ester, 1,3-dioxide-2-solren (E.g., 5-methyl-1,3-dioxolen-2-onylmethyl) ester, and C 1-6 alkoxycarbonyloxyethyl (such as 1-methoxycarbonyloxyethyl) Can be formed at any carboxy group in the compounds of the invention.
    [234] Hydrolytic hydrolysable esters of compounds of formula (I) containing hydroxy include inorganic esters such as phosphate esters and alpha -acyloxyalkyl ethers, and related compounds that are degraded as a result of the in-vivo degradation of the ester to yield the parent hydroxy group . Examples of -acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. In vivo hydrolysable esters forming hydroxy groups include, but are not limited to, alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (alkyl carbonate ester), dialkyl carbamoyl and N- Alkylaminoethyl) -N-alkylcarbamoyl (carbamate-forming), dialkylaminoacetyl, and carboxyacetyl.
    [235] Suitable amides are selected from the group consisting of NC 1-6 alkyl and N, N-di- (C 1-6 alkyl) amide (for example N-methyl, N-ethyl, -N-methyl or N, N-diethyl amide). ≪ / RTI >
    [236] Esters that are not in vivo hydrolysable can be useful as intermediates in the preparation of compounds of formula (I).
    [237] Specific examples of compounds of formula (I) are shown in Tables 1 to 16 below.
    [238] No. R 9 No. R 9One Phenyl 45 2-indolyl 2 2-furan 46 5-fluoro-2-indolyl 3 (E) -CH = CH-phenyl 47 3-fluorophenyl
    [239] 4 3,4,5-trimethoxyphenyl 48 3,5-dinitrophenyl 5 2,4-difluorophenyl 49 3- (Trifluoromethyl) benzyl 6 2-nitro-4,5-dimethoxyphenyl 50 4-fluorobenzyl 7 2,4-dinitrophenyl 51 4-chlorobenzyl 8 2-fluorobenzyl 52 4-methoxybenzyl 9 Cyclopentyl 53 4- (iso-propyl) benzyl 10 Methylbut-3-enyl 54 3-nitrobenzyl 11 CH 2 CN 55 2-phenoxyethyl 12 n-heptyl 56 2- (3,4-dimethoxyphenyl) ethyl 13 2- (methylthio) ethyl 57 2- (4-methoxybenzoyl) ethyl 14 2-ethoxyethyl 58 3-Chloro-1-propyl 15 C (CH 3) = CH 2 59 3-phenoxy-1-propyl 16 5-methyl-2-pyrazine 60 3-phenyl-1-propyl 17 3-furyl 61 3-benzoylpropyl 18 3-cyanophenyl 62 Deck-9-enyl 19 4-acetoxyphenyl 63 1-methylbut-1-enyl 20 2-nitro-3-methoxyphenyl 64 (2-thiophene) methyl 21 2-methylthiophenyl 65 (3-thiophene) methyl 22 3-acetoxyphenyl 66 2- (3-nitro-4-hydroxyphenyl) ethyl 23 4-Aminosulfonyl-1-hydroxy-2-naphthyl 67 3,5-difluorobenzyl 24 2-pyridyl 68 4-phenylbenzyl 25 2-quinolinyl 69 3,4-methylenedioxybenzyl 26 1,5-dimethyl-1H-pyrazolyl 70 2,6-difluorobenzyl 27 2-fluoro-5-nitrophenyl 71 4- (n-butoxy) benzyl 28 3-pyridyl 72 3-methyl-1-butyl 29 2-Chloro-3-pyridyl 73 Pent-4-ynyl 30 2-fluorophenyl 74 3-phenoxybenzyl 31 2,3-difluorophenyl 75 3- (5-bromo-4-methoxy) thiophene 32 2,5-difluorophenyl 76 3- (5-chloro-4-methoxy) thiophene 33 2,3-dimethoxyphenyl 77 3-Methoxy-4-ethoxybenzyl 34 3,5-dimethoxy-4-hydroxy-phenyl 78 4- (benzyloxy) benzyl 35 3-Chloro-4-carboxyphenyl 79 3- (2-thiophene) propyl 36 3-Nitro-4- (methylsulfonyl) -phenyl 80 Hex-5-ynyl 37 3-nitro-4-methoxyphenyl 81 1- (4-chlorophenyl) cyclopropyl 38 (E) -CH = CH- (2-nitrophenyl) 82 Cyclopentylmethyl 39 (E) -CH = CH- (3-nitrophenyl) 83 2- (Cyclopentyl) ethyl 40 (E) -CH = CH- (4-nitrophenyl) 84 Cyclohexylmethyl 41 (E) -CH = CH- (4-chlorophenyl) 85 2- (cyclohexyl) ethyl 42 (E) -CH = CH- (2,3,4-Trifluoro-phenyl) 86 3- (cyclohexyl) propyl 43 (E) -CH = CH- (3- (trifluoromethyl) phenyl) 87 1-phenoxyethyl 44 (E) -CH = CH- (4-fluorophenyl) 88 (E) -C (CH 3) = CH- phenyl
    [240] No. R 3 R 7 R 7 '89 OCH 3 Cl H 90 OCH 3 CH 3 H 91 OCH 3 H CH 392 OCH 3 OCH 3 H 93 OCH 3 CN H 94 OCH 3 H CF 395 Benzyloxy CH 3 H 96 Benzyloxy CN H 97 OCH 2 CH 2 CH 2 - (4-morpholine) CH 3 H 98 OCH 2 CH 2 CH 2 - (4-morpholine) CF 3 H
    [241] No. R 7 No. R 799 H 100 Cl
    [242]
    [243] No. R 9 No. R 9165 Phenyl 178 2,4-dinitrophenyl 166 2-Chloro-5-nitrophenyl 179 2,4-difluorophenyl 167 Cyclopentyl 180 Pent-4-ynyl 168 (Cyclohexyl) methyl 181 3- (tetrahydrothiophene-1,1'-dioxide) methyl 169 3-nitro-4-methoxyphenyl 182 2-methoxyethyl 170 n-heptyl 183 2-fluoro-5-nitrophenyl 171 2-furyl 184 2-nitro-3-methoxyphenyl 172 3-furyl 185 2- (methylthio) phenyl 173 (2-thiophene) methyl 186 5-methyl-2-pyrazinyl 174 2-indolyl 187 Hex-5-ynyl 175 2-Tetrahydrofuryl 188 3-acetoxyphenyl 176 2-pyridyl 189 1,5-dimethyl-3-pyrazolyl 177 3-pyridyl
    [244] No. R 6 R 2 R 3190 H Acetoxy OCH 3191 H 2-methoxyethoxy 2-methoxyethoxy 192 H OCH 3 Benzyloxy 193 H OCH 3 (1-methyl-4-piperidin) methoxy 194 4-morpholine OCH 3 OCH 3195 H OH OCH 3196 H OCH 3 OH
    [245] No. R 2197 OCH 2 CH 2 (4-morpholine) 198 OCH 2 CH 2 CH 2 (4-morpholine) 199 OCH 2 CH 2 CH 2 (4-thiomorpholine-1,1'-dioxide) 200 3- (methylsulfonyl) propoxy 201 (1-triazolyl) ethoxy 202 2- (dimethylamino) ethoxy 203 (3-pyridyl) methoxy 204 2-methoxyethoxy 205 3- (dimethylamino) propoxy 206 Benzyloxy 207 2-hydroxyethoxy
    [246] No. R 3208 OCH 2 CH 2 CH 2 (4-thiomorpholine-1,1'-dioxide) 209 OCH 2 CH 2 CH 2 (4-morpholine) 210 OCH 2 CH 2 (4-morpholine) 211 2- (dimethylamino) ethoxy 212 (1-triazolyl) ethoxy 213 3- (methylsulfonyl) propoxy 214 N- (t-butoxycarbonyl) -2-aminoethoxy 215 (3-pyridyl) methoxy 216 2-methoxyethoxy 217 Acetoxy 218 3,4,5-Trifluorobenzyl 219 OCH 2 CH 2 CH 2 (1- (4,5-dihydro-1-H-imidazolyl)) 220 (Z) -4- (1-pyrrolidin) but-2-enoxy 221 (E) -4- (1-pyrrolidine) but-2-enoxy 222 (Z) -4- (4-morpholine) but-2-enoxy 223 (E) -4- (4-morpholine) but-2-enoxy 224 (E) -4- (1-methyl-4-piperazin) but-2-enoxy 225 2-hydroxyethoxy 226 3-chloropropoxy 227 228 N- (t-butoxycarbonyl) -3-pyrrolidinyloxy 229 N- (iso-propyl) -3-azetidyloxy 230 * Indicates the attachment position.
    [247] No. R 3231 2- (2,2,2-Trifluoroethoxy) ethoxy 232 2-aminoethoxy 233 O- (3-pyrrolidine) 234 2-pyrrolidinomethoxy 235 O- (4-piperidine) 236 O- (1-methyl-4-piperidine) 237 (1-methyl-2-pyrrolidine) methoxy 238 O- (1-methyl-3-pyrrolidine) 239 OCH 2 CH 2 CH 2 -N (CH 3 ) - (2-methoxyethyl) 240 OCH 2 CH 2 CH 2 -N (CH 3 ) -COCH 3241 OCH 2 CH 2 CH 2 -N (CH 3 ) -CO-N (CH 3 ) 2242 O- (1- (2-hydroxyethyl) -3-pyrrolidine) 243 O- (1- (2-methoxyethyl) -3-pyrrolidine) 244 O- (1- (Cyanomethyl) -3-pyrrolidine) 245 O- (1- (2-hydroxyethyl) -4-piperidine) 246 O- (1- (Cyanomethyl) -4-piperidine) 247 (1- (cyclopropyl) methyl-2-pyrrolidine) methoxy 248 (1- (cyclobutyl) methyl-2-pyrrolidine) methoxy 249 (1- (2-hydroxyethyl) -2-pyrrolidine) methoxy 250 (1- (2- (thioethyl) ethyl) -2-pyrrolidine) methoxy 251 (1- (Cyclopropyl) methyl-4-piperidine) methoxy 252 (1- (2-hydroxyethyl) -4-piperidine) methoxy 253 (1- (2-methoxyethyl) -4-piperidine) methoxy 254 (1- (Cyanomethyl) -4-piperidine) methoxy 255 (4,5-dihydro-2-imidazolyl) methoxy
    [248]
    [249] 287 NH- (2,3-dihydroxypropyl) 338 2,6-dimethyl-4-morpholine 288 NH- (2- (dimethylamino) ethyl) 339 1-acetyl-4-piperazine 289 NH- (2- (diethylamino) ethyl) 340 N (CH 3) - allyl 290 NH- (2-methoxyethyl) 341 2-methylpyrrolidine 291 NH- (2- (2-hydroxyethoxy) ethyl) 342 N (CH 2 CH 3 ) - (iso-butyl) 292 NH- (2-hydroxyethyl) 343 N (CH 2 CH 3 ) - (2-cyanoethyl) 293 NH- (2-mercaptoethyl) 344 N (CH 3) - (iso-butyl) 294 NH- (2- (thioethyl) ethyl) 345 4-ethyl-1-piperazine 295 NH- (3-ethoxypropyl) 346 4- (4-fluorophenyl) -1-piperazine 296 NH- (3-n-butoxypropyl) 347 2-carboxy-3-thiazolidine 297 NH- (3-hydroxypropyl) 348 4- (2-hydroxyethyl) -1-piperidine 298 NH- (5-hydroxypentyl) 349 N (CH 3) - (3- pyridyl) methyl 299 NH- (1-methoxy-2-propyl) 350 N (CH 3) - (2- pyridyl) methyl 300 NH- (4-hydroxybutyl) 351 2,5-dimethylpyrrolidine 301 NH- (3-methyl-5-pyrazolyl) 352 1- (1,2,3,6-tetrahydropyridyl) 302 NH- (1-methyl-4-piperazinyl) -propyl 353 4-methylpiperidine 303 NH- (4-carboethoxy-4-piperidinyl) 354 4- (2-hydroxyethyl) -1-piperazine 304 NH- (2- (di-n-butyl) amino) ethyl 355 2- (2-hydroxyethyl) piperidine 305 NH- (2- (di-n-propyl) amino) ethyl 356 2-ethyl-4,5-dihydro-1-imidazolyl 306 NH- (tetrahydropyranyl) methyl 357 4,5-dihydro-1-imidazolyl
    [250]
    [251] 364 NH- (3- (1-imidazolyl) propyl 406 NH- (4-hydroxy-3-tetrahydrofuryl) 365 NH-cyclohexyl 407 4-methylpiperidine 366 NH- (4-hydroxy) cyclohexyl 408 3,5-dimethylpiperidine 367 NH- (cyclohexyl) methyl 409 N (CH 3) - (4- hydroxy-4-methyl-3-tetrahydropyranyl 368 NH- (1,1-di (hydroxymethyl) ethyl 410 1- (2,3-dihydropyrrolyl) 369 NH- (tri (hydroxymethyl) -methyl) 411 2- (hydroxymethyl) -4-hydroxypyrrolidine 370 NH- (3- (hydroxymethyl) -4-hydroxy-3-butyl) 412 N (CH 3) - (3- hydroxy-4-tetrahydropyranyl 371 NH- (1-hydroxy-4-methyl-2-pentyl) 413 N (CH 3) - (cyclobutyl) methyl) 372 NH- (2-tetrahydrofuryl) methyl 414 3-hydroxyazetidine 373 4- (carboxamido) piperidine 415 N (CH 3) - (2- cyanoethyl) 374 NH- (2- (4-morpholine) ethyl) 416 N (CH 3) - (2- (4- morpholino) ethyl) 375 NH- (2-methyl-3-hydroxy-2-propyl) 417 1- (2-methoxyethyl) -4-piperazine 376 NH- (2-methyl-4-hydroxy-2-butyl) 418 2,6-dimethylmorpholine 377 NH-iso-propyl 419 Thiomorpholine 378 NH- (1-hydroxy-2-propyl) 420 2-methylpiperidine 379 NH- (1-hydroxy-2-butyl) 421 2,6-dimethylpiperidine 380 NH- (2,3-dihydroxypropyl) 422 2- (hydroxymethyl) piperidine 381 NH- (2-methoxyethyl) 423 3- (hydroxy) piperidine 382 NH- (2-hydroxyethoxy) ethyl 424 1- (2,5-dihydropyrrolyl) 383 NH- (2-mercaptoethyl) 425 Di (2-methoxyethyl) amino 384 NH- (2-thioethyl) ethyl 426 4-hydroxypiperidine 385 NH- (3- (diethylamino) propyl) 427 2- (Carboxamido) pyrrolidine 386 NH- (3-ethoxypropyl) 428 4- (iso-propyl) -1-piperazine 387 NH- (3-hydroxypropyl) 429 N (CH 3) - (( 2- tetrahydrofuryl) methyl) 388 NH- (5-hydroxypentyl) 430 4-acetyl-1-piperidine 389 2- (Carboxamido) pyrrolidine 431 3-hydroxypyrrolidine 390 NH- (3-methyl-5-pyrazolyl) 432 N (CH 3) - (1- methyl-4-piperidinyl) 391 NH- (2-tetrahydropyran) -methyl 433 4-pyrrolidinio-1-piperidine 392 NH- (1-hydroxy-6-hexyl) 434 4-methyl-1-diazepinyl 393 NH- (5-methyl-2-furyl) -methyl 435 2,2-dimethyl-4-tetrahydropyranyl 394 NH- (2-methyl-3-hydroxy-2-propyl) 436 1- (2-hydroxyethyl) -4-piperazine 395 NH- (3-thiophene) methyl 437 N (CH 3) - (2- hydroxyethyl) 396 NH-2-hydroxyethyl 438 2- (hydroxymethyl) -pyrrolidine 397 NH- (2-thiophene) methyl 439 3- (hydroxymethyl) piperidine 398 Piperidine 440 2,5-dimethyl-1-piperazine 399 Pyrrolidine 441 NH-CH 3
    [252]
    [253] 471 NH- (2-tetrahydrofuryl) methyl 513 NH- (1-ethyl-2-pyrrolidino) methyl 472 4- (carboxamido) piperidine 514 NH- (2-tetrahydrofuryl) methyl 473 NH- (2- (4-morpholino) ethyl) 515 4- (carboxamido) piperidine 474 NH- (2-methyl-3-hydroxy-2-propyl) 516 NH- (2- (4-morpholino) ethyl) 475 NH- (2-methyl-4-hydroxy-2-butyl) 517 NH- (2-methyl-3-hydroxy-2-propyl) 476 NH- (iso-propyl) 518 NH- (2-methyl-4-hydroxy-2-butyl) 477 NH- (1-methyl-2-hydroxyethyl) 519 NH- (iso-propyl) 478 NH-cyclopropyl 520 NH- (1-methyl-2-hydroxyethyl) 479 NH- (2-thiophene) methyl (S) 521 NH-cyclopropyl 480 NH- (N-acetyl-2-aminoethyl) 522 NH- (2-thiophene) methyl (R) 481 NH- (2- (methylthio) ethyl) 523 NH- (N-acetyl-2-aminoethyl) 482 NH- (2- (1-piperidino) ethyl) 524 NH- (2- (methylthio) ethyl) 483 2- (Carboxamido) pyrrolidine 525 Di (2-hydroxyethyl) amino
    [254] No. R C R D526 t-butyl t-butyl 527 benzyl benzyl 528 H H
    [255] No. R 3 R 2529 (E) -CH = CH-CO -OCH 3 OCH 3530 (E) -CH = CH-CO 2 H OCH 3531 3-hydroxyprop-1-enyl OCH 3532 (E) -CH = CH-CO- (1-piperidine) OCH 3533 3-hydroxypropyl OCH 3534 (E) -CH = CH-CO- (4- (2- (dimethylamino) ethyl) -1-piperazine) OCH 3535 3-hydroxy-3-methylbut-1-enyl H 536 3-Hydroxy-prop-1-ynyl OCH 3537 NH 3 H 538 NHCO- (4-pyridyl) H 539 NHCO- (2- (1-piperidino) ethyl) H 540 NHCO- (acetoxymethyl) H
    [256] No. X R 9 R E541 O Phenyl H 542 NH CH 3 OCH 3
    [257]
    [258] 572 OCH 2 CH 2 CH 2 (4-morpholine) NH CO 2 H H H 573 OCH 2 CH 2 CH 2 (4-morpholine) NH SO 2 NH 2 H H 574 OCH 2 CH 2 CH 2 (4-morpholine) NH SO 2 NH- (5-methoxy-2-pyrimidinyl) H H 575 OCH 2 CH 2 CH 2 (4-morpholine) NH SO 2 NH- (4,5-dimethyl-2-oxazolyl) H H 576 OCH 2 CH 2 CH 2 (4-morpholine) NH S0 2 NH- (3,4- dimethyl-5-isopropyl-oxazolyl) H H 577 Benzyloxy NH CONH 2 H H 578 Benzyloxy NH CO-phenyl H H 579 OCH 2 CF 3 NH CO- (4-fluorophenyl) H Cl 580 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (cyclopentyl) H H 581 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (cyclohexyl) H H 582 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (cyclohexyl) methyl H H 583 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (6-Chloro-3-pyridyl) H H 584 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (2-furyl) methyl H H 585 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (2-tetrahydrofuryl) methyl H H 586 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (2-pyridyl) H H 587 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (3-pyridyl) H H 588 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (1, 3-dimethylbut-1-yl) H H 589 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH-CH 2 CF 3 H H 590 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (3-ethoxypropyl) H H 591 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (3- (methylthio) propyl) H H 592 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (1-methyl-2-methoxy-ethyl) H H 593 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (3-methylcyclohexyl) H H 594 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (2-indanyl) H H 595 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (2- (cyclohex-1-enyl) -ethyl) H H 596 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH-2- (2-thiophene) ethyl H H 597 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (5-methyl-2-furyl) methyl H H 598 OCH 2 CH 2 CH 2 (4-morpholine) NH CONH- (3- (tetrahydro-thiophen-1, 1 ' -dioxide H H 599 OCH 3 NH CONH- (2-methylpentyl) H H 600 OCH 3 NH CONH- (3-ethoxypropyl) H H 601 OCH 3 NH CONH- (3- (methylthio) propyl) H H 602 OCH 3 NH CONH- (n-hexyl) H H 603 OCH 2 CF 3 NH CONH 2 H H 604 OCH 2 CF 3 NH S0 2 NH- (4,5- dimethyl-2-oxazolyl) H H 605 OCH 2 CF 3 NH CO- (4-chlorophenyl) H Cl 606 OCH 2 CF 3 NH S0 2 NH- phenyl H H 607 OCH 2 CF 3 NH CO-phenyl H H 608 OCH 2 CF 3 NH S0 2 - (4- nitrophenyl) H H 609 OCH 2 CF 3 NH CONH- (3- (trifluoromethyl) phenyl) H H 610 OCH 2 CF 3 NH CONH-2- (methylthio) ethyl H H
    [259] 611 OCH 2 CF 3 NH CONH- (cyclopentyl) H H 612 OCH 2 CF 3 NH CONH- (cyclohexyl) H H 613 OCH 2 CF 3 NH CONH (6-chloro-3-pyridyl) H H 614 OCH 2 CF 3 NH CONH- (2-tetrahydrofurylmethyl) H H 615 OCH 2 CF 3 NH CONH- (2- (4-morpholino) ethyl) H H 616 OCH 2 CF 3 NH CONH- (2-pyridyl) H H 617 OCH 2 CF 3 NH CONH- (3-pyridyl) H H 618 OCH 2 CF 3 NH CONH- (1, 3-dimethylbut-1-yl) H H 619 OCH 2 CF 3 NH CONH-CH 2 CF 3 H H 620 OCH 2 CF 3 NH COHN- (2,3-dihydroxypropyl) H H 621 OCH 2 CF 3 NH CONH- (2-methylpentyl) H H 622 OCH 2 CF 3 NH CONH- (3- (dimethylamino) -propyl) H H 623 OCH 2 CF 3 NH CONH- (3-ethoxypropyl) H H 624 OCH 2 CF 3 NH CONH- (3-methylcyclohexyl) H H 625 OCH 2 CF 3 NH CONH- (2-indanyl) H H 626 OCH 2 CF 3 NH CONH- (2- (cyclohex-1-enyl) ethyl) H H 627 OCH 2 CF 3 NH CONH-2- (2-thiophene) ethyl H H 628 OCH 2 CF 3 NH CONH- (2- (1-methyl-2-pyrrolidino) ethyl) H H
    [260] In all the above tables, Ph is phenyl, Me is methyl and Et is ethyl.
    [261] Certain compounds of formula I are novel and form a further aspect of the invention. Accordingly, the present invention includes a compound of formula II as defined above,
    [262] (i) when R 1 , R 4 , R 6 , R 7 and R 8 are both hydrogen and R 2 and R 3 are both hydrogen or both are methoxy, then R 64 is not phenyl;
    [263] (ii) when R 1 , R 4 , R 6 , R 7 and R 8 are both hydrogen, R 2 and R 3 are methoxy and Z is C (O), R 64 is not methyl;
    [264] (iii) when all of R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are hydrogen, X is oxygen, R 6 is 4-methyl-1-piperazinyl, (O), R < 64 > is not methyl,
    [265] Or a salt, ester, amide or prodrug thereof.
    [266] Examples of such compounds are compounds of formula < RTI ID = 0.0 > (IIC) < / RTI > and salts, esters or amides thereof:
    [267] (IIC)
    [268]
    [269] In this formula,
    [270] X is O, or S, S (O) or S (O) 2 , or NR 8 wherein R 8 is hydrogen or C 1-6 alkyl;
    [271] Z is C (O) or S (O) 2 ;
    [272] R 64 is an optionally substituted hydrocarbyl or an optionally substituted heterocyclyl;
    [273] R 7 and R 8 are independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxymethyl, di (C 1-4 alkoxy) methyl, C 1-4 alkanoyl, trifluoromethyl A 5- to 6-membered heterocyclic group having 1-3 heteroatoms independently selected from O, S and N, or a 5- to 6-membered heterocyclic group having 1 to 6 heteroatoms independently selected from nitrogen, oxygen, cyano, amino, C 2-5 alkenyl, C 2-5 alkynyl, Wherein the heterocyclic group may be aromatic or non-aromatic and may be saturated (linked via a ring carbon or nitrogen atom) or unsaturated (linked via a ring carbon atom), and the phenyl, benzyl or heterocyclic group may be substituted by to 1 or more of the ring carbon hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro, C 2-4 alkanoyl , C 1-4 alkanoylamino, C 1-4 alkoxycarbonyl, C 1-4 alkylsulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, carbamoyl, NC 1-4 alkyl Carbamoyl, N, N- Di (C 1-4 alkyl) carbamoyl, aminosulfonyl, NC 1-4 alkylaminosulfonyl, N, N-di (C 1-4 alkyl) aminosulfonyl, C 1-4 alkylsulfonylamino, And a saturated heterocyclic group selected from morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl imidazolidinyl and pyrazolidinyl, the saturated heterocyclic group being optionally substituted with oxo, hydroxy, halogeno Which may have 1 or 2 substituents selected from C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro and C 1-4 alkoxycarbonyl ≪ / RTI > optionally substituted with up to five substituents selected from halogen;
    [274] R 1, R 2, R 3 and R 4 is halo, cyano, nitro, trifluoromethyl, C 1-3 alkyl, -NR 13 R 14 (wherein, R 13 and R 14 may be the same or different , Each independently represent hydrogen or C 1-3 alkyl), or -X 1 R 15 , wherein X 1 is a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, - S-, -SO-, -SO 2 -, -NR 16 CO-, -CONR 16 -, -SO 2 NR 16 -, -NR 17 SO 2 - or -NR 18 - (wherein, R 16, R 17, and R 18 represents each independently represent hydrogen, C 1-4 alkyl or C 1-3 alkoxy C 2-3 alkyl), R 15 is selected from one of the following groups:
    [275] 1 ') C 1-5 alkyl which is unsubstituted or may be substituted with one or more groups selected from hydroxy, fluoro or amino, or hydrogen;
    [276] 2 ') C 1-5 alkyl X 2 COR 19 wherein X 2 is -O- or -NR 20 - wherein R 20 is hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl , R 19 represents C 1-3 alkyl, -NR 21 R 22 or -OR 23 wherein R 21 , R 22 and R 23 may be the same or different and each represents hydrogen, C 1 -3 alkyl or C 1-3 alkoxyC 2-3 alkyl;
    [277] 3 ') C 1-5 alkyl X 3 R 24 wherein X 3 is -O-, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 25 CO-, -C (O) NR 26 -, -SO 2 NR 27 -, -NR 28 SO 2 - or -NR 29 - wherein R 25 , R 26 , R 27 , R 28 and R 29 are each independently hydrogen, C 1 3 alkyl or C 1-3 alkoxy C 2-3 alkyl, and R 24 represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl, or one or two independently selected from O, S and N Wherein the C 1-3 alkyl group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy, and wherein the C 1-3 alkyl group may be substituted with one or two substituents selected from the group consisting of The cyclic group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy;
    [278] 4 ') C 1-5 alkyl X 4 C 1-5 alkyl X 5 R 30 wherein X 4 and X 5 may be the same or different and are each -O-, -S-, -SO-, -SO 2 -, -NR 31 CO-, -CONR 32 -, -SO 2 NR 33 -, -NR 34 SO 2 - or -NR 35 - represents a (wherein, R 31, R 32, R 33, R 34 and R 35 each independently represent hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl), and R 30 represents hydrogen or C 1-3 alkyl;
    [279] 5 ') R 36 wherein R 36 is a 5 or 6 membered saturated heterocyclic ring (linked via carbon or nitrogen) having 1 or 2 heteroatoms independently selected from O, S and N, The heterocyclic group may be optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl and C 1-4 alkylsulfonyl Lt; / RTI > alkyl optionally substituted with one or two substituents selected from C1-4 alkyl;
    [280] 6 ') C 1-5 alkyl R 36 wherein R 36 is as defined in 5'above;
    [281] 7 ') C 2-5 alkenyl R 36 wherein R 36 is as defined in 5'above;
    [282] 8 ') C 2-5 alkynyl R 36 wherein R 36 is as defined in 5'above;
    [283] 9 ') R 37 wherein R 37 is a pyridone group, a phenyl group, or a 5 or 6 membered aromatic heterocyclic group (linked via carbon or nitrogen) having 1 to 3 heteroatoms selected from O, N and S Wherein said pyridone, phenyl or aromatic heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogeno, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, C 1-4 hydroxy alkoxy, carboxy, trifluoromethyl, cyano, -C (O) NR 38 R 39, and -NR 40 C (O) R 41 ( wherein, R 38 , R 39 , R 40 and R 41 , which may be the same or different, each represent hydrogen, C 1-4 alkyl or C 1-3 alkoxy C 2-3 alkyl) May be on};
    [284] 10 ') C 1-5 alkyl R 37 wherein R 37 is as defined in 9'above;
    [285] 11 ') C 2-5 alkenyl R 37 wherein R 37 is as defined in 9'above;
    [286] 12 ') C 2-5 alkynyl R 37 wherein R 37 is as defined in 9'above;
    [287] 13 ') C 1-5 alkyl X 6 R 37 wherein X 6 is -O-, -S-, -SO-, -SO 2 -, -NR 42 CO-, -CONR 43 -, -SO 2 NR 44 -, -NR 45 SO 2 - or -NR 46 - (wherein, R 42, R 43, R 44, R 45 and R 46 are independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2 each -3 alkyl, and R 37 is the same as defined in 9 ');
    [288] 14 ') C 2-5 alkenyl X 7 R 37 wherein X 7 is -O-, -S-, -SO-, -SO 2 -, -NR 47 CO-, -CONR 48 -, -SO 2 NR 49 -, -NR 50 SO 2 - or -NR 51 -, wherein R 47 , R 48 , R 49 , R 50 and R 51 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl), and R 37 is the same as defined in 9 ');
    [289] 15 ') C 2-5 alkynyl X 8 R 37 wherein X 8 is -O-, -S-, -SO-, -SO 2 -, -NR 52 CO-, -CONR 53 -, -SO 2 NR 54 -, -NR 55 SO 2 - or -NR 56 - (wherein, R 52, R 53, R 54, R 55 and R 56 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C Gt ; and R < 37 > are as defined above;
    [290] 16 ') C 1-3 alkyl X 9 C 1-3 alkyl R 37 wherein X 9 is -O-, -S-, -SO-, -SO 2 -, -NR 57 CO-, -CONR 58 - , -SO 2 NR 59 -, -NR 60 SO 2 - or -NR 61 - (wherein, R 57, R 58, R 59, R 60 and R 61 are independently hydrogen, C 1-3 alkyl, or C 1 each -3 alkoxyC 2-3 alkyl, and R 37 is as defined above; And
    [291] 17 ') C 1-3 alkyl X 9 C 1-3 alkyl R 36 wherein X 9 and R 36 are as defined in 5'above;
    [292] With the proviso that when i) R 1 , R 4 , R 7 and R 8 are both hydrogen and R 2 and R 3 are both hydrogen or both are methoxy, then R 64 is not phenyl;
    [293] ii) when R 1 , R 4 , R 6 , R 7 and R 8 are both hydrogen, R 2 and R 3 are methoxy and Z is C (O), R 64 is not methyl.
    [294] A particularly preferred group of novel compounds is a compound of formula IIB, or a salt, ester, amide or prodrug thereof:
    [295]
    [296] Wherein R 1 , R 4 , R 6 , R 7 , R 8 , R 64 , Z and X are as defined in claim 15 and R 2 ' and R 3' are each R 2 and R 3 , At least one of said groups, preferably R 3 ', is of the formula X 1 -R 15' , wherein X 1 is as defined above and R 15 ' is as defined in claim 1, but not methyl.
    [297] This includes compounds of formula IID, or salts, esters or amides thereof:
    [298]
    [299] Wherein, R 1, R 4, R 7, R 8, X, Z and R 64 are as defined with respect to formula IIC, R 2 'and R 3' are R 2 and R as defined with respect to formula IIC, respectively 3 , with the proviso that at least one of said groups, preferably R 3 ', is of the formula X 1 -R 15' , wherein X 1 is as defined for formula IIC and R 15 ' is R 15 , but not methyl).
    [300] The preferred variables as described above apply to the compounds of formulas IIA, IIB, IIC and IID whenever possible.
    [301] In another embodiment of the present invention there is provided a compound of formula VIA, or a salt, ester, amide or prodrug thereof:
    [302]
    [303] In the formula, X, Y, R 1, R 4, R 6, R 7, R 8 are as defined with respect to formula I, R65 is as defined with respect to formula VI, R 68 and R 69 is at least one of which the general formula X 1 R 15 and is, but for the R 2 and R 3 as defined with respect to formula I, however, the R 68 or R 69, except that the (here, R 15 are as defined W of the formula I) Is morpholinophoxy, the remainder is not a group of formula (18), and when either R 68 or R 69 is methoxyethoxy, the remainder is not methoxy.
    [304] A specific example is a compound of formula VIB, or a salt, ester or amide thereof:
    [305]
    [306] Wherein, X, Y, R 1, R 4, R 6, R 7, R 8 are as defined with respect to formula VIC, R 65 are as defined with respect to formula VIC, R 68 and R 69 is at least of which one has the general formula X 1 R 15 and is, but for the R 2 and R 3 as defined with respect to formula VIC, however, the R 68 or R 69, except that the (here, R 15 are as defined with respect to formula VIC) Is morpholinopurine, the remainder is not a group of formula (18) as defined in claim 18, and when either of R 68 or R 69 is methoxyethoxy, the remainder is methoxy no.
    [307] In another embodiment the present invention provides a compound of formula VI wherein the structure is similar to that of formula VIA above but X, Y, R 1 , R 4 , R 6 , R 7 , R 8 and R 65 are as defined in relation to formula VI, R 68 is halo, cyano, nitro, trifluoromethyl, C 1-3 alkyl, -NR 13 R 14 (wherein, R 13 and R 14 are as defined above in connection with formula I), or -X 1 R 15 group wherein X 1 and R 15 are as defined in relation to formula I and R 15 is in particular a group of the lower group (1) or (10) and R 69 is a fluorine or X 12 R 71 group wherein, X 12 is a C 1-6 alkoxy substituted optionally by will selected from groups defined above for X 1), R 71 is one selected from 1-3 heterocyclic group, in particular, O, N and S (Connected via nitrogen) 5-6 membered aromatic heterocyclic group with a heteroatom, with the proviso that at least one of R 68 and R 69 is other than unsubstituted methoxy, ≪ / RTI >
    [308] Preferably, at least one of R 68 or R 69 as defined in relation to formula (VIA) is selected from the group of (1), (3), (6), (10) or (22).
    [309] A preferred example of R 69 is 3-morpholinoproxy.
    [310] Preferably, at least R < 69 > is other than unsubstituted alkoxy.
    [311] When R 68 or R 69 is unsubstituted alkoxy, it is preferably methoxy.
    [312] Suitable halo substituents for R 68 and R 69 are fluoro.
    [313] Other examples of R 68 and / or R 69 include 3,3,3-trifluoroethoxy.
    [314] The above-defined preferred variables are reapplied, if possible, in relation to the formula VIA, VIB, VIC or VID.
    [315] Preferably, in the novel compounds, X is NH.
    [316] Also preferably, X 1 is oxygen.
    [317] The compounds of formula (I) can be prepared by methods known in the art or by analogous methods. For example, after to, the compounds of formula I react with of formula VIII to a compound of formula IX in the compound, if necessary, R 1 a group of the ', R 2 ", R 3 " and R 4' each of R 1, R < 2 & gt ; , R < 3 > and R < 4 > or other such groups:
    [318]
    [319] [Wherein, R 1 ', R 2 " , R 3", and R 4' are groups R 1, R 2, R 3 and R 4, or corresponds to a precursor thereof, and, R 85 as defined with respect to formula (I) Leaving group]
    [320]
    [321] Wherein X, R 5 , R 7 and R 8 are as defined in relation to formula (I).
    [322] Suitable leaving groups for R 85 include halo, such as chloro, mesylate and tosylate. It is suitable to carry out the reaction in an organic solvent such as an alcohol (for example, isopropanol) under elevated temperature, conveniently at the reflux temperature of the solvent.
    [323] Conversion of the R 1 ' , R 2 " , R 3" or R 4' groups to the R 1 , R 2 , R 3 and R 4 groups respectively or to such different groups may be particularly useful in connection with the preparation of compounds of formula IIB Examples of such fabrication are described below.
    [324] Compounds of formula (VIII) and (IX) can be derived from known compounds or by known methods.
    [325] Utilizing such a method to prepare the novel compounds of the invention forms a further aspect of the present invention. Therefore, the present invention also to if "a compound of formula IX 'formula VIII comprising the compound and reaction of, and if necessary, groups R 1', R 2", R 3 " or R 4 'groups R 1 each , R 2 or R 2 'or R 68, R 3 or R 3' or R 69, and to switch to R 4, or comprising the step of converting a group other such, formula IIA, IIB, IIC, IID, VIA or Lt; RTI ID = 0.0 > VIB < / RTI >
    [326]
    [327]
    [328] Wherein R 1 ' corresponds to a group of R 1 , or a precursor thereof, as defined in relation to the above formulas IIA, IIB, IIC, IID, VIA or VIB;
    [329] R 2 " corresponds to a group of R 2 or R 2 ' or R 68 , or a precursor thereof, as defined in relation to the above formula IIA, IIB, IIC, IID, VIA or VIB;
    [330] R 3 " corresponds to a group of R 3 or R 3 ' or R 69 , or a precursor thereof, as defined in relation to the above formulas IIA, IIB, IIC, IID, VIA or VIB;
    [331] R 4 ' corresponds to a group of R 4 , or a precursor thereof, as defined with respect to Formulas IIA, IIB, IIC, IID, VIA or VIB;
    [332] R 6 ' is R 6 when present in any one of the above formulas IIA, IIB, IIC, IID, VIA or VIB and is hydrogen when R 6 is absent;
    [333] R 85 is a leaving group;
    [334] X, R < 7 > and R < 8 > are as defined for a compound according to any one of claims 19 to 26;
    [335] R 86 is a group of the formula NHZR 64 or Y (O) R 65 , wherein Z, R 64 , Y and R 65 are as defined for a compound of any of claims 19 to 26.
    [336] The compounds of formula I are inhibitors of Aurora 2 kinase. As a result, these compounds can be used to treat diseases caused by this mediator, especially proliferative diseases.
    [337] The present invention also provides a method of treating such a condition, comprising administering to a warm-blooded animal, such as a human, an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof, or a prodrug thereof, Lt; RTI ID = 0.0 > aurora < / RTI >
    [338] The use of the compounds of formula I for therapy has not been proposed so far. Accordingly, the invention also relates to the use of a compound of formula IIA, IIB or VIA as defined herein, or a pharmaceutically acceptable salt thereof, or a in vivo hydrolysable ester or amide or prodrug thereof, ≪ / RTI > In particular, the compounds are used in the treatment of proliferative diseases such as cancer, especially cancers such as colorectal cancer or breast cancer in which Aurora 2 is upregulated.
    [339] The compounds of formula I are suitable for administration in the form of pharmaceutical compositions. Preferred compounds of formula I for use in the compositions of the present invention are as described above.
    [340] Some of these are novel and form a further aspect of the present invention. Accordingly, the invention also relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier, together with a compound of formula IIA, IIB or VIA as defined herein, or a pharmaceutically acceptable salt, or in vivo hydrolysable ester thereof, Lt; / RTI >
    [341] The compositions of the compounds of formula I may be formulated for oral use (for example, as tablets, pills, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or creams) (For example, as a powder or liquid aerosol), insufflation (for example, as a powder of a fine powder), or as an injection (e.g., as a cream, ointment, gel or as an aqueous or oily solution or suspension) (For example as a sterile aqueous or oily solution for intravenous, subcutaneous, or intramuscular administration, or as a suppository for rectal administration).
    [342] The composition of the present invention can be obtained by a conventional method using conventional pharmaceutical excipients well known in the art. Thus, the oral composition may comprise, for example, one or more coloring agents, sweetening, flavoring and / or preservatives.
    [343] Suitable pharmaceutically acceptable excipients for tablet formulations include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granules and disintegrants such as corn starch or alginic acid, binders such as starch, , Lubricants such as magnesium stearate, stearic acid or talc, preservatives such as ethyl or propyl p-hydroxybenzoate, and antioxidants such as ascorbic acid. The tablet formulation may be uncoated and may be coated using conventional coatings and methods well known in the art to modify its disintegration and subsequent absorption of active ingredients in the gastrointestinal tract or to improve its stability and / or appearance .
    [344] Oral compositions are prepared by mixing the active ingredient with a hard gelatine in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil Lt; RTI ID = 0.0 > encapsulated < / RTI > gelatin capsules.
    [345] Aqueous suspensions generally contain one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, tragacanth and acacia rubbers in combination with the active ingredient in its finely divided form ), Dispersants or wetting agents (for example, condensation products of lecithin or alkylene oxide with fatty acids such as polyoxyethylene stearate) or condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxyethanol) Products or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols such as polyoxyethylene sorbitol monooleate or with ethylene oxide and long chain aliphatic alcohols such as heptadecaethyleneoxyethanol, Condensation products, or mixtures of ethylene oxide with fatty acids and hexitols such as polyoxyethylene sor Contains a condensation product of a partial ester derived from a polyethylene sorbitan monooleate): Tall monol and condensation products, or ethylene oxide with a partial ester derived from a rate), fatty acids and hexitol anhydrides (for example. The aqueous suspensions may also contain one or more preservatives such as ethyl or propyl p-hydroxybenzoate, antioxidants such as ascorbic acid, colorants, flavors, and / or sweeteners such as sucrose, saccharin, Partham).
    [346] Oily suspensions may be prepared by suspending the active ingredient in a vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or a mineral oil (e.g., liquid paraffin). Oily suspensions may also contain thickening agents such as beeswax, hard paraffin or cetyl alcohol. A sweetener and a flavoring agent as described above may be added to provide a delicious oral preparation. Such a composition can be preserved by adding an antioxidant such as ascorbic acid.
    [347] Dispersible powders and granules for the preparation of aqueous suspensions by the addition of water may generally contain a dispersing or wetting agent, a suspending agent and at least one preservative in combination with the active ingredient. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents may also be present.
    [348] The pharmaceutical compositions of the present invention may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil (e.g., olive oil or peanut oil), or a mineral oil (e.g., liquid paraffin), or a mixture thereof. Suitable emulsifiers include, for example, natural rubber (e.g., acacia rubber or tragacanth rubber), natural phosphatides (e.g., soybean, lecithin, fatty acids and hexitol anhydrides such as sorbitan monooleate) Derived esters or partial esters, and condensation products of said partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening, flavoring and preservative agents.
    [349] The syrups and the emollients may be prepared with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain analgesics, preservatives, flavors and / or coloring agents.
    [350] The pharmaceutical composition may be in the form of a sterile injectable aqueous or oleaginous suspension, which may be prepared according to known methods using one or more of the above-mentioned suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in an acceptable diluent or solvent, for example, 1,3-butanediol for non-toxic injections.
    [351] Suppository formulations may be prepared by mixing the active ingredient with a suitable non-polar excipient which is solid at normal temperature but liquid at the rectal temperature and therefore melts in the rectum to release the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.
    [352] The topical formulations, such as creams, ointments, gels, and aqueous or oily solutions or suspensions, can generally be obtained by mixing the active ingredient with conventional topically acceptable excipients or diluents using conventional methods well known in the art .
    [353] The composition for insufflation administration may be in the form of a finely divided powder containing particles having an average diameter of, for example, 30 mu or less. The powder itself contains only the active ingredient or is diluted with at least one physiologically acceptable carrier such as lactose. Conveniently, the aeration powder may then be packaged, for example, in a capsule containing from 1 to 50 mg of active ingredient, followed by the use of a turbo inhaler device (e.g., one used for the venting of a known medicament sodium cromoglycate) .
    [354] The composition for inhalation administration may be in the form of a conventional compressed aerosol which is arranged to dispense the active ingredient as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants, such as volatile fluorinated hydrocarbons or hydrocarbons, may be used, and it is convenient for the aerosol device to be arranged to dispense a metered amount of active ingredient.
    [355] For additional information on formulations, see Corwin Hansch (Chairman of Editorial Board), Comprehensive Medicinal Chemistry, Vol. 5, Chapter 25.2, Pergamon Press, 1990).
    [356] The amount of active ingredient that is combined with one or more excipients to produce a single formulation will necessarily vary depending upon the subject being treated and the particular route of administration. For example, formulations for oral administration in humans will generally contain, for example, 0.5 mg to 2 g of active agent in a suitable and convenient amount of excipient (which may vary from about 5 to about 98% by weight of the total composition) It will be contained by pounding. The unit dosage form will generally contain from about 1 mg to about 500 mg of the active ingredient. Refer to Corwin Hansch (Chairman of Editorial Board), Comprehensive Medicinal Chemistry, Vol. 5, Chapter 25.2, Pergamon Press, 1990 for additional information on route of administration and regimen.
    [357] The dosage of a compound of formula I used for therapeutic or prophylactic purposes will, depending on the well-known medical principles, vary naturally depending on the nature and extent of the animal or patient's condition, age and sex, and the route of administration. As indicated above, the compounds of formula I are useful for treating diseases or diseases which are caused, alone or in part, by aurora 2 kinase.
    [358] When a compound of formula I is used for therapeutic or prophylactic purposes, if divided doses are required, generally a daily dose is administered, for example, 0.5 mg to 75 mg per kg of body weight. Generally, when using the scanning route, a lower dose is administered. Thus, for example, in the case of intravenous administration, the dosage range used is generally 0.5 mg to 30 mg per kg of body weight. Similarly, in the case of inhalation administration, for example, a dose of 0.5 mg to 25 mg per kg of body weight is used.
    [359] The treatments described above may be applied alone or in combination with one or more other substances and / or therapies in addition to using the compounds according to the present invention. Such co-treatment may be achieved by simultaneous, sequential or separate administration of the individual components of the therapy. In the field of medical oncology, it is common to treat each cancer patient with a combination of different forms of therapy. Other components of this co-therapy may be, for example, surgery, radiation therapy or chemotherapy. Chemotherapy may include one or more of the following types of therapeutic agents.
    [360] (i) inhibitors of metalloproteinase inhibitors and urokinase plasminogen activator receptor functions such as anti-invasive agents (e. g., marimastat);
    [361] (ii) antiproliferative / anti-tumorigenic drugs and combinations thereof used in oncology such as platinum derivatives (e.g., cis-platin, carboplatin); Alkylating agents such as cyclophosphamide, nitrogen mustard, melaran, chlorambucil, bisulfan and nitroso urea; Antimetabolites, such as anti-folates; Fluoropyrimidines such as 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea; Antitumor antibiotics such as anthracycline such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, dirubicin, mitomycin-C, dactinomycin and missramycin; Anti-mitotic agents such as vincristine, vinblastine, vinca alkaloids such as vindesine and vinorelbine, and taxoids such as taxol and taxoterea; And topoisomerase inhibitors (e. G., Epi-grape pilotoxins such as etoposide and teniposide, amasacrine, topotecan and camptothecin);
    [362] (iii) cell proliferation inhibitors such as anti-estrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene and iodoxifene); Antiandrogens such as bicalutamide, flutamide, neilutamide and ciproterone acetate; LHRH antagonists or LHRH agonists (such as goserelin, lyprolelin and buserelin); Progestogens (such as megestrol acetate); Inhibitors of aromatase inhibitors (such as anastrozole, retrazole, vorazole and exemestane) and 5-lead deacetylases (such as finasteride);
    [363] (iv) inhibitors of growth factor function, for example, such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and serine / threonine kinase inhibitors such as inhibitors of the epidermal growth factor family, such as EGFR tyrosine kinase inhibitors For example, inhibitors of the platelet-derived growth factor family and inhibitors of the hepatocyte growth factor family, for example; And
    [364] (v) anti-angiogenic agents such as those inhibiting vascular endothelial growth factor, such as those disclosed in international patent applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354, And those acting by other mechanisms (e.g., linomide, an inhibitor of integrin alpha v beta 3 function and angiostatin).
    [365] Such formulations use the compounds of the present invention and other pharmacologically active agents within the accepted dosage range within the dosage ranges described above.
    [366] The present invention will now be described in the following non-limiting embodiments. Common techniques known to the skilled chemist and techniques similar to those described in these examples can be used where appropriate,
    [367] (i) evaporation was carried out by rotary evaporation under vacuum and the work-up procedure was carried out after removal of the residual solids such as drying agent by filtration;
    [368] (ii) The operation was carried out in ambient air, usually in the range of 18-25 ° C, and in air, unless otherwise noted or otherwise manipulated by a person skilled in the art in an inert gas atmosphere such as argon;
    [369] (iii) Column chromatography (by flash procedure) and intermediate pressure liquid chromatography (MPLC) were performed on Merck Kieselgel silica (Art. 9385) or Merck Lichroprep RP- 18 (Art. 9303) reversed phase silica and the bond elute chromatography was performed on a Varian Mega Bond Elut cartridge (10 g, order code 1225-6034) obtained from Varian Sample Preparation Products ≪ / RTI >
    [370] (iv) The yield is for example only and not necessarily the maximum value;
    [371] (v) The structure of the final product of formula (I) is generally confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectrometry techniques, and the proton magnetic resonance transduction value is deuterated DMSOd 6 ) Was measured using a Varian Gemini 2000 spectrometer operating at 300 MHz in a delta scale (downfield from tetramethylsilane), or a Bruker DPX 300 spectrometer operating at a field intensity of 300 MHz, S, single line; d, doublet; dd, double doublet; t, triple line; q, quadrature; qu, O Heavy line; m, multiplet; bs, wide single line; Mass spectroscopy (MS) was performed by electrospray on a VG platform;
    [372] (vi) Robotic synthesis was performed using a Zymate XP robot, adding the solution through the Zymate Master Laboratory Station and stirring through a Stem RS5000 Reacto-Station at 25 ° C;
    [373] (vii) Post-treatment and purification of the reaction mixture from the robotic synthesis was carried out as follows: Evaporation was carried out under vacuum using Savant AES 2000 and column chromatography was carried out using an Anachem Sympur MPLC or Jones Flashmaster MPLC system Using a Varian Mega Bond Elut cartridge, and the structure of the final product was verified by LCMS on a Micromass OpenLynx system using: retention time (RT) in minutes:
    [374] Column: 4.6 mm x 3 cm Hichrom RPB
    [375] Solvent A: 5% methanol in water + 0.1% formic acid
    [376] Solvent B: 5% methanol in acetonitrile + 0.1% formic acid
    [377] Flow rate: 1.4 ml / min
    [378] Driving time: 5 minutes, gradient from 0-100% B for 4.5 minutes
    [379] Wavelength: 254 nm, bandwidth: 10 nm
    [380] Mass detector: Micromass Platform LC
    [381] Injection volume: 0.002 ml
    [382] (vii) Analysis of Compounds Not Made by Robot Synthesis LCMS was performed on a Waters Alliance HT system using the following and the retention time (RT) in minutes:
    [383] Column: 2.0 mm x 5 cm Phenomenex Max-RP 80A
    [384] Solvent A: Water
    [385] Solvent B: acetonitrile
    [386] Solvent C: methanol + 1% formic acid
    [387] Flow rate: 1.1 ml / min
    [388] Driving time: 5 minutes, 0-95% B + 5% 4.5 minutes gradient from solvent C
    [389] Wavelength: 254 nm, bandwidth: 10 nm
    [390] Injection volume: 0.005 ml
    [391] Mass detector: Micromass ZMD
    [392] (viii) Preparation High Performance Liquid Chromatography (HPLC) was performed on a Gilson apparatus using the following and the retention time (RT) in minutes:
    [393] Column: 21 mm x 10 cm Hichrom RPB
    [394] Solvent A: Water + 0.1% Trifluoroacetic acid
    [395] Solvent B: Acetonitrile + 0.1% Trifluoroacetic acid
    [396] Flow rate: 18 ml / min
    [397] Driving time: 15 minutes, 5-100% 10 minutes from B
    [398] Wavelength: 254 nm, bandwidth: 10 nm
    [399] Injection volume: 2.0-4.0 ml
    [400] (ix) The intermediates were largely not fully characterized and purity was assessed by thin layer chromatography (TLC), HPLC, infrared (IR), MS or NMR analysis.
    [401] The following examples illustrate the invention.
    [402] Example 1 - Preparation of Compound No. 1 in Table 1
    [403] A solution of 4-chloro-6,7-dimethoxyquinazoline (3.176 g, 14.13 mmol) and N-benzoyl 4-aminoaniline (3.00 g, 14.13 mmol) in isopropanol (200 ml) The reaction was then cooled to ambient temperature. The precipitated solid was collected by suction filtration and washed with diethyl ether (2 x 50 ml). This material was dried to give the title compound (5.66 g, 92% yield) as a light yellow solid:
    [404]
    [405] 4-Chloro-6,7-dimethoxyquinazoline and N-benzoyl 4-aminoaniline used as starting materials were obtained as follows:
    [406] a) A mixture of 4,5-dimethoxy anthranilic acid (19.7 g, 100 mmol) and formamide (10 ml) was heated at 190 < 0 > C for 5 hours. The mixture was cooled to about 80 < 0 > C and water (50 ml) was added. It was then left at ambient temperature for 3 hours. The solid was collected by suction filtration, washed with water (2 x 50 ml) and dried under vacuum to give 6,7-dimethoxy-3,4-dihydroquinazolin-4-one (3.65 g, 18% yield) ≪ / RTI > as a white solid:
    [407]
    [408] b) Dimethylformamide (0.2 ml) was added dropwise to a solution of 6,7-dimethoxy-3,4-dihydro-quinazolin-4-one (10.0 g, 48.5 mmol) in thionyl chloride , And the reaction was heated under reflux for 6 hours. The reaction was cooled and excess thionyl chloride was removed in vacuo and the residue was azeotroped with toluene (2 x 50 ml) to remove the final thionyl chloride. The residue was dissolved in dichloromethane (550 ml), the solution was washed with saturated aqueous sodium hydrogen carbonate (2 x 250 ml) and the organic phase was dried over magnesium sulfate. Evaporation of the solvent in vacuo afforded 4-chloro-6,7-dimethoxyquinazoline (10.7 g, 98% yield) as a white solid:
    [409]
    [410] MS (+ ve ESI): 225 (M + H) < + & gt ; .
    [411] c) Benzoyl chloride (10.7 ml, 92.5 ml) was added to a stirred solution of 1,4-phenylenediamine (10.0 g, 92.5 mmol) and triethylamine (14.2 ml, 102 mmol) in dichloromethane Lt; / RTI > The reaction was warmed to ambient temperature over 3 hours and the solid was filtered off and water (100 ml) was added to the filtrate to cause a second solid precipitation. The solid was collected by suction filtration and dried under vacuum to give N-benzoyl 4-aminoaniline (5.55 g, 28% yield) as a white solid:
    [412]
    [413] Example 2 - Preparation of compound 2 of Table 1
    [414] (44 mg, 0.34 mmol) was reacted with 4- (4-aminoanilino) -6,7-dimethoxyquinazoline (100 mg, 0.34 mmol) and triethylamine (0.052 ml, 0.37 mmol) in dichloromethane mmol) at ambient temperature under an inert atmosphere. The reaction was stirred at ambient temperature for 2 hours, additional furoyl chloride was added (15 mg, 0.11 mmol) and the reaction stirred for an additional 30 minutes before the volatiles were removed in vacuo. The crude product was purified by flash chromatography on silica gel (eluting with 5% methanol in dichloromethane) to give the title compound (70 mg, 53% yield) as a clear yellow solid:
    [415]
    [416] Example 3 - Preparation of compound 3 of Table 1
    [417] (48 mg, 0.25 mmol) and 4- (dimethylamino) pyridine (3 mg, 0.025 mmol) were dissolved in dimethylformamide Was added to a solution of 4- (4-aminoanilino) -6,7-dimethoxyquinazoline (50 mg, 0.17 mmol) and cinnamic acid (28 mg, 0.19 mmol) in dichloromethane Stir for 18 hours. The reaction was cooled, poured into water (10 ml), treated with saturated aqueous sodium bicarbonate solution (3 ml), and the solid material was collected by suction filtration. Drying in vacuo afforded the title compound (60 mg, 83% yield) as a brown solid:
    [418]
    [419] Example 4 - Preparation of compound 4 of Table 1
    [420] The title compound (69 mg, 83% yield) was obtained as a yellow solid, starting with 3,4,5-trimethoxybenzoic acid (39.4 mg, 0.186 mmol), analogous to the reaction described in Example 3:
    [421]
    [422] Example 5 - Preparation of compound 5 of Table 1
    [423] The title compound (70 mg, 48% yield) was obtained as a white solid starting from 2,4-difluorobenzoic acid (59 mg, 0.38 mmol), analogous to the reaction described in Example 3:
    [424]
    [425] Example 6 - Preparation of compound 6 of Table 1
    [426] The title compound (57 mg, 33% yield) was obtained as a light yellow solid starting with 3,4-dimethoxy-6-nitrobenzoic acid (84 mg, 0.37 mmol), analogous to the reaction described in Example 3:
    [427]
    [428] Example 7 - Preparation of compound 7 of Table 1
    [429] N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) (192 mg, 0.50 mmol) was dissolved in dimethylformamide (1.5 ml ) Was added to a suspension of 2,4-dinitrobenzoic acid (71.5 mg, 0.337 mmol). After 5 min, 4- (4-aminoanilino) -6,7-dimethoxyquinazoline (100 mg, 0.17 mmol) was added and the reaction was heated at 50 <0> C for 3 h. The reaction was cooled, poured into water (15 ml) and diethyl ether (5 ml) was added. The precipitated solid was collected by suction filtration and washed with water (10 ml) and diethyl ether (10 ml). Drying the solid in vacuo afforded the title compound (57 mg, 34% yield) as a white solid:
    [430]
    [431] Example 8 - Preparation of compound 8 of Table 1
    [432] Analogously to the reaction described in Example 7 but starting with (2-fluorophenyl) acetic acid (57 mg, 0.37 mmol) the title compound (116 mg, 60% yield) was obtained as a white solid:
    [433]
    [434] Example 9 - Preparation of compound 9 of Table 1
    [435] The title compound (125 mg, 69% yield) was obtained as a white solid starting from cyclopentanecarboxylic acid (42 mg, 0.37 mmol), analogous to the reaction described in Example 7:
    [436]
    [437] Example 10 - Preparation of compound 10 of Table 1
    [438] The title compound (85 mg, 47% yield) was obtained as a white solid starting from 2-methyl-4-pentenoic acid (42 mg, 0.37 mmol), analogous to the reaction described in Example 7:
    [439]
    [440] Example 11 - Preparation of compound 11 of Table 1
    [441] Analogously to the reaction described in Example 7 but starting with cyanoacetic acid (31.6 mg, 0.37 mmol) the title compound (126 mg, 73% yield) was obtained as a white solid:
    [442]
    [443] Example 12 - Preparation of compound 12 of Table 1
    [444] N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) (192 mg, 0.50 mmol) was dissolved in dimethylacetamide (1.0 ml ) (53 mg, 0.371 mmol) in THF (5 mL). After 20 minutes 4- (4-aminoanilino) -6,7-dimethoxyquinazoline (100 mg, 0.17 mmol) was added and the reaction was heated at 50 &lt; 0 &gt; C for 2 h. The reaction was cooled and poured into water (10 ml). The precipitated solid was collected by suction filtration and washed with water (10 ml) and diethyl ether (10 ml). In the case of some similar reactions (described in Examples 23-99), no precipitation occurred at this stage, and the reaction mixture was neutralized by adding a saturated aqueous solution of sodium bicarbonate to obtain the hexafluorophosphate salt obtained in this Example It was necessary to cause precipitation of the free base). Drying the solid in vacuo afforded the title compound (133 mg, 69% yield) as a white solid:
    [445]
    [446] Example 13 - Preparation of compound 13 of Table 1
    [447] Analogously to the reaction described in Example 12 but starting with 3- (methylthio) propanoic acid (45 mg, 0.37 mmol) the title compound (151 mg, 82% yield) was obtained as a white solid:
    [448]
    [449] Example 14 - Preparation of compound 14 of Table 1
    [450] Analogously to the reaction described in Example 12 but starting with 3-ethoxypropanoic acid (44 mg, 0.37 mmol) the title compound (139 mg, 76% yield) was obtained as a white solid:
    [451]
    [452] Example 15 - Preparation of compound 15 of Table 1
    [453] The title compound (118 mg, 692% yield) was obtained as a white solid starting with the reaction described in Example 12, but starting with methacrylic acid (32 mg, 0.37 mmol)
    [454]
    [455] Example 16 - Preparation of compound 16 of Table 1
    [456] Methyl-2-pyrazinecarboxylic acid (31 mg, 0.22 mmol) and 4- (4-aminoanilino) -6,7-dimethoxyquinazoline (60 mg, 0.20 mmol), the title compound (94 mg, 83% yield) was obtained as a white solid:
    [457]
    [458] Example 17 - Preparation of compound 17 of Table 1
    [459] (25 mg, 0.22 mmol) and 4- (4-aminoanilino) -6,7-dimethoxyquinazoline (60 mg, 0.20 mmol) in analogy to the reaction described in example 12, The title compound (79 mg, 73% yield) was obtained as a white solid:
    [460]
    [461] MS (+ ve ESI): 391 (M + H) &lt; + & gt ; .
    [462] Example 18 - Preparation of compound 18 of Table 1
    [463] Analogously to the reaction described in Example 12, starting with 3-cyanobenzoic acid (55 mg, 0.37 mmol) and heating the reaction for 4 h afforded the title compound (159 mg, 83% yield) as a white solid:
    [464]
    [465] Example 19 - Preparation of compound 19 of Table 1
    [466] Starting with 4-acetoxybenzoic acid (67 mg, 0.37 mmol) and heating the reaction for 3 h, the title compound (150 mg, 70% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [467]
    [468] Example 20 - Preparation of compound 20 of Table 1
    [469] The title compound was obtained as a white solid (185 mg, 89% yield), by proceeding in analogy to the reaction described in example 12 but starting from 3-methoxy-2-nitrobenzoic acid (73 mg, 0.37 mmol) and heating the reaction for 3 h. Lt; / RTI &gt;
    [470]
    [471] Example 21 - Preparation of compound No. 21 in Table 1
    [472] Analogously to the reaction described in Example 12, starting with 2- (methylthio) benzoic acid (62 mg, 0.37 mmol) and heating the reaction for 3 h afforded the title compound (134 mg, 67% yield) as a white solid :
    [473]
    [474] Example 22 - Preparation of compound No. 22 in Table 1
    [475] Starting with 3-acetoxybenzoic acid (67 mg, 0.37 mmol) and heating the reaction for 3 hours, the title compound (150 mg, 74% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [476]
    [477] Example 23 - Preparation of compound 23 of Table 1
    [478] Starting with 4-aminosulfonyl-1-hydroxy-2-naphthoic acid (94 mg, 0.37 mmol) and heating the reaction for 3 h, the title compound (66 mg, 36 % Yield) as a white solid: &lt; RTI ID = 0.0 &gt;
    [479]
    [480] Example 24 - Preparation of compound 24 of Table 1
    [481] (27 mg, 0.22 mmol) and 4- (4-aminoanilino) -6,7-dimethoxyquinazoline (60 mg, 0.20 mmol) in analogy to the reaction described in Example 12 To give the title compound (94 mg, 85% yield) as a white solid:
    [482]
    [483] Example 25 - Preparation of compound 25 of Table 1
    [484] (38 mg, 0.22 mmol) and 4- (4-aminoanilino) -6,7-dimethoxyquinazoline (60 mg, 0.20 mmol) in analogy to the reaction described in Example 12, The compound (108 mg, 89% yield) was obtained as a white solid:
    [485]
    [486] Example 26 - Preparation of compound 26 of Table 1
    [487] Pyrazole-3-carboxylic acid (31 mg, 0.22 mmol) and 4- (4-aminoanilino) -6,7-dimethoxy Quinazoline (60 mg, 0.20 mmol), the title compound (83 mg, 73% yield) was obtained as a white solid:
    [488]
    [489] Example 27 - Preparation of compound 27 of Table 1
    [490] Starting with 2-fluoro-5-nitrobenzoic acid (69 mg, 0.37 mmol) and heating the reaction for 3 h, the title compound (140 mg, 68% yield) was obtained as a white solid Obtained:
    [491]
    [492] Example 28 - Preparation of compound 28 of Table 1
    [493] Analogously to the reaction described in Example 12 but starting with nicotinic acid (27 mg, 0.22 mmol) and 4- (4-aminoanilino) -6,7-dimethoxyquinazoline (60 mg, 0.20 mmol) the title compound (77 mg, 70% yield) as a white solid:
    [494]
    [495] Example 29 - Preparation of compound 29 of Table 1
    [496] Analogously to the reaction described in Example 12, starting with 2-chloronicotinic acid (35 mg, 0.22 mmol) and 4- (4-aminoanilino) -6,7-dimethoxyquinazoline (60 mg, 0.20 mmol) , The title compound (44 mg, 50% yield) was obtained as a white solid:
    [497]
    [498] Example 30 - Preparation of compound 30 of Table 1
    [499] Starting with 2-fluorobenzoic acid (52 mg, 0.22 mmol) and heating the reaction for 3 hours, the title compound (52 mg, 37% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [500]
    [501] Example 31 - Preparation of compound 31 of Table 1
    [502] Starting with 2,3-difluorobenzoic acid (59 mg, 0.37 mmol), the title compound (82 mg, 56% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [503]
    [504] Example 32 - Preparation of compound 32 of Table 1
    [505] Starting from 2,5-difluorobenzoic acid (59 mg, 0.37 mmol), the title compound (75 mg, 51% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [506]
    [507] MS (+ ve ESI): 437 (M + H) &lt; + & gt ; .
    [508] Example 33 - Preparation of compound 33 of Table 1
    [509] Starting from 2,3-methoxybenzoic acid (68 mg, 0.37 mmol), the title compound (154 mg, 75% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [510]
    [511] MS (+ ve ESI): 461 (M + H) &lt; + & gt ; .
    [512] Example 34 - Preparation of compound 34 of Table 1
    [513] The title compound (42 mg, 26% yield) was obtained as a white solid starting from 3,5-dimethoxy-4-hydroxybenzoic acid (73 mg, 0.37 mmol), analogous to the reaction described in Example 12:
    [514]
    [515] Example 35 - Preparation of compound 35 of Table 1
    [516] The title compound (164 mg, 78% yield) was obtained as a white solid, starting with 3-chloro-4-carboxybenzoic acid (75 mg, 0.37 mmol)
    [517]
    [518] Example 36 - Preparation of compound 36 of Table 1
    [519] Starting with 4- (methylsulfonyl) -3-nitrobenzoic acid (91 mg, 0.37 mmol), the title compound (150 mg, 66% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [520]
    [521] Example 37 - Preparation of compound 37 of Table 1
    [522] Starting with 4-methoxy-3-nitrobenzoic acid (73 mg, 0.37 mmol), the title compound (160 mg, 76% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [523]
    [524] Example 38 - Preparation of compound 38 of Table 1
    [525] The title compound was obtained as a white solid (75 mg, 79% yield), by proceeding in analogy to the reaction described in example 12 but starting with 2-nitrocinnamic acid (73 mg, 0.37 mmol) and heating the reaction for 2.5 h:
    [526]
    [527] Example 39 - Preparation of compound No. 39 of Table 1
    [528] Starting with 3-nitrocinnamic acid (43 mg, 0.37 mmol), the title compound (86 mg, 91% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [529]
    [530] MS (+ ve ESI): 472 (M + H) &lt; + & gt ; .
    [531] Example 40 - Preparation of compound 40 of Table 1
    [532] Starting with 4-nitrocinnamic acid (43 mg, 0.22 mmol), the title compound (66 mg, 69% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [533]
    [534] Example 41 - Preparation of compound 41 of Table 1
    [535] The title compound (55 mg, 59% yield) was obtained as a white solid, starting with 4-chlorocinnamic acid (40 mg, 0.22 mmol), analogous to the reaction described in Example 12:
    [536]
    [537] Example 42 - Preparation of compound 42 of Table 1
    [538] The title compound (64 mg, 66% yield) was obtained as a white solid starting from 2,3,4-trifluorosuccinic acid (45 mg, 0.22 mmol), analogous to the reaction described in Example 12:
    [539]
    [540] Example 43 - Preparation of compound 43 of Table 1
    [541] The title compound (104 mg, 81% yield) was obtained as a white solid starting from 3- (trifluoromethyl) -cinnamic acid (48 mg, 0.22 mmol), analogous to the reaction described in Example 12:
    [542]
    [543] Example 44 - Preparation of compound 44 of Table 1
    [544] Starting from 4-fluorosinamic acid (37 mg, 0.22 mmol), the title compound (83 mg, 70% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [545]
    [546] Example 45 - Preparation of compound 45 of Table 1
    [547] Starting from indole-2-carboxylic acid (36 mg, 0.22 mmol), the title compound (53 mg, 60% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [548]
    [549] Example 46 - Preparation of compound 46 of Table 1
    [550] Starting with 5-fluoroindole-2-carboxylic acid (40 mg, 0.22 mmol), the title compound (58 mg, 63% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [551]
    [552] Example 47 - Preparation of compound 47 of Table 1
    [553] Starting from 3-fluorobenzoic acid (31 mg, 0.22 mmol), the title compound (81 mg, 71% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [554]
    [555] Example 48 - Preparation of compound 48 of Table 1
    [556] Starting from 3,5-dinitrobenzoic acid (47 mg, 0.22 mmol), the title compound (97 mg, 75% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [557]
    [558] Example 49 - Preparation of compound 49 of Table 1
    [559] Analogously to the reaction described in Example 12, starting with 3- (trifluoromethyl) -phenylacetic acid (75.5 mg, 0.37 mmol) and heating the reaction for 18 h afforded the title compound (103 mg, 64% yield) Obtained as a white solid:
    [560]
    [561] Example 50 - Preparation of compound 50 of Table 1
    [562] Starting with 4-fluorophenylacetic acid (57.0 mg, 0.37 mmol), the title compound (141 mg, 73% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [563]
    [564] Example 51 - Preparation of compound 51 of Table 1
    [565] Starting with 4-chlorophenylacetic acid (62.9 mg, 0.37 mmol), the title compound (167 mg, 84% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [566]
    [567] Example 52 - Preparation of compound 52 of Table 1
    [568] Starting with 4-methoxyphenylacetic acid (61.4 mg, 0.37 mmol), the title compound (155 mg, 78% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [569]
    [570] Example 53 - Preparation of compound 53 of Table 1
    [571] Starting with 4-isopropylphenylacetic acid (65.9 mg, 0.37 mmol), the title compound (143 mg, 93% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [572]
    [573] Example 54 - Preparation of compound 54 of Table 1
    [574] Starting with 3-nitrophenylacetic acid (67.0 mg, 0.37 mmol), the title compound (104 mg, 67% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [575]
    [576] MS (+ ve ESI): 460 (M + H) &lt; + & gt ; .
    [577] Example 55 - Preparation of compound 55 of Table 1
    [578] Starting with 3-phenoxypropanoic acid (61.4 mg, 0.37 mmol), the title compound (103 mg, 52% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [579]
    [580] Example 56 - Preparation of compound 56 of Table 1
    [581] Analogously to the reaction described in Example 12 but starting with 77.7 mg (0.37 mmol) of 3- (3,4-dimethoxy-phenyl) propanoic acid, the title compound (164 mg, 77% yield) was obtained as a white solid Obtained:
    [582]
    [583] Example 57 - Preparation of compound 57 of Table 1
    [584] The title compound (61 mg, 37% yield) was obtained as a white solid starting from 3- (4-methoxybenzoyl) -propanoic acid (77.0 mg, 0.37 mmol), analogous to the reaction described in Example 12:
    [585]
    [586] Example 58 - Preparation of compound 58 of Table 1
    [587] Starting with 4-chlorobutyric acid (45.1 mg, 0.37 mmol), the title compound (132 mg, 72% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [588]
    [589] Example 59 - Preparation of compound 59 of Table 1
    [590] Starting with 4-phenoxybutyric acid (66.6 mg, 0.37 mmol), the title compound (157 mg, 77% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [591]
    [592] Example 60 - Preparation of compound 60 of Table 1
    [593] Starting with 4-phenoxybutyric acid (60.7 mg, 0.37 mmol), the title compound (143 mg, 72% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [594]
    [595] Example 61 - Preparation of compound 61 of Table 1
    [596] Starting with 4-benzoylbutyric acid (71.0 mg, 0.37 mmol), the title compound (174 mg, 85% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [597]
    [598] Example 62 - Preparation of compound 62 of Table 1
    [599] Starting with dundec-10-enoic acid (68.1 mg, 0.37 mmol), the title compound (149 mg, 73% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [600]
    [601] Example 63 - Preparation of compound 63 of Table 1
    [602] Starting from trans-2-methylpent-2-enoic acid (42.2 mg, 0.37 mmol), the title compound (47 mg, 36% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [603]
    [604] Example 64 - Preparation of compound 64 of Table 1
    [605] Starting from 2-thiophene acetic acid (52.5 mg, 0.37 mmol), the title compound (84 mg, 59% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [606]
    [607] Example 65 - Preparation of compound 65 of Table 1
    [608] Starting with 3-thiophene acetic acid (52.5 mg, 0.37 mmol), the title compound (116 mg, 61% yield) was obtained as a white solid, analogous to the reaction described in Example 12:
    [609]
    [610] MS (+ ve ESI): 421 (M + H) &lt; + & gt ; .
    [611] Example 66 - Preparation of compound 66 of Table 1
    [612] Starting from 78.1 mg (0.37 mmol) of the title compound (156 mg, 73% yield) was obtained in analogy to the reaction described in Example 12 but starting from 3- (4-hydroxy-3-nitrophenyl) propanoic acid Lt; / RTI &gt;
    [613]
    [614] Example 67 - Preparation of compound 67 of Table 1
    [615] Starting with 3,5-difluorophenyl-acetic acid (63.6 mg, 0.37 mmol), the title compound (133 mg, 66% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [616]
    [617] Example 68 - Preparation of compound 68 of Table 1
    [618] The title compound (108 mg, 65% yield) was obtained as a white solid starting from 4-biphenylacetic acid (78.4 mg, 0.37 mmol), analogous to the reaction described in Example 12:
    [619]
    [620] Example 69 - Preparation of compound 69 of Table 1
    [621] The title compound (155 mg, 76% yield) was obtained as a white solid starting with (3,4-methylenedioxy-phenyl) acetic acid (66.6 mg, 0.37 mmol), analogous to the reaction described in Example 12:
    [622]
    [623] Example 70 - Preparation of compound No. 70 in Table 1
    [624] Starting with 2,6-difluorophenyl-acetic acid (63.6 mg, 0.37 mmol), the title compound (158 mg, 79% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [625]
    [626] Example 71 - Preparation of compound 71 of Table 1
    [627] Starting with 4- (n-butoxy) phenylacetic acid (77.2 mg, 0.37 mmol), the title compound (110 mg, 67% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [628]
    [629] Example 72 - Preparation of compound 72 of Table 1
    [630] Starting with 4-methylpentanoic acid (42.9 mg, 0.37 mmol), the title compound (108 mg, 60% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [631]
    [632] Example 73 - Preparation of compound 73 of Table 1
    [633] Starting with 5-hexenoic acid (41.4 mg, 0.37 mmol), the title compound (144 mg, 80% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [634]
    [635] Example 74 - Preparation of compound 74 of Table 1
    [636] Starting from 3-phenoxyphenylacetic acid (84.4 mg, 0.37 mmol), the title compound (121 mg, 71% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [637]
    [638] Example 75 - Preparation of compound 75 of Table 1
    [639] 4-carboxylic acid (87.3 mg, 0.37 mmol), the title compound (190 mg, 86% yield) was obtained as a white solid Lt; / RTI &gt;
    [640]
    [641] Example 76 - Preparation of compound 76 of Table 1
    [642] 4-carboxylic acid (71.0 mg, 0.37 mmol), the title compound (166 mg, 80% yield) was obtained as a white solid Obtained:
    [643]
    [644] Example 77 - Preparation of compound 77 of Table 1
    [645] The title compound (54 mg, 33% yield) was obtained as a white solid starting with (4-ethoxy-3-methoxy-phenyl) acetic acid (77.7 mg, 0.37 mmol) :
    [646]
    [647] Example 78 - Preparation of compound 78 of Table 1
    [648] Starting from 4-benzyloxyphenyl-acetic acid (89.5 mg, 0.37 mmol), the title compound (102 mg, 58% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [649]
    [650] Example 79 - Preparation of compound 79 of Table 1
    [651] The title compound (133 mg, 67% yield) was obtained as a white solid starting from 4- (2-thienyl) butyric acid (62.9 mg, 0.37 mmol), analogous to the reaction described in Example 12:
    [652]
    [653] Example 80 - Preparation of compound 80 of Table 1
    [654] Starting with 6-heptenoic acid (46.6 mg, 0.37 mmol), the title compound (132 mg, 71% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [655]
    [656] MS (+ ve ESI): 405 (M + H) &lt; + & gt ; .
    [657] Example 81 - Preparation of compound 81 of Table 1
    [658] The title compound (114 mg, 71% yield) was obtained as a white solid starting from 1- (4-chlorophenyl) -cyclopropanecarboxylic acid (72.5 mg, 0.37 mmol) :
    [659]
    [660] Example 82 - Preparation of compound 82 of Table 1
    [661] Analogously to the reaction described in Example 12 but starting with cyclopentylacetic acid (47.4 mg, 0.37 mmol) the title compound (139 mg, 75% yield) was obtained as a white solid:
    [662]
    [663] Example 83 - Preparation of compound 83 of Table 1
    [664] Analogous to the reaction described in Example 12 but starting with 3- (cyclopentyl) -propanoic acid (52.5 mg, 0.37 mmol) the title compound (137 mg, 72% yield) was obtained as a white solid:
    [665]
    [666] Example 84 - Preparation of compound 84 of Table 1
    [667] Starting from cyclohexaneacetic acid (52.5 mg, 0.37 mmol), the title compound (106 mg, 56% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [668]
    [669] Example 85 - Preparation of compound 85 of Table 1
    [670] Starting with 3- (cyclohexyl) -propanoic acid (57.7 mg, 0.37 mmol), the title compound (141 mg, 73% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [671]
    [672] Example 86 - Preparation of compound 86 of Table 1
    [673] Analogous to the reaction described in Example 12 but starting with 4- (cyclohexyl) butyric acid (62.9 mg, 0.37 mmol) the title compound (146 mg, 73% yield) was obtained as a white solid:
    [674]
    [675] Example 87 - Preparation of compound 87 of Table 1
    [676] Starting from 2-phenoxypropanoic acid (61.4 mg, 0.37 mmol), the title compound (140 mg, 93% yield) was obtained as a white solid analogous to the reaction described in Example 12:
    [677]
    [678] Example 88 - Preparation of compound 88 of Table 1
    [679] The title compound (44 mg, 30% yield) was obtained as a white solid, starting with -Methyl cinnamic acid (59.9 mg, 0.37 mmol), analogous to the reaction described in Example 21:
    [680]
    [681] Example 89 - Preparation of compound 89 of Table 2
    [682] Benzoyl 2-chloro-4-aminoaniline (5.60 g, 22.7 mmol) and 4-chloro-6,7-dimethoxyquinazoline (5.10 g, 22.7 mmol) in analogy to the reaction described in example 1 To give the title compound (10.53 g, 98% yield) as a light yellow solid:
    [683]
    [684] The N-benzoyl 2-chloro-4-aminoaniline used as starting material was obtained as follows:
    [685] a) 2-Chloro-4-nitroaniline (15.0 g, 86.9 mmol), triethylamine (13.3 ml, 95.6 mmol) and benzoyl chloride (11.1 ml, 95.6 mmol) were refluxed in toluene And heated in an inert atmosphere. The reaction was cooled to ambient temperature overnight resulting in the precipitation of a white solid. The solid was collected by suction filtration, washed with toluene (3 x 50 ml) and dried under vacuum. The crude product was dissolved in dichloromethane (300 ml) and washed with a 2.0 N aqueous hydrochloric acid solution (3 x 100 ml), water (100 ml), and saturated aqueous sodium bicarbonate solution (3 x 100 ml) and water (100 ml) . The organic layer was dried over magnesium sulfate and the solvent was evaporated under vacuum to give N-benzoyl 2-chloro-4-nitroaniline (6.83 g, 28% yield) as a yellow crystalline solid:
    [686]
    [687] MS (+ ve ESI): 277 (M + H) &lt; + & gt ; .
    [688] b) N-Benzoyl 2-chloro-4-nitroaniline (5.77 g, 20.8 mmol) and tin (II) chloride (23.5 g, 104. mmol) were stirred in ethyl acetate (250 ml) And heated. The reaction was cooled to ambient temperature and concentrated aqueous ammonia (40 ml) was added. The reaction was filtered and the solid material was washed with ethyl acetate (3 x 30 ml) and the combined organic layers were evaporated in vacuo. The resulting solid was dried in vacuo to give N-benzoyl 2-chloro-4-aminoaniline (4.63 g, 90% yield) as a cream colored crystalline solid:
    [689]
    [690] Example 90 - Preparation of compound 90 of Table 2
    [691] Benzoyl 2-methyl-4-aminoaniline (111 mg, 0.50 mmol) and 4-chloro-6,7-dimethoxyquinazoline (100 mg, 0.45 mmol) in analogy to the reaction described in example 1 To give the title compound (188 mg, 94% yield) as a white solid:
    [692]
    [693] The N-benzoyl 2-methyl-4-aminoaniline used as starting material was obtained as follows:
    [694] a) A mixture of 2-methyl-4-nitroaniline (2.03 g, 13.3 mmol), triethylamine (2.00 ml, 14.6 mmol) and benzoyl chloride (1.70 ml, 14.6 mmol) Lt; / RTI &gt; for 1 hour under an inert atmosphere. The reaction was cooled to ambient temperature overnight resulting in the precipitation of a white solid. The solid was collected by suction filtration, washed with toluene (3 x 50 ml), dissolved in dichloromethane (100 ml) and washed with water (3 x 50 ml). The organic layer was dried over magnesium sulfate and the solvent was evaporated under vacuum to give N-benzoyl 2-methyl-4-nitroaniline (3.06 g, 90% yield) as a white solid:
    [695]
    [696] b) A mixture of N-benzoyl 2-methyl-4-nitroaniline (2.93 g, 11.4 mmol) and tin (II) chloride (12.9 g, 57.2 mmol) was refluxed in ethyl acetate (100 ml) Lt; / RTI &gt; The reaction was cooled to ambient temperature and concentrated aqueous ammonia (20 ml) was added. The reaction was filtered and the solid material was washed with ethyl acetate (3 x 30 ml), then the combined organic layers were evaporated in vacuo. The resulting solid was dried under vacuum to give N-benzoyl 2-methyl-4-aminoaniline (1.03 g, 40% yield) as a white crystalline solid:
    [697]
    [698] Example 91 - Preparation of compound 91 of Table 2
    [699] (90.8 mg, 0.40 mmol) and 4-chloro-6,7-dimethoxyquinazoline (90 mg, 0.40 mmol) in analogy to the reaction described in Example 1, , The title compound (145 mg, 81% yield) was obtained as a light yellow solid:
    [700]
    [701] Example 92 - Preparation of compound 92 of Table 2
    [702] Benzoyl 2-methoxy-4-aminoaniline hydrochloride (127 mg, 0.45 mmol) and 4-chloro-6,7-dimethoxyquinazoline (102 mg, 0.45 mmol ), The title compound (176 mg, 84% yield) was obtained as a light yellow solid:
    [703]
    [704] The N-benzoyl 2-methoxy-4-aminoaniline used as starting material was obtained as follows:
    [705] a) A mixture of 2-methoxy-4-nitroaniline (2.23 g, 13.3 mmol), triethylamine (2.00 ml, 14.6 mmol) and benzoyl chloride (1.70 ml, 14.6 mmol) Lt; / RTI &gt; at ambient temperature under an inert atmosphere. The solid was collected by suction filtration and washed with toluene (3 x 50 ml) and diethyl ether (50 ml). The crude product was purified by flash chromatography on silica gel (eluting with dichloromethane) to give N-benzoyl 2-methoxy-4-nitroaniline (2.79 g, 77% yield) as a white solid:
    [706]
    [707] b) A mixture of N-benzoyl 2-methoxy-4-nitroaniline (2.63 g, 9.66 mmol) and tin (II) chloride (10.9 g, 48.3 mmol) was refluxed in ethyl acetate (200 ml) And heated in an inert atmosphere. The reaction was cooled to ambient temperature and concentrated aqueous ammonia (20 ml) was added. The reaction was filtered and the solid material was washed with ethyl acetate (3 x 30 ml), then the combined organic layers were evaporated in vacuo. The orange solid was dissolved in ethyl acetate (45 ml) and a 1.0 N solution of hydrogen chloride in diethyl ether (25 ml) was added to precipitate a white solid. This solid was recrystallized from methanol / ethyl acetate to give N-benzoyl 2-methoxy-4-aminoaniline hydrochloride (1.06 g, 39% yield) as a white crystalline solid:
    [708]
    [709] Example 93 - Preparation of compound 93 of Table 2
    [710] Benzoyl 2-cyano-4-aminoaniline (107 mg, 0.45 mmol) and 4-chloro-6,7-dimethoxyquinazoline (101 mg, 0.45 mmol) in analogy to the reaction described in example 1 , The title compound (21 mg, 10% yield) was obtained as a light yellow solid:
    [711]
    [712] The N-benzoyl 2-cyano-4-aminoaniline used as starting material was obtained as follows:
    [713] a) A mixture of 2-cyano-4-nitroaniline (5.00 g, 30.6 mmol), triethylamine (4.70 ml, 33.7 mmol) and benzoyl chloride (3.90 ml, 33.7 mmol) was added at reflux in toluene And heated under an inert atmosphere for 3 hours. The reaction was cooled to ambient temperature, the solid was collected by suction filtration and washed with toluene (3 x 50 ml). The product was dissolved in dichloromethane (100 ml) and washed with a 2.0 N aqueous hydrochloric acid solution (2 x 50 ml), a saturated aqueous sodium bicarbonate solution (50 ml) and water (2 x 50 ml). The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo to give N, N-di (benzoyl) 2-methyl-4-nitroaniline (3.90 g, 62% yield) as a yellow solid:
    [714]
    [715] b) Hydrogen peroxide (8.60 ml, 76.2 mmol) and lithium hydroxide (0.98 g, 23.4 mmol) were added to a solution of N, N-di (benzoyl) -Nitroaniline (4.34 g, 11.7 mmol) at O &lt; 0 &gt; C. The reaction was warmed to ambient temperature over 18 hours, then re-cooled to 0 &lt; 0 &gt; C, and then a 1.5 N aqueous sodium sulfate solution (60 ml, 90 mmol) was added. Tetrahydrofuran was removed in vacuo and acidified to pH 6 by addition of 2.0 N aqueous hydrochloric acid solution. The solid precipitated by suction filtration was collected to give N-benzoyl 2-cyano-4-nitroaniline (3.04 g, 97% yield) as a light yellow solid:
    [716]
    [717] c) A mixture of N-benzoyl 2-cyano-4-nitroaniline (3.38 g, 12.6 mmol) and tin (II) chloride (14.3 g, 63.2 mmol) was refluxed in ethyl acetate (200 ml) Lt; / RTI &gt; The reaction was cooled to ambient temperature, concentrated aqueous ammonia (20 ml) was added, and then the reaction was filtered. The organic layer was evaporated in vacuo to give N-benzoyl 2-cyano-4-aminoaniline (2.64 g, 88% yield) as a yellow solid:
    [718]
    [719] Example 94 - Preparation of compound 94 of Table 2
    [720] Benzoyl 3- (trifluoromethyl) -4-aminoaniline (154 mg, 0.55 mmol) and 4-chloro-6,7-dimethoxyquinazoline (112 mg, 0.50 mmol), the title compound (157 mg, 62% yield) was obtained as a white solid:
    [721]
    [722] MS (-ve ESI): 467 (MH) - ,
    [723] MS (+ ve ESI): 469 (M + H) &lt; + & gt ; .
    [724] The N-benzoyl 2- (trifluoromethyl) -4-aminoaniline used as the starting material was obtained as follows:
    [725] a) A mixture of 3- (trifluoromethyl) -4-nitroaniline (1.00 g, 4.85 mmol) and benzoyl chloride (0.62 ml, 5.34 mmol) was heated at reflux in pyridine (3 ml) Respectively. The reaction was cooled to ambient temperature, poured into water (200 ml) and basified by the addition of 2.0 N aqueous sodium hydroxide solution. The oily liquid was separated and allowed to crystallize overnight at 4 &lt; 0 &gt; C. The solid was collected by suction filtration, washed with water (3 x 20 ml), and then purified by flash chromatography on silica gel (eluting with dichloromethane). Thus, N-benzoyl 3- (trifluoromethyl) -4-nitroaniline (1.01 g, 67% yield) was obtained as a white solid:
    [726]
    [727] b) platinum dioxide (100 mg, 0.44 mmol) was added to a solution of N-benzoyl 3- (trifluoromethyl) -4-nitroaniline (913 mg, 2.94 mmol) in ethanol (50 ml) The reaction was stirred for 1.5 hours under a hydrogen atmosphere. The reaction was filtered through a celite pad and the solvent was evaporated in vacuo to give N-benzoyl 3- (trifluoromethyl) -4-aminoaniline (750 mg, 91% yield) as an off- white solid:
    [728]
    [729] Example 95 - Preparation of compound 95 of Table 2
    [730] To a solution of 4-chloro-6-methoxy-7-benzyloxyquinazoline (150 mg, 0.50 mmol) and N- (4-amino-2-methylphenyl) benzamide (113 mg, 0.50 mmol) in isopropanol After heating the solution at 40 占 폚 for 30 minutes and then at 83 占 폚 for 12 hours, the reaction was cooled to ambient temperature. The precipitated solid was collected by suction filtration and washed with diethyl ether (2 x 10 ml). This material was dried to give the title compound (242 mg, 92% yield) as an off-white solid:
    [731]
    [732] Example 96 - Preparation of compound 96 of Table 2
    [733] The title compound (230 mg, 86% yield) was obtained as a white solid starting from N- (4-amino-2-cyanophenyl) benzamide (118 mg, 0.50 mmol), analogous to the reaction described in Example 95. Obtained:
    [734]
    [735] Example 97 - Preparation of compound 97 of Table 2
    [736] A solution of 1.0 N hydrochloric acid in ether (0.50 ml, 0.50 mmol) was added to a solution of N- (4-amino-2-methylphenyl) benzamide (113 mg, 0.50 mmol) and 4-chloro- Was added to a solution of 7- (3-morpholinoproxy) quinazoline (168 mg, 0.50 mmol). The reaction was heated at 40 &lt; 0 &gt; C for 30 min and then at 83 &lt; 0 &gt; C for 12 h. The reaction was cooled to ambient temperature and the precipitated solid was collected by suction filtration and washed with diethyl ether (2 x 10 ml). This material was dried to give the title compound (275 mg, 98% yield) as a white solid:
    [737]
    [738] Example 98 - Preparation of compound 98 of Table 2
    [739] The title compound (289 mg, 94% yield), analogous to the reaction described in Example 97 but starting with N- (4-amino-2- (trifluoromethyl) phenyl) benzamide (140 mg, 0.50 mmol) &Lt; / RTI &gt; as a white solid:
    [740]
    [741] Example 99 - Preparation of compound 99 of Table 3
    [742] To a solution of 4-chloro-6,7-dimethoxyquinazoline (224 mg, 1.00 mmol), potassium carbonate (152 mg, 1.10 mmol) and N-benzoyl 4- hydroxyaniline (235 mg, 1.10 mmol) in dichloromethane (10 mL) was heated at 110 &lt; 0 &gt; C for 2 h, then the reaction was allowed to cool to ambient temperature. The reaction was poured into water and the precipitated solid was collected by suction filtration and washed with a mixture of diethyl ether (10 ml), ethyl acetate (10 ml) and isohexane (10 ml) The compound (325 mg, 81% yield) was obtained as a beige solid:
    [743]
    [744] The N-benzoyl 4-hydroxyaniline used as starting material was obtained as follows:
    [745] A solution of benzoyl chloride (2.30 ml, 20.0 mmol) in tetrahydrofuran (25 ml) was added to a solution of 4-aminophenol (2.18 g, 20.0 mmol) and triethylamine (10 ml) in tetrahydrofuran Was added dropwise at ambient temperature, and the reaction was stirred for an additional 18 hours. The reaction was poured into water and the solid material formed was collected by suction filtration. Recrystallization from ethyl acetate / isohexane (1: 1) followed by evaporation of the solvent in vacuo gave N-benzoyl 4-hydroxyaniline (3.05 g, 72% yield) as a white solid:
    [746]
    [747] Example 100 - Preparation of compound 100 of Table 3
    [748] Starting from N-benzoyl 2-chloro-4-hydroxyaniline (199 mg, 0.80 mmol), the title compound (172 mg, 54% yield) was obtained as a white solid analogous to the reaction described in Example 99:
    [749]
    [750] The N-benzoyl 2-chloro-4-hydroxyaniline used as starting material was obtained as follows:
    [751] Triethylamine was added to a suspension of 3-chloro-4-aminophenol hydrochloride (1.80 g, 10.0 mmol) in tetrahydrofuran (200 ml) and benzoyl chloride (3.00 ml, 20.0 mmol) Was stirred at ambient temperature for 18 hours. The reaction was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in methanol (200 ml), treated with aqueous potassium carbonate solution (0.6 N, 25 ml, 15 mmol) and the mixture was stirred at ambient temperature for 4 h. A saturated aqueous solution of sodium hydrogencarbonate (100 ml) was added to precipitate an off-white solid, which was collected by suction filtration. Drying in vacuo afforded N-benzoyl 2-chloro-4-hydroxyaniline (2.08 g, 83% yield) as a light purple solid:
    [752]
    [753] Example 101 - Preparation of Compound No. 101 of Table 4
    [754] (3.37 g, 10.0 mmol), the title compound (3.00 g, 58%) was obtained as white crystals. MS: m / e = % Yield) as a white solid after purification by flash chromatography on silica gel (eluting with 10% methanol in dichloromethane): &lt; RTI ID = 0.0 &gt;
    [755]
    [756] 4-Chloro-6-methoxy-7- (3-morpholinopropoxy) quinazoline used as starting material was obtained as follows:
    [757] a) A mixture of morpholine (261 ml, 3.00 mol) and 1-bromo-3-chloropropane (148 ml, 1.50 mol) in toluene (900 ml) was stirred at ambient temperature for 18 hours. Additional 1-bromo-3-chloropropane (25 ml, 0.25 mol) was added and the reaction stirred for an additional hour, after which the precipitated solid was removed by filtration and the filtrate was concentrated in vacuo. The crude oil was distilled to give N- (3-chloropropyl) -morpholine (119.3 g, 49% yield) as a boiling fraction at 70-80 DEG C / 2.6 mmHg:
    [758]
    [759] b) N- (3-Chloropropyl) morpholine (90 g, 0.55 mol) was added over 30 minutes to a solution of ethyl vanillylate (98 g, 0.50 mol) and powdered potassium carbonate in dimethylformamide (300 ml) , 0.75 mol) at 80 &lt; 0 &gt; C. The reaction was heated at 80 &lt; 0 &gt; C for 90 minutes, cooled to ambient temperature, filtered and the filtrate was concentrated in vacuo. The crude product was dissolved in diethyl ether (1000 ml), filtered, and washed with water (2 x 200 ml) and NaCl (200 ml). Evaporation of the solvent in vacuo afforded ethyl 3-methoxy-4- (3-morpholinopropoxy) benzoate (161.5 g, 100% yield) as a pale yellow oil which crystallized to leave a light yellow solid Obtained:
    [760]
    [761] c) Concentrated sulfuric acid (110 ml) and concentrated nitric acid (19.0 ml, 0.289 mol) were added over a period of 50 minutes to a solution of ethyl 3-methoxy-4- (3-morpholinoproxy) benzoate (76.5 g, 0.237 mol) at 5 [deg.] C. The reaction was warmed to ambient temperature over 18 h, the aqueous phase was separated and made to pH 9 by the addition of 40% aqueous sodium hydroxide (775 ml). The aqueous phase was extracted with dichloromethane (3 x 600 ml) and then the solvent was evaporated in vacuo to give ethyl 3-methoxy-4- (3-morpholinoproxy) -6-nitrobenzoate (141.3 g, 86 % Yield) as a yellow rubber: &lt; RTI ID = 0.0 &gt;
    [762]
    [763] d) A suspension of ethyl 3-methoxy-4- (3-morpholinopropoxy) -6-nitrobenzoate (132.2 g, 359 mmol) in a mixture of ethanol (200 ml) and ethyl acetate (2000 ml) And the mixture was stirred under a hydrogen atmosphere for 18 hours. After removing the catalyst by filtration, the solvent was removed in vacuo to give ethyl 3-methoxy-4- (3-morpholinopropoxy) -6-aminobenzoate (122 g, 100% yield) as a brown oil :
    [764]
    [765] e) A solution of ethyl 3-methoxy-4- (3-morpholinopropoxy) -6-aminobenzoate (130 g, 384 mmol) in formamide (280 ml) , And a small amount of liquid (25 ml) was distilled from the reaction. The reaction was cooled to 125 &lt; 0 &gt; C and the excess formamide was evaporated in vacuo. The solid residue was triturated with isopropanol (100 ml) and dried under vacuum to give 6-methoxy-7- (3-morpholinoproxy) -3,4-dihydroquinazoline- 4-one (83.0 g, 68% yield) as a light brown solid:
    [766]
    [767] f) A solution of 6-methoxy-7- (3-morpholinopropoxy) -3,4-dihydro-quinazolin-4-one (83.0 mmol) in dimethylformamide (2.0 ml) g, 261 mmol) in THF (5 mL) and the reaction was heated at reflux for 3.5 hours. The reaction was cooled, excess thionyl chloride was removed in vacuo and the residue was dissolved in water (500 ml), and to this solution was added a saturated aqueous sodium bicarbonate solution (300 ml) to pH 9. The aqueous phase was extracted with dichloromethane (2 x 400 ml), the organic solution was washed with cold water (400 ml) and the solvent removed under vacuum. The solid residue was triturated with ethyl acetate (150 ml) and dried under vacuum to give 4-chloro-6-methoxy-7- (3-morpholinopropoxy) quinazoline , 60% yield) as a light brown solid:
    [768]
    [769] Example 102 - Preparation of compound No. 102 in Table 4
    [770] (3-morpholinoproxy) quinazoline (8.44 mg, 25.0 mmol) and N- (t-butoxycarbonyl) quinazoline analogously to the reaction described in Example 1, but starting from 4-chloro-6-methoxy- 4-aminoaniline (5.73 g, 27.5 mmol), the title compound (13.79 mg, 95% yield) was obtained as a white solid:
    [771]
    [772] Example 103 - Preparation of compound 103 of Table 4
    [773] N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) (143 mg, 0.375 mmol) was dissolved in dimethylacetamide (1.0 ml Was added to a solution of 2-chloro-5-nitrobenzoic acid (33 mg, 0.275 mmol). After 20 minutes, a solution of 4- (4-aminoanilino) -6-methoxy-7- (3-morpholinopropoxy) quinazoline (102 mg, 0.25 mmol) in dimethylacetamide And the reaction was heated at 50 &lt; 0 &gt; C for 18 hours. The reaction was cooled and water (10 ml) was added and neutralized by addition of a saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate. Evaporation of the solvent and drying of the solid in vacuo afforded the title compound (65 mg, 44% yield) as a white solid:
    [774]
    [775] 4- (4-Aminoanilino) -6-methoxy-7- (3-morpholinopropoxy) quinazoline used as starting material was obtained as follows:
    [776] Trifluoroacetic acid (1.00 ml, 13.1 mmol) was added to a solution of 4- (N-Boc-amino) anilino) -6-methoxy- 7- (3-morpholinopropoxy) ) Quinazoline dihydrochloride (100 mg, 0.172 mmol) in tetrahydrofuran and the reaction was stirred for 1 h at ambient temperature. The solvent was removed in vacuo and the residue was suspended in water (2.0 ml) and a saturated aqueous sodium bicarbonate solution (4.0 ml) was added. The aqueous phase was extracted with dichloromethane (3 x 10 ml) and the combined organic layers were washed with brine (25 ml) and evaporated in vacuo. The solid was dried in vacuo to give 4- (4-aminoanilino) -6-methoxy-7- (3-morpholinopropoxy) quinazoline (53 mg, 75% yield) as a white solid:
    [777]
    [778] Example 104 - Preparation of compound 104 of Table 4
    [779] (3-morpholinopropoxy) quinazoline (74 mg, 0.22 mmol) and 4-aminoacetanilide (33 mg, 0.22 mmol) in analogy to the reaction described in example 1, but starting from 4-chloro-6-methoxy- 0.24 mmol), the title compound (108 mg, 97% yield) was obtained as a white solid:
    [780]
    [781] Example 105 - Preparation of compound 105 of Table 4
    [782] (72 mg, 0.50 mmol) and 4- (4-aminoanilino) -6-methoxy-7- (3-morpholinopropoxy) quinazoline (151 mg, mg, 0.45 mmol), the title compound (136 mg, 51% yield) was obtained as a white solid:
    [783]
    [784] Example 106 - Preparation of compound 106 from Table 4
    [785] Starting with furan-2-carboxylic acid (56 mg, 0.50 mmol), the title compound (146.6 mg, 58% yield) was obtained as an off- white solid analogous to the reaction described in Example 103:
    [786]
    [787] Example 107 - Preparation of compound 107 of Table 4
    [788] Starting with 3-furoic acid (56 mg, 0.50 mmol), the title compound (135 mg, 54% yield) was obtained as an off-white solid analogous to the reaction described in Example 103:
    [789]
    [790] Example 108 - Preparation of compound 108 of Table 4
    [791] Starting with 2-thiophene acetic acid (71 mg, 0.50 mmol), the title compound (149 mg, 56% yield) was obtained as an off-white solid analogous to the reaction described in Example 103:
    [792]
    [793] Example 109 - Preparation of compound 109 of Table 4
    [794] Starting with indole-2-carboxylic acid (80 mg, 0.50 mmol), the title compound (170 mg, 62% yield) was obtained as an off- white solid analogous to the reaction described for Example 103:
    [795]
    [796] Example 110 - Preparation of compound 110 of Table 4
    [797] Starting with 2,4-difluorobenzoic acid (79 mg, 0.50 mmol), the title compound (140 mg, 51% yield) was obtained as an off-white solid analogous to the reaction described in Example 103:
    [798]
    [799] Example 111 - Preparation of compound 111 of Table 4
    [800] Starting with 4-methylsulfonyl-3-nitrobenzoic acid (122 mg, 0.50 mmol), the title compound (199 mg, 63% yield) was obtained as an off- white solid analogous to the reaction described for Example 103:
    [801]
    [802] Example 112 - Preparation of compound 112 from Table 4
    [803] The title compound (146 mg, 58% yield) was obtained as an off-white solid starting from 5-hexenoic acid (56 mg, 0.50 mmol), analogous to the reaction described in Example 103:
    [804]
    [805] Example 113 - Preparation of compound 113 of Table 4
    [806] Starting with 2-fluoro-5-nitrobenzoic acid (92 mg, 0.50 mmol), the title compound (180 mg, 62% yield) was obtained as an off- white solid analogous to the reaction described in Example 103:
    [807]
    [808] Example 114 - Preparation of compound 114 from Table 4
    [809] Starting with 3-methoxy-2-nitrobenzoic acid (99 mg, 0.50 mmol), the title compound (168 mg, 57% yield) was obtained as an off- white solid analogous to the reaction described for Example 103:
    [810]
    [811] Example 115 - Preparation of compound No. 115 in Table 4
    [812] The title compound (72 mg, 26% yield) was obtained as a white solid starting from 3- (methylthio) -benzoic acid (84 mg, 0.50 mmol), analogous to the reaction described in Example 103:
    [813]
    [814] Example 116 - Preparation of compound No. 116 in Table 4
    [815] The title compound (117 mg, 44% yield) was obtained as a white solid starting from 2-methylpyrazine-5-carboxylic acid (69 mg, 0.50 mmol), analogous to the reaction described for Example 103:
    [816]
    [817] Example 117 - Preparation of compound 117 of Table 4
    [818] Starting with 6-heptenoic acid (63 mg, 0.50 mmol), the title compound (146 mg, 56% yield) was obtained as an off-white solid analogous to the reaction described in Example 103:
    [819]
    [820] Example 118 - Preparation of compound 118 from Table 4
    [821] Starting with cyclopentane-carboxylic acid (57 mg, 0.50 mmol), the title compound (150 mg, 59% yield) was obtained as an off-white solid analogous to the reaction described for Example 103:
    [822]
    [823] Example 119 - Preparation of compound 119 of Table 4
    [824] Starting with cyclohexyl acetic acid (71 mg, 0.50 mmol), the title compound (139 mg, 52% yield) was obtained as an off-white solid analogous to the reaction described for Example 103:
    [825]
    [826] Example 120 - Preparation of compound 120 of Table 4
    [827] Starting with 4-methoxy-3-nitrobenzoic acid (99 mg, 0.50 mmol), the title compound (172 mg, 59% yield) was obtained as an off- white solid analogous to the reaction described for Example 103:
    [828]
    [829] Example 121 - Preparation of compound No. 121 in Table 4
    [830] The title compound (151 mg, 60% yield) was obtained as an off-white solid starting from the tetrahydro 2-furoic acid (58 mg, 0.50 mmol), analogous to the reaction described for Example 103:
    [831]
    [832] Example 122 - Preparation of compound 122 of Table 4
    [833] The title compound (133 mg, 52% yield) was obtained as an off-white solid following a similar procedure to that described for example 103 but starting from picoloric acid (62 mg, 0.50 mmol)
    [834]
    [835] Example 123 - Preparation of compound 123 of Table 4
    [836] The title compound (139 mg, 54% yield) was obtained as an off-white solid through a similar procedure to that described for example 103 but starting with nicotinic acid (62 mg, 0.50 mmol)
    [837]
    [838] Example 124 - Preparation of compound 124 from Table 4
    [839] The title compound (176 mg, 60% yield) was obtained as an off-white solid following a similar procedure to that described for Example 103 but starting from 4-nitrocinnamic acid (96 mg, 0.50 mmol)
    [840]
    [841] Example 125 - Preparation of compound 125 of Table 4
    [842] The title compound (181 mg, 60% yield) was obtained as an off-white solid following a similar procedure to that described for example 103 but starting from 2,4-dinitrobenzoic acid (106 mg, 0.50 mmol)
    [843]
    [844] MS (+ ve ESI): 604 (M + H) &lt; + & gt ;
    [845] Example 126 - Preparation of compound 126 of Table 4
    [846] The title compound (161 mg, 56% yield) was obtained as an off-white solid following a similar procedure to that described for example 103 but starting from acetoxybenzoic acid (90 mg, 0.50 mmol)
    [847] HPLC / LCMS (RT): 1.56 min:
    [848] MS (+ ve ESI): 572 (M + H) &lt; + & gt ; .
    [849] Example 127 - Preparation of compound 127 of Table 4
    [850] The title compound (146 mg, 55% yield) was prepared in analogy to the reaction described in example 103 but starting from 1,5-dimethyl-1H-pyrazole- Obtained as an off-white solid:
    [851]
    [852] Example 128 - Preparation of compound 128 from Table 4
    [853] Carboxylic acid (40 mg, 0.40 mmol) and 4- (4-aminoanilino) -6-methoxy-7- (3-morpholinopropoxy) (12 mg, 7% yield) as a white solid via the reaction starting from 4-amino-2-methyl-quinazoline (143 mg, 0.35 mmol)
    [854]
    [855] Example 129 - Preparation of compound 129 of Table 4
    [856] The title compound (134 mg, 70% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 2-methoxybenzoic acid (61 mg, 0.40 mmol)
    [857]
    [858] Example 130 - Preparation of compound No. 130 in Table 4
    [859] The title compound (153 mg, 78% yield) was obtained as a white solid through a similar procedure to that described for example 103 but starting from 3-nitrobenzoic acid (67 mg, 0.40 mmol)
    [860] HPLC / LCMS (RT): 3.31 min:
    [861] MS (+ ve ESI): 559 (M + H) &lt; + & gt ; .
    [862] Example 131 - Preparation of compound No. 131 in Table 4
    [863] The title compound (95 mg, 49% yield) was obtained as a white solid through a similar procedure to that described in Example 103 but starting from 4-nitrobenzoic acid (67 mg, 0.40 mmol)
    [864]
    [865] Example 132 - Preparation of compound 132 of Table 4
    [866] The title compound (102 mg, 56% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from cyclohexane-carboxylic acid (51 mg, 0.40 mmol)
    [867]
    [868] Example 133 - Preparation of compound 133 of Table 4
    [869] The title compound (97 mg, 51% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 4-nitropyrrole-2-carboxylic acid (62 mg, 0.40 mmol)
    [870]
    [871] Example 134 - Preparation of compound 134 of Table 4
    [872] The title compound (162 mg, 81% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 4-methyl-3-nitro- benzoic acid (72 mg, 0.40 mmol)
    [873]
    [874] Example 135 - Preparation of compound 135 of Table 4
    [875] The title compound (96 mg, 48% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 4-fluoro-3-nitro-benzoic acid (74 mg, 0.40 mmol)
    [876]
    [877] Example 136 - Preparation of compound 136 of Table 4
    [878] The title compound (148 mg, 79% yield) was obtained as a white solid through a similar procedure to that described in Example 103 but starting from thiophene-3-acetic acid (57 mg, 0.40 mmol)
    [879]
    [880] Example 137 - Preparation of compound 137 of Table 4
    [881] The title compound (189 mg, 89% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 3-chlorobenzothiophene-2-carboxylic acid (85 mg, 0.40 mmol) :
    [882]
    [883] Example 138 - Preparation of compound 138 in Table 4
    [884] The title compound (167 mg, 81% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 5-chloroindole-2-carboxylic acid (78 mg, 0.40 mmol)
    [885]
    [886] Example 139 - Preparation of compound No. 139 of Table 4
    [887] The title compound (68 mg, 35% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 1-piperidinepropanoic acid (63 mg, 0.40 mmol)
    [888]
    [889] Example 140 - Preparation of compound 140 of Table 4
    [890] The title compound (119 mg, 61% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 3,4-methylenedioxybenzoic acid (66 mg, 0.40 mmol)
    [891] HPLC / LCMS (RT): 3.21 min:
    [892] MS (+ ve ESI): 558 (M + H) &lt; + & gt ; .
    [893] Example 141 - Preparation of compound No. 141 in Table 4
    [894] The title compound (119 mg, 69% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 3-butynoic acid (39 mg, 0.40 mmol)
    [895] HPLC / LCMS (RT): 2.82 min:
    [896] MS (+ ve ESI): 490 (M + H) &lt; + & gt ; .
    [897] Example 142 - Preparation of compound 142 from Table 4
    [898] The title compound (156 mg, 83% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 3-cyanobenzoic acid (59 mg, 0.40 mmol)
    [899] HPLC / LCMS (RT): 3.18 min:
    [900] MS (+ ve ESI): 539 (M + H) &lt; + & gt ; .
    [901] Example 143 - Preparation of compound 143 of Table 4
    [902] The title compound (55 mg, 30% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from N-acetyl 3-aminopropanoic acid (52 mg, 0.40 mmol)
    [903]
    [904] Example 144 - Preparation of compound 144 of Table 4
    [905] The title compound (153 mg, 75% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 4- (trifluoromethyl) -benzoic acid (76 mg, 0.40 mmol)
    [906]
    [907] Example 145 - Preparation of compound 145 of Table 4
    [908] The title compound (98 mg, 49% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 3-chloro-4-fluoro- benzoic acid (70 mg, 0.40 mmol)
    [909]
    [910] Example 146 - Preparation of compound 146 of table 4
    [911] The title compound (188 mg, 89% yield) was obtained as a white solid after the reaction starting from 4-fluoro-3- (trifluoromethyl) benzoic acid (83 mg, 0.40 mmol) Lt; / RTI &gt;
    [912] HPLC / LCMS (RT): 3.85 min:
    [913] MS (-ve ESI): 598 (MH) - .
    [914] Example 147 - Preparation of compound 147 of Table 4
    [915] The title compound (146 mg, 78% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 4-fluorobenzoic acid (56 mg, 0.40 mmol)
    [916]
    [917] Example 148 - Preparation of compound 148 from Table 4
    [918] The title compound (203 mg, 97% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 5-bromothiophene-2-carboxylic acid (83 mg, 0.40 mmol) :
    [919]
    [920] Example 149 - Preparation of compound 149 of Table 4
    [921] The title compound (143 mg, 75% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 4-methoxybenzoic acid (61 mg, 0.40 mmol)
    [922]
    [923] Example 150 - Preparation of compound 150 of Table 4
    [924] The title compound (104 mg, 56% yield) was obtained as a white solid through a similar procedure to that described in Example 103 but starting from 6-methylnicotinic acid (55 mg, 0.40 mmol)
    [925]
    [926] Example 151 - Preparation of compound No. 151 in Table 4
    [927] The title compound (158 mg, 83% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 5-nitro-2-furoic acid (63 mg, 0.40 mmol)
    [928] HPLC / LCMS (RT): 3.10 min:
    [929] MS (-ve ESI): 548 (MH) - .
    [930] Example 152 - Preparation of compound 152 of Table 4
    [931] The title compound (166 mg, 85% yield) was obtained as a white solid through a similar procedure to that described in Example 103 but starting from 2-nitrobenzoic acid (67 mg, 0.40 mmol)
    [932] HPLC / LCMS (RT): 3.08 min:
    [933] MS (+ ve ESI): 559 (M + H) &lt; + & gt ; .
    [934] Example 153 - Preparation of compound 153 of Table 4
    [935] The title compound (81 mg, 41% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 3-chlorocinnamic acid (73 mg, 0.40 mmol)
    [936] HPLC / LCMS (RT): 3.87 min:
    [937] MS (+ ve ESI): 574 (M + H) &lt; + & gt ; .
    [938] Example 154 - Preparation of compound 154 of table 4
    [939] The title compound (121 mg, 66% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from thiophene-2-carboxylic acid (51 mg, 0.40 mmol)
    [940] HPLC / LCMS (RT): 3.14 min:
    [941] MS (+ ve ESI): 520 (M + H) &lt; + & gt ; .
    [942] Example 155 - Preparation of compound 155 of Table 4
    [943] The title compound (147 mg, 88% yield) was obtained as a white solid through a similar procedure to that described for example 103 but starting from cyclopropanecarboxylic acid (34 mg, 0.40 mmol)
    [944] HPLC / LCMS (RT): 2.82 min:
    [945] MS (+ ve ESI): 478 (M + H) &lt; + & gt ; .
    [946] Example 156 - Preparation of compound 156 of Table 4
    [947] The title compound (71 mg, 39% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 3-toluic acid (54 mg, 0.40 mmol)
    [948]
    [949] Example 157 - Preparation of compound 157 of Table 4
    [950] The title compound (134 mg, 70% yield) was obtained as a white solid through a similar procedure to that described in Example 103 but starting from 2-chlorobenzoic acid (63 mg, 0.40 mmol)
    [951]
    [952] Example 158 - Preparation of compound 158 of table 4
    [953] The title compound (138 mg, 74% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 2-fluorobenzoic acid (56 mg, 0.40 mmol)
    [954] HPLC / LCMS (RT): 3.21 min:
    [955] MS (+ ve ESI): 532 (M + H) &lt; + & gt ; .
    [956] Example 159 - Preparation of compound 159 of Table 4
    [957] The title compound (191 mg, 94% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 2,5-dichlorobenzoic acid (76 mg, 0.40 mmol)
    [958] HPLC / LCMS (RT): 3.57 min:
    [959] MS (+ ve ESI): 582 (M + H) &lt; + & gt ; .
    [960] Example 160 - Preparation of compound 160 of Table 4
    [961] The title compound (154 mg, 83% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 3-fluorobenzoic acid (56 mg, 0.40 mmol)
    [962] HPLC / LCMS (RT): 3.31 min:
    [963] MS (+ ve ESI): 532 (M + H) &lt; + & gt ; .
    [964] Example 161 - Preparation of compound No. 161 in Table 4
    [965] The title compound (70 mg, 36% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 6-chloronicotinic acid (63 mg, 0.40 mmol)
    [966]
    [967] Example 162 - Preparation of compound 162 of Table 4
    [968] The title compound (192 mg, 94% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 5-bromo-2-furoic acid (76 mg, 0.40 mmol)
    [969]
    [970] Example 163 - Preparation of compound 163 of Table 4
    [971] The title compound (141 mg, 71% yield) was obtained as a white solid through a similar procedure to that described in example 103 but starting from 2-methyl-3-nitro- benzoic acid (72 mg, 0.40 mmol)
    [972] HPLC / LCMS (RT): 3.32 min:
    [973] MS (+ ve ESI): 573 (M + H) &lt; + & gt ; .
    [974] Example 164 - Preparation of compound 164 of table 4
    [975] The title compound (46 mg, 24% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 3-chlorobenzoic acid (63 mg, 0.40 mmol)
    [976]
    [977] Example 165 - Preparation of compound 165 of Table 5
    [978] 4-Chloro-6-methoxy-7- (2,2,2-trifluoroethoxy) quinazoline (400 mg, 1.37 mmol) and isobutyrate in isopropanol (100 ml) The title compound (553 mg, 86% yield) was obtained as an off-white solid following the reaction starting from N-benzoyl 4-aminoaniline (290 mg, 1.37 mmol)
    [979]
    [980] 4-Chloro-6-methoxy-7- (2,2,2-trifluoroethoxy) quinazoline used as starting material was obtained as follows:
    [981] a) Potassium carbonate (62.2 g, 450 mmol) was added to a solution of ethyl vanillylate (58.9 g, 300 mmol) in dimethylformamide (400 ml) and the reaction was heated to 120 &lt; 0 &gt; C. 2,2,2-Trifluoroethyl methanesulfonate (63.4 g, 360 mmol) was added over 15 min and the reaction was heated at 120 &lt; 0 &gt; C for 15 h. The reaction was cooled to ambient temperature, diethyl ether (400 ml) was added and the reaction was filtered. The filtrate was evaporated in vacuo and the residue was dissolved in a mixture of diethyl ether (375 ml) and isohexane (375 ml). The organic layer was concentrated under vacuum to a total volume of 250 ml and the crystallized solid was collected by suction filtration. The solid was dried in vacuo to give ethyl 4- (2,2,2-trifluoroethoxy) -3-methoxybenzoate (43.0 g, 52% yield) as a white crystalline solid:
    [982]
    [983] b) Concentrated sulfuric acid (64 ml) and concentrated nitric acid (10.0 ml, 0.152 mol) were added carefully at 5 ° C over 1 hour to a solution of ethyl 4- (2,2,2-trifluoro Was added to a two-phase system containing a stirred solution of 2-ethoxy-3-methoxybenzoate (35.3 g, 0.127 mol), acetic acid (173 ml) and water (40 ml). The reaction was warmed to room temperature over 60 h (with vigorous mechanical stirring), the aqueous phase was separated and the organic phase was washed with water (6 x 250 ml). The organic phase was concentrated to a total volume of ~ 200 ml, and isohexane (150 ml) was added, and the precipitated solid was collected by suction filtration. The solid was dried in vacuo to give ethyl 3-methoxy-4- (2,2,2-trifluoroethoxy) -6-nitrobenzoate (21.7 g, 52% yield) as a yellow solid. A mixture of the product (28%) and the starting material (72%) was contained in the mother liquor, which was circulated to the post-reaction:
    [984]
    [985] c) To a solution of ethyl 3-methoxy-4- (2,2,2-trifluoroethoxy) -6-nitrobenzoate (24.0 g, 74.3 mmol) in a mixture of ethanol (100 ml) and ethyl acetate ) And 10% palladium on carbon (3.0 g) was stirred under a hydrogen atmosphere for 18 hours. The catalyst was removed by filtration and the solvent was evaporated under vacuum to give ethyl 3-methoxy-4- (2,2,2-trifluoroethoxy) -6-aminobenzoate (20.2 g, 93% yield) Obtained as a light brown solid:
    [986]
    [987] d) A mixture of ethyl 2-amino-4- (2,2,2-trifluoroethoxy) -5-methoxybenzoate (20.2 g, 69.1 mmol) and formamide (50 ml) / RTI &gt; The mixture was cooled to room temperature, ethanol (150 ml) was added and the reaction was allowed to stand for 18 hours. The precipitated solid was collected by filtration, washed with ethanol (2 x 50 ml) and dried under vacuum to give 6-methoxy-7- (2,2,2-trifluoroethoxy) Dihydroquinazolin-4-one (15.8 g, 84% yield) as a light brown crystalline solid:
    [988]
    [989] e) Dimethylformamide (0.1 ml) was added to a solution of 6-methoxy-7- (2,2,2-trifluoroethoxy) -3,4-dihydroquinazolin- (15.8 g, 57.7 mmol) in tetrahydrofuran and the reaction was heated under reflux for 6 hours. The reaction was cooled and excess thionyl chloride was removed in vacuo and the residue was azeotroped with toluene (2 x 50 ml) to remove the final thionyl chloride. The residue was dissolved in dichloromethane (550 ml) and the solution was washed with a saturated aqueous solution of sodium hydrogencarbonate (2 x 250 ml), then the organic phase was dried over magnesium sulfate. Evaporation of the solvent in vacuo gave 4-chloro-6-methoxy-7- (2,2,2-trifluoroethoxy) quinazoline (16.3 g, 97% yield) as a cream solid:
    [990]
    [991] MS (+ ve ESI): 293, 295 (M + H) &lt; + & gt ; .
    [992] Example 166 - Preparation of compound 166 of Table 5
    [993] 6-methoxy-7- (2,2,2-trifluoroethoxy) quinazoline (91 mg, 0.25 mmol) and (4-aminoanilino) The title compound (82 mg, 60% yield) was obtained as a yellow solid via the reaction starting from 2-chloro-3-nitrobenzoic acid (54 mg, 0.27 mmol)
    [994]
    [995] 4- (4-Aminoanilino) -6-methoxy-7- (2,2,2-trifluoroethoxy) quinazoline used as starting material was obtained as follows:
    [996] a) A mixture of 4-chloro-6-methoxy-7- (2,2,2-trifluoroethoxy) quinazoline (4.50 g, 15.4 mmol) and N- (t- -1,4-phenylenediamine (3.21 g, 15.4 mmol) in acetonitrile (5 mL) was heated at reflux for 3.5 hours, then the reaction was cooled to ambient temperature and the reaction was poured into diethyl ether (200 mL). The precipitated solid was collected by suction filtration and dried under vacuum to give 4- (4- (N-Boc-amino) anilino) -6-methoxy-7- (3-morpholinoproxy) quinazoline g, 76% yield) as a light yellow solid:
    [997]
    [998] b) Trifluoroacetic acid (20.0 ml, 260 mmol) was added to a solution of 4- (4- (N-Boc-amino) anilino) -6- -Trifluoroethoxy) quinazoline (7.50 g, 11.7 mmol) and the reaction was stirred at ambient temperature for 45 minutes. The solvent was removed in vacuo and the residue was suspended in water (50 ml) and a saturated aqueous sodium bicarbonate solution was added. The aqueous phase was extracted with ethyl acetate (3 x 100 ml) and the combined organic layers were washed with brine (100 ml) and evaporated in vacuo. The solids were dried under vacuum to give 4- (4-aminoanilino) -6-methoxy-7- (3-morpholinoproxy) quinazoline (5.62 g, 100% yield) as a yellow solid:
    [999]
    [1000] Example 167 - Preparation of compound 167 of Table 5
    [1001] (4-aminoanilino) -6-methoxy-7- (2,2,2-trifluoroethoxy) quinazoline (163 mg, 0.45 mmol) and The title compound (56 mg, 25% yield) was obtained as an off-white solid following the reaction starting from cyclopentanecarboxylic acid (57 mg, 0.50 mmol)
    [1002] HPLC / LCMS (RT): 2.25 min:
    [1003] MS (+ ve ESI): 461 (M + H) &lt; + & gt ; .
    [1004] Example 168 - Preparation of compound 168 of Table 5
    [1005] The title compound (65 mg, 27% yield) was obtained as an off-white solid following a similar procedure to that described for example 103 but starting with cyclohexylacetic acid (71 mg, 0.50 mmol)
    [1006]
    [1007] Example 169 - Preparation of compound 169 of Table 5
    [1008] The title compound (65 mg, 24% yield) was obtained as a white solid through a similar procedure to that described for Example 103 but starting from 4-methoxy-3-nitro- benzoic acid (99 mg, 0.50 mmol)
    [1009]
    [1010] Example 170 - Preparation of compound 170 of Table 5
    [1011] The title compound (104 mg, 43% yield) was obtained as an off-white solid through a similar procedure to that described for example 103 but starting from octanoic acid (72 mg, 0.50 mmol)
    [1012]
    [1013] Example 171 - Preparation of compound 171 of Table 5
    [1014] The title compound (132 mg, 58% yield) was obtained as an off-white solid through a similar procedure to that described for Example 103 but starting from furan-2-carboxylic acid (56 mg, 0.50 mmol)
    [1015]
    [1016] Example 172 - Preparation of compound 172 of table 5
    [1017] The title compound (80 mg, 35% yield) was obtained as an off-white solid following a similar procedure to that described for Example 103 but starting from 3-furoic acid (56 mg, 0.50 mmol)
    [1018]
    [1019] MS (+ ve ESI): 459 (M + H) &lt; + & gt ; .
    [1020] Example 173 - Preparation of compound 173 of Table 5
    [1021] The title compound (64 mg, 26% yield) was obtained as an off-white solid following a similar procedure to that described for Example 103 but starting from 2-thiophene acetic acid (71 mg, 0.50 mmol)
    [1022] HPLC / LCMS (RT): 2.17 min:
    [1023] MS (+ ve ESI): 489 (M + H) &lt; + & gt ; .
    [1024] Example 174 - Preparation of compound 174 of table 5
    [1025] The title compound (8 mg, 3% yield) was obtained as an off-white solid through a similar procedure to that described for Example 103 but starting from indole-2-carboxylic acid (80 mg, 0.50 mmol)
    [1026] HPLC / LCMS (RT): 2.41 min:
    [1027] MS (+ ve ESI): 508 (M + H) &lt; + & gt ; .
    [1028] Example 175 - Preparation of compound 175 of Table 5
    [1029] The title compound (71 mg, 31% yield) was obtained as an off-white solid following a similar procedure to that described for example 103 but starting from tetrahydro 2-furoic acid (58 mg, 0.50 mmol)
    [1030]
    [1031] Example 176 - Preparation of compound 176 in Table 5
    [1032] The title compound (28 mg, 12% yield) was obtained as an off-white solid through a similar procedure to that described for example 103 but starting from picolinic acid (62 mg, 0.50 mmol)
    [1033]
    [1034] Example 177 - Preparation of compound 177 of Table 5
    [1035] The title compound (14 mg, 6% yield) was obtained as an off-white solid through a similar procedure to that described for example 103 but starting from nicotinic acid (62 mg, 0.50 mmol)
    [1036]
    [1037] Example 178 - Preparation of compound 178 from Table 5
    [1038] The title compound (17 mg, 6% yield) was obtained as an off-white solid following a similar procedure to that described for Example 103 but starting from 2,4-dinitrobenzoic acid (106 mg, 0.50 mmol)
    [1039] HPLC / LCMS (RT): 2.36 min:
    [1040] MS (+ ve ESI): 559 (M + H) &lt; + & gt ; .
    [1041] Example 179 - Preparation of compound 179 from Table 5
    [1042] The title compound (38 mg, 15% yield) was obtained as an off-white solid following a similar procedure to that described for Example 103 but starting from 2,4-difluorobenzoic acid (79 mg, 0.50 mmol)
    [1043]
    [1044] Example 180 - Preparation of compound 180 of Table 5
    [1045] The title compound (39 mg, 17% yield) was obtained as an off-white solid following a similar procedure to that described for Example 103 but starting from 5-hexenoic acid (56 mg, 0.50 mmol)
    [1046]
    [1047] Example 181 - Preparation of compound 181 of Table 5
    [1048] The title compound (58 mg, 22% yield) was obtained as an off-white solid following a similar procedure to that described for Example 103 but starting from 3-sulforanyl acetic acid (89 mg, 0.50 mmol)
    [1049] HPLC / LCMS (RT): 1.86 min:
    [1050] MS (+ ve ESI): 525 (M + H) &lt; + & gt ; .
    [1051] Example 182 - Preparation of compound 182 from Table 5
    [1052] The title compound (14 mg, 6% yield) was obtained as an off-white solid following a similar procedure to that described for Example 103 but starting from 3-methoxy-propionic acid (52 mg, 0.50 mmol)
    [1053] HPLC / LCMS (RT): 1.84 min:
    [1054] MS (+ ve ESI): 451 (M + H) &lt; + & gt ; .
    [1055] Example 183 - Preparation of compound 183 of Table 5
    [1056] The title compound (115 mg, 43% yield) was obtained as an off-white solid following a similar procedure to that described for Example 103 but starting from 2-fluoro-5-nitro-benzoic acid (92 mg, 0.50 mmol)
    [1057]
    [1058] Example 184 - Preparation of compound 184 from Table 5
    [1059] The title compound (42 mg, 16% yield) was obtained as an off-white solid following a similar procedure to that described for Example 103 but starting from 3-methoxy-2-nitrobenzoic acid (99 mg, 0.50 mmol)
    [1060]
    [1061] Example 185 - Preparation of compound 185 of Table 5
    [1062] The title compound (67 mg, 26% yield) was obtained as an off-white solid following a similar procedure to that described for Example 103 but starting from 2- (methylthio) benzoic acid (84 mg, 0.50 mmol)
    [1063]
    [1064] Example 186 - Preparation of compound 186 from Table 5
    [1065] The title compound (198 mg, 82% yield) was obtained as an off-white solid through a similar procedure to that described for example 103 but starting from 2-methylpyrazine-5-carboxylic acid (69 mg, 0.50 mmol)
    [1066]
    [1067] Example 187 - Preparation of compound 187 of Table 5
    [1068] The title compound (29 mg, 12% yield) was obtained as an off-white solid through a similar procedure to that described for Example 103 but starting from 6-heptenoic acid (63 mg, 0.50 mmol)
    [1069] HPLC / LCMS (RT): 2.19 min:
    [1070] MS (+ ve ESI): 473 (M + H) &lt; + & gt ; .
    [1071] Example 188 - Preparation of compound 188 of Table 5
    [1072] The title compound (39 mg, 15% yield) was obtained as an off-white solid following a similar procedure to that described for example 103 but starting from 3-acetoxybenzoic acid (90 mg, 0.50 mmol)
    [1073]
    [1074] Example 189 - Preparation of compound 189 of Table 5
    [1075] The title compound (43 mg, 18% yield) was prepared in analogy to the reaction described in example 103 but starting from 1,5-dimethyl- lH-pyrazole-3-carboxylic acid (70 mg, 0.50 mmol) Obtained as an off-white solid:
    [1076]
    [1077] Example 190 - Preparation of compound 190, Table 6
    [1078] The title compound (4.09 g, 100% yield) was obtained in analogy to the reaction described in example 1 but starting from 4-chloro-6-acetoxy-7-methoxyquinazoline hydrochloride (2.52 g, 8.75 mmol) &Lt; / RTI &gt; as a white solid:
    [1079]
    [1080] 4-Chloro-6-acetoxy-7-methoxyquinazoline used as starting material was obtained as follows:
    [1081] a) A mixture of 6,7-dimethoxy-3,4-dihydro-quinazolin-4-one (20.0 g, 97 mmol) and racemic methionine (21.7 g, 146 mmol) in methanesulfonic acid (150 ml) Was heated at 100 &lt; 0 &gt; C for 5.5 hours and then cooled to ambient temperature over 18 hours. The reaction was poured into cold water (750 ml), the pH of the aqueous solution was adjusted to pH 6 (by addition of 2.0 N aqueous sodium hydroxide solution) and the solids formed were collected by suction filtration. The solid was dried in vacuo and then dissolved in a mixture of pyridine (20 ml) and acetic anhydride (150 ml). The solution was heated at 100 &lt; 0 &gt; C for 1 hour, cooled and poured into cold water (1050 ml). The resulting solid was collected by suction filtration and dried under vacuum to give 6-acetoxy-7-methoxy-3,4-dihydro-quinazolin-4-one (13.9 g, 57% yield) as a light brown solid Lt; / RTI &gt;
    [1082]
    [1083] b) Dimethylformamide (0.25 ml) was added to a solution of 6-acetoxy-7-methoxy-3,4-dihydroquinazolin-4-one (13.8 g, 59.0 mmol) in thionyl chloride The reaction was heated at reflux for 1.5 hours. The reaction was cooled and excess thionyl chloride was removed in vacuo and the residue was azeotroped with toluene (2 x 50 ml) to remove the final thionyl chloride. Drying in vacuo gave 4-chloro-6,7-dimethoxyquinazoline hydrochloride (14.7 g, 87% yield) as a beige solid which was used without further purification:
    [1084]
    [1085] Example 191 - Preparation of compound 191 of Table 6
    [1086] The title compound (285 mg, 91%) was prepared following a similar procedure to that described in Example 1 but starting from 4-chloro-6,7-di (2-methoxyethoxy) quinazoline (200 mg, 0.64 mmol) Yield) as a light yellow solid: &lt; RTI ID = 0.0 &gt;
    [1087]
    [1088] 4-Chloro-6,7-di (2-methoxyethoxy) quinazoline used as the starting material is analogous to the reaction described in example 1 b) but using 6,7-di (2- methoxyethoxy) -3,4-dihydroquinazolin-4-one (prepared according to U.S. Patent No. 5,747,498):
    [1089]
    [1090] Example 192 - Preparation of compound 192 of Table 6
    [1091] A solution of 4-chloro-6-methoxy-7-benzyloxyquinazoline (2.40 g, 8.00 mmol) and N-benzoyl 4-aminoaniline (1.70 g, 8.00 mmol) in isopropanol (100 ml) &Lt; / RTI &gt; and the reaction was cooled to ambient temperature. The precipitated solid was collected by suction filtration and washed with diethyl ether (2 x 50 ml). This material was dried to give the title compound (3.81 g, 100% yield) as an off-white solid:
    [1092]
    [1093] 4-Chloro-6-methoxy-7-benzyloxyquinazoline used as starting material was obtained as follows:
    [1094] a) A mixture of 2-amino-4-benzyloxy-5-methoxybenzamide (10 g, 0.04 mol - [repared according to J. Med. Chem. 1977, 20, 146-149] in dioxane (100 m) And Gold's reagent (7.4 g, 0.05 mol) was stirred and heated at reflux for 24 hours. Sodium acetate (3.02 g, 0.037 mol) and acetic acid (1.65 ml, 0.029 mol) were added to the reaction mixture and heated for a further 3 hours. The volatiles were removed by evaporation, water was added to the residue, the solid was collected by filtration, washed with water and dried. Recrystallization from acetic acid gave 7-benzyloxy-6-methoxy-3,4-dihydroquinazolin-4-one (8.7 g, 84% yield) as a white solid.
    [1095] b) Dimethylformamide (0.2 ml) was added dropwise to a solution of 6-methoxy 7-benzyloxy-3,4-dihydroquinazolin-4-one (5.00 g, 17.9 mmol) in thionyl chloride , And the reaction was heated under reflux for 1 hour. The reaction was allowed to cool, excess thionyl chloride was removed under vacuum, and the residue was azeotroped with toluene (3 x 50 ml) to remove the final thionyl chloride. The residue was dissolved in dichloromethane (550 ml), and the solution was washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml) and water (100 ml), and then the organic layer was dried over magnesium sulfate. Evaporation of the solvent under vacuum afforded 4-chloro-6,7-dimethoxyquinazoline (4.80 g, 90% yield) as a light brown solid:
    [1096]
    [1097] Example 193 - Preparation of compound 193 of Table 6
    [1098] The reaction starting from 4-chloro-6-methoxy-7- ((1-methyl-4-piperazinyl) methoxy) quinazoline (100 mg, 0.31 mmol) The title compound (21 mg, 14% yield) was obtained as a white solid after purification by flash chromatography on silica gel (eluting with 2-6% 2.0 N ammonia in methanolic dichloromethane (5:95)
    [1099]
    [1100] 4-Chloro-6-methoxy-7 - ((1-methyl-4-piperazinyl) methoxy) quinazoline used as starting material was obtained as follows:
    [1101] a) A solution of di-t-butyl dicarbonate (41.7 g, 0.19 mol) in ethyl acetate (75 ml) was added dropwise to a solution of ethyl 4-piperidinecarboxylate (30 g, 0.19 mol). The reaction was stirred at ambient temperature for 48 h, poured into water (300 ml) and the organic layer was separated i) water (200 ml), ii) 0.1 N aqueous hydrochloric acid solution (200 ml), iii) saturated sodium bicarbonate ) Brine (200 ml). Evaporation and vacuum drying afforded ethyl 4- (1-t-butyloxycarbonyl-piperidine) carboxylate (48 g, yield 98%) as a white solid:
    [1102]
    [1103] b) A solution of 1.0 N lithium aluminum hydride in tetrahydrofuran (133 ml, 0.133 mol) was added at 0 ° C to a solution of ethyl 4- (1-t-butyloxycarbonylpiperidine) carboxylate 48 g, 0.19 mol). The reaction was stirred for 2 h at 0 <0> C, water (30 ml) and 2.0 N sodium hydroxide (10 ml) were added and the precipitate was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was washed with water and brine and evaporated to give 4-hydroxymethyl-1-t-butyloxycarbonylpiperidine (36.3 g, 89% yield) as a white solid:
    [1104]
    [1105] c) 1,4-Diazabicyclo [2.2.2] octane (42.4 g, 0.378 mol) was added to a solution of 4-hydroxymethyl-1-t-butyloxycarbonylpiperidine 52.5 g, 0.244 mol) and the reaction was stirred at ambient temperature for 15 min. The reaction was cooled to 5 캜 and a solution of 4-toluenesulfonyl chloride (62.8 g, 0.33 mmol) in t-butyl methyl ether (525 ml) was added dropwise over 2 hours while maintaining the temperature at 0 캜. The reaction was stirred at ambient temperature for 1 hour, isohexane was added, and the resulting precipitate was collected by reduced pressure filtration. The solvent was evaporated in vacuo to a solid which was dissolved in diethyl ether (250ml) and washed successively with 0.5N aqueous hydrochloric acid (2 x 500ml), water, saturated sodium bicarbonate and brine. Evaporation of the solvent and vacuum drying afforded 4- (4-methylphenylsulfonyloxy-methyl) -1-t-butyloxycarbonylpiperidine (76.7 g, yield 85%) as a white solid:
    [1106]
    [1107] d) To a solution of 4- (4-methylphenylsulfonyloxymethyl) -1-t-butyloxycarbonylpiperidine (40 g, 0.11 mol) in dry dimethylformamide (200 ml) Benzoate (19.6 g, 0.1 mol) and potassium carbonate (28 g, 0.2 mol) and the reaction was heated at 95 &lt; 0 &gt; C for 2.5 h. The reaction was cooled to ambient temperature, partitioned between water and ethyl acetate / diethyl ether, and then the organic layer was washed with water and brine. The solvent was evaporated under vacuum to give a clear oil which crystallized upon standing. The solid was collected by filtration under reduced pressure followed by washing with isohexane and vacuum drying to obtain ethyl 3-methoxy-4- (1-t-butyloxycarbonylpiperidin-4-ylmethoxy) benzoate , 89%): &lt; RTI ID = 0.0 &gt;
    [1108] Melting point 81-83 DEG C:
    [1109]
    [1110] e) Formaldehyde (35 ml of a 37% aqueous solution, 420 mmol) was added to a solution of ethyl 3-methoxy-4- (1-t-butyloxycarbonylpiperidin-4ylmethoxy) benzoate (35 g, 89 mmol) in formic acid (35 ml) And the reaction was heated at 95 &lt; 0 &gt; C for 3 hours. The reaction was cooled, the volatiles were removed in vacuo and the residue was dissolved in dichloromethane. A solution of 3.ON hydrochloric acid in diethyl ether (40 ml, 120 mmol) was added with a small amount of diethyl ether and the solid was precipitated. The solid was collected by vacuum filtration and then vacuum dried to obtain ethyl 3-methoxy-4- (1-methylpiperidin-4-ylmethoxy) benzoate (30.6 g, yield 100%) as a white solid:
    [1111]
    [1112] f) Trifluoroacetic acid (37.5 ml) was added to ethyl 3-methoxy-4- (l-methylpiperidin-4-ylmethoxy) benzoate (30.6 g, 89 mmol) in dichloromethane (75 ml) C and fuming nitric acid (7.42 ml, 178 mmol) in dichloromethane (15 ml) was added dropwise over 15 minutes. The reaction was stirred at ambient temperature for 2 hours, the volatiles were removed in vacuo and the residue was dissolved in dichloromethane (50 ml). The reaction was cooled to 0-5 &lt; 0 &gt; C, diethyl ether (50 ml) was added and the resulting precipitate was collected by vacuum filtration and vacuum dried. The solid was taken up in dichloromethane (500 ml), and a solution of 3.ON hydrochloric acid in diethyl ether (30 ml) was added. Then, diethyl ether (500 ml) was added to precipitate a solid. The solid was collected by vacuum filtration and then vacuum dried to obtain ethyl 3-methoxy-4- (1-methylpiperidin-4-ylmethoxy) -6-nitrobenzoate (28.4 g, yield 82% Lt; / RTI &gt;
    [1113]
    [1114] g) To a solution of ethyl 3-methoxy-4- (1-methylpiperidin-4-ylmethoxy) -6- Nitrobenzoate (3.89 g, 10 mmol) was hydrogenated at 1.8 atm until hydrogenation ceased. The reaction was filtered through celite, the filtrate was evaporated and the residue was dissolved in water (30 ml) and the pH was adjusted to 10 with saturated sodium bicarbonate solution. The mixture was diluted with ethyl acetate / diethyl ether (1: 1) and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate / ether and the organic layer was collected and washed with water and brine. The solvent was evaporated in vacuo and then triturated with a mixture of diethyl ether / isohexane and dried in vacuo to give ethyl 6-amino-3-methoxy-4- (1-methylpiperidin- Benzoate (2.58 g, yield 80%): &lt; RTI ID = 0.0 &gt;
    [1115] Melting point. 111-112 DEG C
    [1116]
    [1117] h) A mixture of ethyl 6-amino-3-methoxy-4- (l -methylpiperidin-4ylmethoxy) benzoate (1.00 g, 10 mmol) in 2-methoxyethanol (160 ml) containing formamidine acetate (16.1 g, 50 mmol) was heated at 115 &lt; 0 &gt; C for 2 h. Formamidineacetate (10.4 g, 100 mmol) was added to the reaction mixture over several hours every 30 minutes over 4 hours, and the reaction was heated for 30 minutes after the last addition. The reaction was cooled, the volatiles were removed in vacuo and the residue was dissolved in ethanol (100 ml) and dichloromethane (50 ml). The reaction was filtered and the filtrate was concentrated to a final volume of 100 ml. (5 &lt; 0 &gt; C) followed by drying in vacuo to give 6-methoxy-7 ((1- methylpiperidin-4- yl) methoxy) Dihydroquinazolin-4-one (12.7 g, yield 70%):
    [1118]
    [1119] i) To a solution of 6-methoxy-7- ((1-methylpiperidin-4-yl) methoxy) -3,4-dihydroquinacetanilide in 28 ml of thionyl chloride containing 0.28 ml of dimethylformamide Zolin-4-one (2.8 g, 9.24 mmol) was heated to reflux for 1 hour. The reaction was cooled, the volatiles were removed in vacuo, the resulting solid was triturated with diethyl ether, filtered, washed with diethyl ether and vacuum dried. The solid was dissolved in dichloromethane and washed with saturated sodium bicarbonate, water and brine. Evaporation of the solvent and vacuum drying afforded 4-chloro-6-methoxy-7- ((1-methylpiperidin-4- yl) methoxy) quinazoline (2.9 g, yield 98%
    [1120]
    [1121] Example 194 - Preparation of compound No. 194 in Table 6
    [1122] Starting from 2- (1-morpholino) -4-chloro-6,7-dimethoxyquinazoline (90 mg, 0.29 mmol), the title compound (123 mg, yield 81 %) &Lt; / RTI &gt; as an off-white solid:
    [1123]
    [1124] 2- (1-Morpholino) -4-chloro-6,7-dimethoxyquinazoline used as starting material was obtained as follows:
    [1125] 2,4-Dichloro-6,7-dimethoxyquinazoline (1.55 g, 6.00 mmol) and N-methylmorpholine (1.32 ml, 12.0 mmol) in dioxane (30 ml) was heated to reflux under an inert atmosphere for 24 hours . The reaction was cooled, stirred with saturated sodium bicarbonate solution (40 ml) for 15 min and then extracted with ethyl acetate (2 x 50 ml). The collected organic layer was washed with brine (50 ml) and then the solvent was evaporated in vacuo to give 2- (1-morpholino) -4-chloro-6,7-dimethoxyquinazoline (1.67 g, yield 90% Lt; / RTI &gt;
    [1126]
    [1127] Example 195 - Preparation of compound No. 195 in Table 6
    [1128] To a solution of 4 - ((4- (N-benzoyl) amino) anilino) -6-acetoxy-7- methoxyquinazoline hydrochloride (4.40 g, 9.48 mmol) in methanol (100 ml) and aqueous concentrated ammonia And the solution was heated at 50 &lt; 0 &gt; C for 2 hours. The solvent was evaporated in vacuo and the resulting white paste was filtered off and then triturated with methanol (75 ml). The solid was stirred with 5.0 N hydrochloric acid (150 ml), and the solid hydrochloride salt was collected by filtration under reduced pressure. To give the title compound (3.74 g, yield 93%) as a pale yellow solid:
    [1129]
    [1130] Example 196 - Preparation of compound No. 196 in Table 6
    [1131] (4- (N-benzoyl) amino) anilino) -6-methoxy-7-benzyloxyquinazoline (3.70 g, 7.20 mmol) in trifluoroacetic acid (50 ml) was heated to reflux for 2 hours . The reaction was cooled, evaporated in vacuo and the residue so formed was triturated with diethyl ether (3 x 25 ml). Drying of the material gave the title compound (3.84 g, 100% yield) as a pale yellow solid:
    [1132]
    [1133] Example 197 - Preparation of compound No. 197 in Table 7
    [1134] Diethyl azodicarboxylate (0.06 ml, 0.33 mmol) was added to a solution of 4 - ((4- (N-benzoyl) amino) anilino) -6-hydroxy-7-methoxyquinazoline To a stirred suspension of triethylamine (0.036 ml, 0.27 mmol), N- (3-hydroxyethyl) morpholine (65 mg, 0.50 mmol) and triphenylphosphine (65 mg, 0.33 mmol) . The reaction was stirred at ambient temperature for 15 minutes, then additional triphenylphosphine and diethyl azodicarboxylate were added (same amount as before) and stirred for an additional 2 hours, triphenylphosphine and diethyl azodicar (Same amount as before). The reaction mixture was poured into a SCX column washed with 0-10% methanol in dichloromethane and the product was eluted with 3% ammonia in a methanol solution of 20% dichloromethane. Purification of the crude product by flash chromatography on silica gel (eluant; 0-20% methanol in dichloromethane) gave the title compound (32 mg, yield 26%) as a white solid:
    [1135]
    [1136] Example 198 - Preparation of compound No. 198 in Table 7
    [1137] The title compound was obtained in analogy to the method described in example 197, but starting from 4- ((4- (N-benzoyl) -amino) anilino) -6-hydroxy-7- methoxyquinazoline (164 mg, 0.389 mmol) 3-hydroxypropyl) -morpholine (113 mg, 0.78 mmol) to give the title compound (43 mg, 21% yield) as a white solid:
    [1138]
    [1139] Example 199 - Preparation of compound No. 199 in Table 7
    [1140] (164 mg, 0.389 mmol) and 4- ((4-fluorophenyl) amino) anilino) -6-hydroxy-7-methoxyquinazoline analogously to the method described in Example 197, 3-hydroxypropyl) -thiomorpholine-1,1-dioxide (96 mg, 0.50 mmol) gave the title compound (30 mg, 14% yield) as a white solid:
    [1141]
    [1142] Example 200 - Preparation of compound No. 200 in Table 7
    [1143] (100 mg, 0.236 mmol) and 3 &lt; RTI ID = 0.0 &gt; (3-benzoylamino) &lt; / RTI &gt; anilino) -6-hydroxy-7-methoxyquinazoline hydrochloride - hydroxypropylmethylsulfone (55 mg, 0.40 mmol) to give the title compound (41 mg, 41% yield) as a light yellow solid:
    [1144]
    [1145] Example 201 - Preparation of compound No. 201 in Table 7
    [1146] 6-hydroxy-7-methoxyquinazoline hydrochloride (165 mg, 0.39 mmol) and 1 (1-benzoylamino) - (2-hydroxyethyl) -1,2,4-triazole (88 mg, 0.78 mmol) to give the title compound (30 mg, yield 16%) as a light yellow solid:
    [1147]
    [1148] MS (+ ve ESI): 482 (M + H) &lt; + & gt ; .
    [1149] Example 202 - Preparation of compound No. 202 in Table 7
    [1150] (4- (N-benzoyl) amino) anilino) -benzonitrile in tetrahydrofuran under an inert atmosphere was treated with tributylphosphine (0.193 ml, 0.78 mmol) and N, N- dimethylethanolamine (0.052 ml, 0.52 mmol) -6-hydroxy-7-methoxyquinazoline (100 mg, 0.26 mmol) at ambient temperature. After 5 minutes, 1,1 '- (azodicarbonyl) dipiperidine (196 mg, 0.78 mmol) was slowly added over 10 minutes and the reaction was stirred for an additional 2 hours. Additional tributylphosphine and 1,1 '- (azodicarbonyl) dipiperidine (same amount as before) were added and stirred for 40 minutes. The reaction mixture was poured into a SCX column washed with 0-10% methanol in dichloromethane and the product was eluted with 3% ammonia in 20% methanolic dichloromethane. The crude product was purified by flash chromatography on silica gel (eluting with 5-10% methanol in dichloromethane) to give the title compound (42 mg, 36% yield) as a white solid:
    [1151]
    [1152] Example 203 - Preparation of compound No. 203 in Table 7
    [1153] 4- ((4- (N-benzoyl) amino) anilino) -6-heptane hydrochloride was prepared at ambient temperature using sodium hydride (60% dispersion in mineral oil: 26 mg, 0.65 mmol) and benzyltriethylammonium bromide Hydroxy-7-methoxyquinazoline &lt; / RTI &gt; (164 mg, 0.389 mmol). 3-Picolyl chloride hydrochloride (85 mg, 0.52 mmol) was added and the reaction was stirred for 3 hours. Sodium hydride (10.0 mg, 0.25 mmol) and dimethylformamide (3.0 ml) were added and the reaction was heated at 50 &lt; 0 &gt; C for 3 h. The reaction was cooled, diethyl ether (10 ml) was added, and the precipitated solid was collected by vacuum filtration. Purification by reverse phase preparative high pressure chromatography (hplc) (eluting with 5-95% acetonitrile in water) afforded the title compound (25 mg, 20% yield) as a tan solid:
    [1154]
    [1155] Example 204 - Preparation of compound No. 204 in Table 7
    [1156] Benzoyl) amino) anilino) -6-hydroxy-7-methoxyquinazoline (100 mg, 0.25 mmol) and methyl 2-chloro- Starting with ethyl ether (0.024 ml, 0.26 mmol) and heating the reaction at 80 <0> C for 18 h, the title compound (32 mg, yield 28%) was obtained as a white solid:
    [1157]
    [1158] Example 205 - Preparation of compound No. 205 in Table 7
    [1159] Benzoyl) amino) anilino) -6-hydroxy-7-methoxyquinazoline (100 mg, 0.25 mmol) and 3- (dimethyl Amino-1-chloropropane hydrochloride (41 mg, 0.26 mmol) and the reaction heated at 150 <0> C for 2.5 h to give the title compound (53 mg, 43% yield) as a light brown solid:
    [1160]
    [1161] Example 206 - Preparation of compound No. 206 in Table 5
    [1162] (4- (N-benzoyl) amino) anilino) -6- (benzyloxycarbonyl) amino] benzoate was prepared by reacting potassium carbonate (178 mg, 1.29 mmol) and benzyltributylammonium bromide (46 mg, 0.13 mmol) Hydroxy-7-methoxy-quinazoline &lt; / RTI &gt; (50 mg, 0.13 mmol). Benzyl bromide (22 mg, 0.13 mmol) was added and the reaction was heated at 50 &lt; 0 &gt; C for 3 h. The reaction was cooled, poured into water (10 ml) and the precipitated solid was collected by vacuum filtration. Purification by flash chromatography on silica gel (elution with ethyl acetate) gave the title compound (8 mg, 13% yield) as a yellow solid:
    [1163]
    [1164] Example 207 - Preparation of compound No. 207 in Table 5
    [1165] (4- (N-benzoyl) amino) anilino) -6-hydroxy-7-methoxyquinazoline (154 mg, 0.40 mmol) and 2- Starting with ethanol (0.031 ml, 0.44 mmol) and heating the reaction at 80 <0> C for 4.5 h, the title compound (73 mg, 42% yield) was obtained as a white solid:
    [1166]
    [1167] Example 208 - Preparation of compound No. 208 in Table 8
    [1168] (106 mg, yield 76%) was obtained in analogy to the procedure described in example 197 but starting from 4- (3-hydroxypropyl) thiomorpholine-1,1-dioxide (96 mg, 0.50 mmol) Obtained as a solid:
    [1169]
    [1170] Example 209 - Preparation of compound No. 209 of Table 8
    [1171] Starting from 3- (dimethylamino) -propanol (47 mg, 0.40 mmol), by analogy with the method described in example 197, the title compound (39 mg, 41% yield) was obtained as a pale yellow solid:
    [1172]
    [1173] Example 210 - Preparation of compound No. 210 in Table 8
    [1174] Diethyl azodicarboxylate (DEAD) (0.118 ml, 0.75 mmol) was added to a solution of 4 - ((4- (N-benzoyl) amino) anilino) -6-methoxy- (0.061 ml, 0.275 mmol), triphenylphosphine (196 mg, 0.75 mmol) and N- (2-hydroxyethyl) morpholine (0.061 ml, 0.0 &gt; mmol) &lt; / RTI &gt; The reaction was stirred at ambient temperature for 18 hours and then further treated with diethyl azodicarboxylate (0.118 ml, 0.75 mmol), triphenylphosphine (196 mg, 0.75 mmol) and N- (2-hydroxyethyl) morpholine (0.061 ml, 0.50 mmol) was added and the reaction stirred for 30 min. The reaction mixture was transferred to an SCX column and purified by chromatography (eluent; i) dichloromethane, ii) 10% methanol in dichloromethane and iii) 10% methanol in 2% ammonia / dichloromethane. Evaporation of the product fractions gave the title compound (75 mg, yield 60%) as a white solid:
    [1175]
    [1176] Example 211 - Preparation of compound No. 211 in Table 8
    [1177] The title compound (17 mg, 19% yield) was obtained as a pale yellow solid starting from 2- (dimethylamino) -ethanol (0.40 ml, 0.40 mmol), analogous to the method described in example 210:
    [1178]
    [1179] Example 212 - Preparation of compound No. 212 in Table 8
    [1180] The title compound (21 mg, yield 18%) was obtained as a white solid (22% yield), analogous to the procedure described in example 210, but starting from 1- (2 hydroxyethyl) -1,2,4-triazole (57 mg, 0.50 mmol) Lt; / RTI &gt;
    [1181]
    [1182] Example 213 - Preparation of compound No. 213 in Table 8
    [1183] (55 mg, 0.40 mmol) and triethylamine (0.031 ml, 0.22 mmol), tributylphosphine (0.149 ml, 0.60 mmol) and 4-hydroxypropylmethylsulfone (55 mg, 0.40 mmol) in dichloromethane To a suspension of 4- (N-benzoyl) amino) anilino) -6-methoxy-7-hydroxyquinazoline trifluoroacetate (100 mg, 0.200 mmol) was added. After the reaction was stirred for 5 minutes, 1,1 '- (azodicarbonyl) dipiperidine (151 mg, 0.60 mmol) was added, and the mixture was further stirred for 15 minutes. Tributylphosphine (0.149 ml, 0.60 mmol) and 1,1 '- (azodicarbonyl) dipiperidine (151 mg, 0.60 mmol) were added and the reaction was stirred at ambient temperature for 2 hours. The reaction mixture was transferred to an SCX column (eluted with 0-5% methanol in dichloromethane) and the product was eluted with 20% methanol in 3% ammonium hydroxide / dichloromethane. Following vacuum evaporation of the desired fractions, the solid product was triturated with ethyl acetate and, after vacuum drying, the title compound (45 mg, 44% yield) was obtained as a white solid.
    [1184]
    [1185] Example 214 - Preparation of compound No. 214 in Table 8
    [1186] Benzoyl) -amino) anilino) -6-methoxy-7-hydroxyquinazoline (lOOmg, 0.26 mmol) and N- ( The title compound (130 mg, yield 54%) was obtained after purification by flash chromatography on silica gel (eluting with 2-3.5% methanol in dichloromethane), starting with t-butoxycarbonyl) -ethanolamine (0.08 ml, 0.78 mmol) ) As a white solid:
    [1187]
    [1188] Example 215 - Preparation of compound No. 215 in Table 8
    [1189] To a solution of 4 - ((4- (N-benzoyl) amino) anilino) -6-methoxy-7- benzyloxyquinazoline trifluoroacetate (250 mg, 0.50 mmol), 3- (90 mg, 0.55 mmol) and potassium carbonate (230 mg, 1.65 mmol) were heated at 100 &lt; 0 &gt; C for 2 hours under an inert atmosphere. The reaction was cooled to ambient temperature, diluted with water (7.0 ml), and the precipitated solid was collected by reduced pressure filtration. The solid was dissolved in a small amount of dimethylacetamide and purified on a SCX column (eluent; i) dichloromethane, ii) 10% methanol in dichloromethane and iii) 10% methanol in 2% ammonia / dichloromethane . Evaporation of the product fractions gave the title compound (130 mg, 54% yield) as a white solid:
    [1190]
    [1191] Example 216 - Preparation of compound No. 216 in Table 8
    [1192] Starting with (2-chloroethyl) methyl ether (0.050 ml, 0.55 mmol), the title compound (156 mg, 70% yield) was obtained as a white solid analogous to the method described in example 215:
    [1193]
    [1194] Example 217 - Preparation of compound No. 217 in Table 8
    [1195] The title compound (65 mg, 49% yield) was obtained as a white solid starting from acetic anhydride (0.10 ml, 1.06 mmol), analogous to the method described in example 215:
    [1196]
    [1197] Example 218 - Preparation of compound No. 218 from Table 8
    [1198] Analogous to the procedure described in example 215, but starting with 3,4,5-trifluorobenzyl bromide (27 mg, 0.12 mmol) and heating the reaction at ambient temperature in dimethylformamide for 2.5 hours, the title compound ( 25 mg, 39% yield) as a white solid:
    [1199]
    [1200] Example 219 - Preparation of compound No. 219 from Table 8
    [1201] Starting with 1- (3-bromopropyl) -4,5-dihydroimidazole (327 mg, 0.97 mmol) and heating the reaction at 60 &lt; 0 &gt; C for 24 hours, After purification by flash chromatography on silica gel (eluting with 5-15% methanol in dichloromethane), the title compound (84 mg, yield 26%) was obtained as a white solid:
    [1202]
    [1203] 1- (3-Bromopropyl) -4,5-dihydroimidazole used as starting material was obtained by the following method:
    [1204] A solution of l- (3-hydroxypropyl) -4,5-dihydroimidazole (1.0 g, 3.65 mmol) in tetrahydrofuran (15 ml) was treated with carbon tetrabromide (1.43 g, 5.47 mmol) and triphenylphosphine 1.43 g, 5.47 mmol) at ambient temperature for 18 hours. The solvent was evaporated under vacuum and 1- (3-bromopropyl) -4,5-dihydroimidazole (429 mg, yield 35%) was obtained as a white solid by flash chromatography on silica gel (eluting with 10% methanol in dichloromethane) &Lt; / RTI &gt; as a white solid:
    [1205]
    [1206] Example 220 - Preparation of compound No. 220 in Table 8
    [1207] (0.138 ml, 1.29 mmol) was added to a solution of potassium carbonate (178 mg, 1.29 mmol) and 4 - ((4- (N-benzoyl) amino) anilino ) -6-methoxy-7-hydroxyquinazoline (100 mg, 0.26 mmol) in dichloromethane and the reaction was stirred at ambient temperature for 8 hours. Pyrrolidine (0.42 ml, 5.05 mmol) was added and the reaction stirred at ambient temperature for 16 hours, poured into water and the resulting yellow solid collected by vacuum filtration. Purification by flash chromatography on silica gel (eluting with 5% methanol in dichloromethane) gave the title compound (18 mg, yield 17%) as a pale yellow solid:
    [1208]
    [1209] Example 221 - Preparation of compound 221 of Table 8
    [1210] (0.138 ml, 1.29 mmol) was added to a solution of potassium carbonate (178 mg, 1.29 mmol) and 4 - ((4- (N-benzoyl) amino) anilino ) -6-methoxy-7-hydroxyquinazoline (125 mg, 0.32 mmol) and the reaction was stirred at ambient temperature for 18 hours. Additional carbonate (134mg, 0.97mmol) and trans-1,4-dichloro-2-butene (0.102ml, 0.97mmol) were added and the reaction was stirred for additional 5h and pyrrolidine (0.673ml, 8.10 mmol) were added. After stirring at ambient temperature for 16 hours, the reaction was poured into water, the aqueous layer was extracted with ethyl acetate, and the collected organic layer was dried over magnesium sulfate. Evaporation of the solvent gave the title compound (46 mg, 28% yield) as a white solid:
    [1211]
    [1212] Example 222 - Preparation of compound No. 222 in Table 8
    [1213] The title compound (45 mg, 27% yield) was obtained as a white solid after purification in reversed phase hplc starting from piperidine (0.80 ml, 8.10 mmol), analogous to the method described in example 221:
    [1214]
    [1215] Example 223 - Preparation of compound No. 223 in Table 8
    [1216] The title compound (39 mg, yield 23%) was obtained as a white solid after purification in reversed phase hplc, starting from morpholine (0.70 ml, 8.10 mmol), analogous to the method described in example 221:
    [1217]
    [1218] MS (+ ve ESI): 526 (M + H) &lt; + & gt ; .
    [1219] Example 224 - Preparation of compound No. 224 in Table 8
    [1220] The title compound (23 mg, yield 13%) was obtained as a white solid after purification in reversed phase hplc starting from N-methylpiperidine (0.844 ml, 8.10 mmol), analogous to the method described in example 221:
    [1221]
    [1222] Example 225 - Preparation of compound No. 225 in Table 8
    [1223] 2-Bromoethanol (0.031 ml, 0.44 mmol) was added to a solution of potassium carbonate (276 mg, 2.00 mmol) and 4 - ((4- (N-benzoyl) amino) anilino) -6- Was added to a stirred suspension of 7-hydroxy-quinazoline trifluoroacetate (200 mg, 0.40 mmol) and the reaction was stirred at 85 &lt; 0 &gt; C for 3.5 hours. 2-Bromoethanol (0.031 ml, 0.44 mmol) was added and the reaction was stirred for an additional hour, then poured into water (10 ml) and the solid product was collected by vacuum filtration. Purification by flash chromatography on silica gel (eluting with 4-6% methanol in dichloromethane) gave the title compound (37 mg, 21% yield) as a white solid:
    [1224]
    [1225] Example 226 - Preparation of compound No. 226 in Table 8
    [1226] Starting with 3-chloro-1-bromo-propane (0.256 ml, 2.59 mmol), the title compound (897 mg, yield 75%) was obtained as a white solid analogous to the method described in example 225:
    [1227]
    [1228] Example 227 - Preparation of compound No. 227 in Table 8
    [1229] (5.00 g, 21.9 mmol) was added to a solution of potassium carbonate (7.26 g, 52.6 mmol) and 4 - ((4- (N-benzoyl) amino ) Anilino) -6-methoxy-7-hydroxyquinazoline (6.77 g, 17.5 mmol) and the reaction was stirred at 60 <0> C for 3.5 h. Additional (2S) - (+) - glycidyl tosylate (0.30 g, 1.1 mmol) was added and the reaction was stirred at 60 ° C for a further 3 hours. The dimethylformamide was evaporated in vacuo, the residue was triturated with methanol and then triturated with saturated aqueous sodium hydrogen carbonate solution.
    [1230] Trituration with dichloromethane allowed the residue to solidify, followed by collection of the solid by gentle filtration. Vacuum drying afforded the title compound (4.87 g, 63% yield) as a pale yellow solid:
    [1231]
    [1232] Example 228 - Preparation of compound No. 228 from Table 8
    [1233] Starting with N- (t-butoxycarbonyl) -3-hydroxypyrrolidine methanesulfonate (21 mg, 0.079 mmol), which is analogous to the method described in example 225, but starting with cesium carbonate (108 mg, 0.33 mmol), the title compound was obtained (30 mg, 82% yield) as a white solid:
    [1234]
    [1235] The N- (t-butoxycarbonyl) -3-hydroxypyrrolidine methanesulfonate used as the starting material was obtained in the following manner:
    [1236] Triethylamine (4.5 ml, 32.0 mmol) was added to a stirred solution of N- (t-butoxy-carbonyl) -3-hydroxypyrrolidine (2.00 g, 10.7 mmol) in diethyl ether , The reaction was cooled to 0 C and then methanesulfonyl chloride (1.65 ml, 21.4 mmol) was added, stirred for 2 h and warmed to ambient temperature at 0 &lt; 0 &gt; C. The reaction was filtered and the filtrate was washed with 1.0 N hydrochloric acid (100 ml) and brine (100 ml) and dried over magnesium sulfate.
    [1237] Evaporation of the solvent gave N- (t-butoxycarbonyl) -3-hydroxypyrrolidine methanesulfonate (2.9 g, yield 100%) as a colorless oil:
    [1238]
    [1239] Example 229 - Preparation of compound No. 229 in Table 8
    [1240] The title compound (21 mg, yield 10%) was obtained as an off-white solid after purification by reverse phase hplc starting from N-isopropyl-3-hydroxyacetidine (100 mg, 0.87 mmol) As a solid.
    [1241]
    [1242] Example 230 - Preparation of compound No. 230 in Table 8
    [1243] Starting with (2.R) - (-) - glycidyl tosylate (4.87 g, 21.3 mmol), by analogy with the method described in example 227, the title compound (5.15 gmg, yield 60%) was obtained as a white solid :
    [1244]
    [1245] Example 231 - Preparation of compound No. 231 of Table 9
    [1246] (2-hydroxyethoxy) quinazoline (60 mg, 0.14 mmol), which is analogous to the method described for 210, but starting from 4 - ((4- (N-benzoyl) -amino) anilino) -6-methoxy- And purification by flash chromatography on SCX column (elution with 0-20% methanol in dichloromethane) starting from 2,2,2-trifluoroethanol (0.104 ml, 0.417 mmol), the title compound (14 mg, Yield 20%) as a white solid,
    [1247]
    [1248] Example 232: Preparation of compound No. 232 in Table 9
    [1249] 6-methoxy-7- ((Nt-butoxycarbonyl) -2-aminoethoxy) -7-methoxy- Quinazoline &lt; / RTI &gt; (35 mg, 0.066 mmol) in tetrahydrofuran and the reaction was stirred at ambient temperature for 1 hour. The volatiles were evaporated in vacuo, water (1 ml) was added, and a saturated aqueous sodium hydrogen carbonate solution was added to neutralize the reaction. The precipitated solid was collected by vacuum filtration and washed with diethyl ether and water. Vacuum drying gave the title compound as an off-white solid (25 mg, 88% yield):
    [1250]
    [1251] Example 233 - Preparation of compound No. 233 in Table 9
    [1252] Benzoyl) amino) anilino) -6-methoxy-7- ((Nt-butoxycarbonyl) (20 mg, yield 98%) as an off-white solid, starting with 20 mg (0.036 mmol) of the title compound:
    [1253]
    [1254] Example 234 - Preparation of compound No. 234 in Table 9
    [1255] ((Nt-butoxycarbonyl) -2-piperazin-l-yl) -methanone was obtained in analogy to the procedure described in example 232, but starting from 4- ( Pyrrolidine) methoxy) quinazoline (453 mg, 0.79 mmol), the title compound (515 mg, 93% yield) was obtained as an off- white solid:
    [1256]
    [1257] Example 235 - Preparation of compound No. 235 of Table 9
    [1258] The title compound was obtained in analogy to the procedure described in example 232, but starting from 4- ((4- (N-benzoyl) -amino) anilino) -6-methoxy- Pyridine) methoxy) quinazoline (1.53 g, 3.19 mmol), the title compound (1.00 g, yield 54%) was obtained as an off- white solid:
    [1259]
    [1260] Example 236 - Preparation of compound No. 236 in Table 9
    [1261] An aqueous solution of paraformaldehyde (1 ml, 40% w / v solution) was added to a solution of 4 - ((4- (N-benzoyl) amino) anilino) -6-methoxy-7- Deoxy) quinazoline (100 mg, 0.143 mmol) in tetrahydrofuran and the reaction was stirred at ambient temperature for 16 hours. The reaction was heated to 95 &lt; 0 &gt; C for 45 minutes, then cooled and absorbed onto silica gel. Purification by flash chromatography on silica gel (eluting with 0-6% methanol in dichloromethane) gave the title compound (32 mg, 48% yield) as an off-white solid:
    [1262]
    [1263] Example 237 - Preparation of compound No. 237 of Table 9
    [1264] (2-pyrrolidinomethoxy) quinazoline (310 mg, 0.25 mmol) in analogy to the procedure described in example 236, but starting from 4 - ((4- (N-benzoyl) -amino) anilino) -6-methoxy- 0.54 mmol), the title compound (47 mg, 18% yield) was obtained as a yellow solid:
    [1265]
    [1266] Example 238 - Preparation of compound No. 238 of Table 9
    [1267] (3-pyrrolidinoxy) quinazoline (100 mg, 0.146 &lt; RTI ID = 0.0 &gt; mmol), the title compound (32 mg, 48% yield) was obtained as a yellow solid:
    [1268]
    [1269] Example 239 - Preparation of compound No. 239 in Table 9
    [1270] Methanesulfonyl chloride (27 mg, 0.24 mmol) was added to a stirred solution of 2-methoxyethanol (18 mg, 0.24 mmol) and triethylamine (33 mg, 0.33 mmol) in tetrahydrofuran (1 ml) Lt; / RTI &gt; for 1 hour. To a solution of 4 - ((4- (N-benzoyl) -amino) anilino) -6-methoxy-7- (N-methyl-3-aminopropoxy) quinazoline (100 mg, 0.22 mmol) in dimethylacetamide ) Was added and the reaction was stirred at 60 &lt; 0 &gt; C for 16 h. After cooling to ambient temperature, a saturated aqueous sodium bicarbonate solution (5 ml) was added and the organic material was extracted with ethyl acetate (3 x 10 ml). After vacuum evaporation of the solvent, purification by flash chromatography on silica gel (elution with 5-10% methanol in dichloromethane) gave the title compound (26 mg, yield 23%) as a pale yellow solid:
    [1271]
    [1272] Example 240 - Preparation of compound No. 240 in Table 9
    [1273] Acetyl chloride (38 mg, 0.48 mmol) was added to a solution of 4 - ((4- (N-benzoyl) -amino) anilino) -6-methoxy- 7- (N-methyl- Foxy) quinazoline (100 mg, 0.22 mmol) and triethylamine (49 mg, 0.48 mmol) and the reaction stirred at ambient temperature for 16 hours. Saline (10 ml) was added, and the resulting precipitate was collected by filtration under reduced pressure, and the residue was taken in methanol (0.5 ml). Diethyl ether (5 ml) was added to precipitate a solid which was dried in vacuo to give the title compound (80 mg, 73% yield) as a pale yellow solid:
    [1274]
    [1275] Example 241 - Preparation of compound No. 241 in Table 9
    [1276] Analogous to the procedure described in example 240, but starting with N, N-dimethyl-carbamoyl chloride (0.044 ml, 0.048 mmol), flash chromatography on silica gel (eluting with 5-10% methanol in dichloromethane) To give the title compound (55 mg, 48% yield) as a white solid:
    [1277]
    [1278] Example 242 - Preparation of compound No. 242 from Table 9
    [1279] The title compound (17 mg, yield = 23% yield) was prepared using the procedure described in Example 225 but starting with 2-bromoethanol (0.031 ml, 0.44 mmol) and using sodium iodide (66 mg, 0.44 mmol) As a pale yellow solid.
    [1280]
    [1281] Example 243 - Preparation of compound No. 243 from Table 9
    [1282] Analogous to the procedure described in example 225 but starting with 2-bromoethyl ethyl ether (0.012 ml, 0.13 mmol) and purification by flash chromatography on silica gel (elution with 5% methanol in dichloromethane) The compound (23 mg, 13% yield) was obtained as a white solid:
    [1283]
    [1284] Example 244 - Preparation of compound No. 244 from Table 9
    [1285] The title compound (9 mg, yield 16%) was obtained as a white solid after purification in reversed phase hplc starting from bromoacetonitrile (0.024 ml, 0.35 mmol), analogous to the method described in example 225:
    [1286]
    [1287] Example 245 - Preparation of compound No. 245 of Table 9
    [1288] Starting from 2-bromoethyl methyl ether (0.009 ml, 0.09 mmol), by analogy with the method described in example 225, the title compound (10 mg, 22% yield) was obtained as a white solid:
    [1289]
    [1290] Example 246 - Preparation of compound No. 246 from Table 9
    [1291] The title compound (25 mg, 55% yield) was obtained as an off-white solid, starting with bromoacetonitrile (0.009 ml, 0.09 mmol), analogous to the method described for Example 225:
    [1292]
    [1293] Example 247 - Preparation of compound No. 247 of Table 9
    [1294] The title compound (25 mg, yield 33%) was obtained as an off-white solid after purification in reversed phase hplc starting from cyclopropylmethyl bromide (0.042 ml, 0.43 mmol), analogous to the method described in example 225:
    [1295]
    [1296] Example 248 - Preparation of compound No. 248 from Table 9
    [1297] The title compound (39 mg, 51% yield) was obtained as an off-white solid after purification in reversed phase hplc starting from cyclobutyl methyl bromide (0.048 ml, 0.43 mmol), analogous to the method described in example 225:
    [1298]
    [1299] Example 249 - Preparation of compound No. 249 from Table 9
    [1300] The title compound (16 mg, yield 22%) was obtained as an off-white solid after purification in reversed phase hplc starting from bromoethanol (0.030 ml, 0.43 mmol), analogous to the method described in example 225:
    [1301]
    [1302] Example 250 - Preparation of compound No. 250 in Table 9
    [1303] The title compound (32 mg, yield 40%) was obtained as an off-white solid after purification in reversed phase hplc starting from (2-chloroethyl) ethyl sulfide (0.050 ml, 0.43 mmol) :
    [1304]
    [1305] Example 251 - Preparation of compound No. 251 in Table 9
    [1306] The title compound (6 mg, yield 6%) was obtained as an off-white solid after purification in reversed phase hplc starting from cyclopropylmethyl bromide (0.063 ml, 0.64 mmol), analogous to the method described in example 225:
    [1307]
    [1308] Example 252 - Preparation of compound No. 252 of Table 9
    [1309] Starting with 2-bromoethanol (0.046 ml, 0.64 mmol), the title compound (38 mg, 33% yield) was obtained as an off-white solid analogous to the method described in example 225:
    [1310]
    [1311] MS (+ ve ESI): 528 (M + H) &lt; + &gt;.
    [1312] Example 253 - Preparation of compound No. 253 in Table 9
    [1313] Starting with (2-bromoethyl) -ethyl ether (0.061 ml, 0.64 mmol), by analogy with the method described in example 225, the title compound (73 mg, 62% yield) was obtained as a white solid:
    [1314]
    [1315] Example 254 - Preparation of compound No. 254 of Table 9
    [1316] The title compound (38 mg, 35% yield) was obtained as an off-white solid starting with bromoacetonitrile (0.045 ml, 0.64 mmol), analogous to the method described in example 225:
    [1317]
    [1318] Example 255 - Preparation of compound No. 255 in Table 9
    [1319] (56 mg, 0.181 mmol) was added to a solution of paratoluenesulfonic acid (192 mg, 0.905 mmol) and 4- (methylthio) -6-methoxy- Was heated with 4-aminobenzanilide (192 mg, 0.905 mmol) at 140 &lt; 0 &gt; C for 2 h, then the solvent was evaporated in vacuo. Purification by flash chromatography on silica gel (eluting with 10% methanol in dichloromethane) gave the title compound (12 mg, 14% yield) as a white solid:
    [1320]
    [1321] 4- (Methylthio) -6-methoxy-7- ((4,5-dihydro-2-imidazolyl) methoxy) quinazoline used as starting material was obtained by the following method:
    [1322] a) A solution of 4- (methylthio) -6-methoxy-7-hydroxyquinazoline (250 mg, 1.126 mmol) in acetone (5 ml) was stirred in the presence of potassium carbonate (233 mg, 1.69 mmol) Was refluxed with cetonitrile (0.12 ml, 1.69 mmol). Water was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over magnesium sulfate, filtered and evaporated. (Methylthio) -6-methoxy-7hydroxyquinazoline (261 mg, 89%) was obtained as a white solid by flash chromatography on silica gel (eluting with 5% methanol in dichloromethane)
    [1323]
    [1324] b) Anhydrous hydrochloric acid in excess ethanol (1 ml) was added to a solution of 4- (methylthio) -6- methoxy-7- (cyanomethoxy) quinazoline (300 mg, 1.15 mmol) in dichloromethane (20 ml) The reaction was stirred at 4 [deg.] C for 20 hours. The solvent was evaporated, ethylenediamine (280 mg, 8.15 mmol) in ethanol (10 ml) was added to the residue and the mixture was refluxed for 2 hours. The solvent was evaporated in vacuo and purified by flash chromatography on silica gel (5% methanol in dichloromethane) to give 4- (methylthio) -6-methoxy-7 - ((4,5- dihydro- Yl) methoxy) quinazoline (56 mg, yield 22%) as a white solid:
    [1325]
    [1326] Example 256 - Preparation of compound No. 256 in Table 10
    [1327] A solution of 4 - ((4- (N-benzoyl) -amino) anilino) -6-methoxy- 7- (2- bromoethoxy) quinazoline (99 mg, 0.2 mmol) was added to a solution of thiophene -2-methylamine (113 mg, 1.00 mmol) and the reaction was heated at 60 &lt; 0 &gt; C for 16 h. After cooling to ambient temperature, the crude reaction mixture was absorbed into silica gel. Purification by flash chromatography (eluting with 0-10% methanol in dichloromethane) gave the title compound (45.2 mg, yield 37%) as an off-white solid:
    [1328]
    [1329] (4- (N-benzoyl) -amino) anilino) -6-methoxy-7- (2-bromoethoxy) quinazoline used as starting material was obtained by the following method:
    [1330] To a solution of potassium carbonate (1.67 g, 12.1 mmol), 1,2-dibromoethane (2.33 ml, 25.9 mmol) and 4 - ((4- (N- benzoyl) amino) anilino) 6-Methoxy-7-hydroxyquinazoline (1.0 g, 2.59 mmol) was heated at 85 &lt; 0 &gt; C for 18 h. The reaction was cooled, filtered and the residue was evaporated in vacuo. The residue was triturated with methanol / diethyl ether to give 4 - ((4- (N-benzoyl) -amino) anilino) -6-methoxy- 7- (2- bromoethoxy) quinazoline 91%) as a white solid:
    [1331]
    [1332] Example 257 - Preparation of compound No. 257 of Table 10
    [1333] Starting with N-acetylethylenediamine (102 mg, 1.00 mmol), the title compound (69.4 mg, 58% yield) was obtained as a white solid analogous to the method described for Example 256:
    [1334]
    [1335] Example 258 - Preparation of compound No. 258 from Table 10
    [1336] Starting with N, N-diisopropyl-ethylenediamine (144 mg, 1.00 mmol), the title compound (124.3 mg, 97% yield) was obtained as a white solid analogous to the method described for Example 256:
    [1337]
    [1338] Example 259 - Preparation of compound No. 259 in Table 10
    [1339] The title compound (81 mg, 69% yield) was obtained as a white solid starting from 2- (methylthio) -ethylamine (91 mg, 1.00 mmol), analogous to the method described for Example 256:
    [1340]
    [1341] Example 260 - Preparation of compound No. 260 in Table 10
    [1342] Starting with L-alaninamide hydrochloride (88 mg, 1.00 mmol), the title compound (15.9 mg, 14% yield) was obtained as a white solid analogous to the method described in example 256:
    [1343] HPLC / LCMS (RT): 5.29 min:
    [1344] MS (+ ve ESI): 501 (M + H) &lt; + &gt;.
    [1345] Example 261 - Preparation of compound No. 261 of Table 10
    [1346] Starting with cyclopropyl-amine (57 mg, 1.00 mmol), the title compound (32.3 mg, 29% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1347]
    [1348] Example 262 - Preparation of compound No. 262 of Table 10
    [1349] Starting with cyclopropane-methylamine (71 mg, 1.00 mmol), the title compound (71.4 mg, 63% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1350]
    [1351] Example 263 - Preparation of compound No. 263 in Table 10
    [1352] Starting with cyclobutylamine (71 mg, 1.00 mmol), the title compound (59.1 mg, 52% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1353]
    [1354] Example 264 - Preparation of compound No. 264 from Table 10
    [1355] Starting with cyclopentylamine (85 mg, 1.00 mmol), by analogy with the method described in example 256, the title compound (48.4 mg, 42% yield) was obtained as an off-white solid:
    [1356]
    [1357] Example 265 - Preparation of compound No. 265 of Table 10
    [1358] Starting with 1- (3-aminopropyl) -imidazole (125 mg, 1.00 mmol), the title compound (96.4 mg, yield 78%) was obtained as an off-white solid analogous to the method described in example 256:
    [1359]
    [1360] Example 266 - Preparation of compound No. 266 from Table 10
    [1361] Starting with cyclohexylamine (99 mg, 1.00 mmol), the title compound (78.9 mg, 67% yield) was obtained as an off-white solid analogous to the method described in example 256:
    [1362]
    [1363] Example 267 - Preparation of compound No. 267 of Table 10
    [1364] Starting with 4-aminocyclohexanol (115 mg, 1.00 mmol), the title compound (67.5 mg, 55% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1365]
    [1366] Example 268 - Preparation of compound No. 268 from Table 1
    [1367] Starting with cyclohexanemethylamine (113 mg, 1.00 mmol), the title compound (80.4 mg, 66% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1368]
    [1369] Example 269 - Preparation of compound No. 269 in Table 1
    [1370] Starting with 2-amino-2-methyl-1,3-propanediol (105 mg, 1.00 mmol), the title compound (54.9 mg, 46% yield) was obtained as an off- white solid analogous to the method described in example 256 :
    [1371]
    [1372] Example 270 - Preparation of compound No. 270 in Table 1
    [1373] Starting with tris (hydroxymethyl) methylamine (121 mg, 1.00 mmol), the title compound (15.1 mg, 12% yield) was obtained as an off-white solid analogous to the method described in example 256:
    [1374]
    [1375] Example 271 - Preparation of compound No. 271 in Table 10
    [1376] Starting with 2-amino-2-ethyl-1,3-propanediol (119 mg, 1.00 mmol), the title compound (59.1 mg, 48% yield) was obtained as an off- white solid analogous to the method described in example 256 :
    [1377]
    [1378] Example 272 - Preparation of compound No. 271 of Table 10
    [1379] Starting with (S) -yluccinol (117 mg, 1.00 mmol), the title compound (109.9 mg, 90% yield) was obtained as an off-white solid analogous to the method described in example 256:
    [1380]
    [1381] Example 273 - Preparation of compound No. 273 in Table 10
    [1382] The title compound (113.1 mg, 91% yield) was obtained as an off-white solid starting from 2- (aminomethyl) -1-ethylpyrrolidine (128 mg, 1.00 mmol), analogous to the method described in example 256:
    [1383]
    [1384] Example 274 - Preparation of compound No. 274 in Table 1
    [1385] Starting with 1- (3-aminopropyl) -2-pyrrolidinone (142 mg, 1.00 mmol), the title compound (127.2 mg, yield 100%) was obtained as an off- white solid analogous to the method described in example 256 :
    [1386]
    [1387] Example 275 - Preparation of compound No. 275 in Table 1
    [1388] The title compound (87.4 mg, 74% yield) was obtained as an off-white solid starting from tetrahydrofurfurylamine (101 mg, 1.00 mmol), analogous to the method described for Example 256:
    [1389]
    [1390] Example 276 - Preparation of compound No. 276 from Table 10
    [1391] Starting with isonipecotamide (128 mg, 1.00 mmol), the title compound (76.4 mg, yield 61%) was obtained as an off-white solid analogous to the method described in example 256:
    [1392]
    [1393] Example 277 - Preparation of compound No. 277 of Table 10
    [1394] Starting with 4- (2-aminoethyl) morpholine (130 mg, 1.00 mmol), the title compound (120.7 mg, 97% yield) was obtained as an off- white solid analogous to the method described in example 256:
    [1395]
    [1396] Example 278 - Preparation of compound No. 278 from Table 10
    [1397] Starting with 4- (3-aminopropyl) morpholine (144 mg, 1.00 mmol), the title compound (88.6 mg, yield 70%) was obtained as an off-white solid analogous to the method described in example 256:
    [1398]
    [1399] MS (+ ve ESI): 557 (M + H) &lt; + &gt;.
    [1400] Example 279 - Preparation of compound No. 279 from Table 10
    [1401] Starting from 2-piperidinoethylamine (128 mg, 1.00 mmol), the title compound (112.4 mg, 90% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1402]
    [1403] Example 280 - Preparation of compound No. 280 in Table 10
    [1404] Starting with l- (2-aminoethyl) -pyrrolidine (114 mg, 1.00 mmol), the title compound (56.6 mg, 47% yield) was obtained as an off- white solid analogous to the method described in example 256:
    [1405]
    [1406] Example 281 - Preparation of compound No. 281 in Table 10
    [1407] Starting with 2-amino-2-methyl-3-hexanol (131 mg, 1.00 mmol), the title compound (123.8 mg, yield 99%) was obtained as an off- white solid analogous to the method described for Example 256:
    [1408]
    [1409] Example 282 - Preparation of compound No. 282 in Table 10
    [1410] Starting with 2-amino-2-methyl-1-propanol (89 mg, 1.00 mmol), the title compound (62.6 mg, 54% yield) was obtained as an off- white solid analogous to the method described in example 256:
    [1411]
    [1412] Example 283 - Preparation of compound No. 283 in Table 10
    [1413] Starting with 3-amino-3-methyl-1-butanol (103 mg, 1.00 mmol), the title compound (51.8 mg, 43% yield) was obtained as an off- white solid analogous to the method described in example 256:
    [1414]
    [1415] Example 284 - Preparation of compound No. 284 from Table 10
    [1416] Starting with isopropylamine (59 mg, 1.00 mmol), the title compound (54.8 mg, yield 50%) was obtained as an off-white solid analogous to the method described in example 256:
    [1417]
    [1418] Example 285 - Preparation of compound No. 285 of Table 10
    [1419] Starting with 2-amino-1-propanol (75 mg, 1.00 mmol), the title compound (43.9 mg, yield 39%) was obtained as an off-white solid analogous to the method described in example 256:
    [1420]
    [1421] Example 286 - Preparation of compound No. 286 in Table 10
    [1422] Starting with D-2-amino-1-butanol (89 mg, 1.00 mmol), the title compound (77.2 mg, 66% yield) was obtained as an off- white solid analogous to the method described in example 256:
    [1423] HPLC / LCMS (RT): 1.41 min:
    [1424] MS (+ ve ESI): 502 (M + H) &lt; + &gt;.
    [1425] Example 287 - Preparation of compound No. 287 in Table 10
    [1426] Starting with 3-amino-1,2-propanediol (91 mg, 1.00 mmol), the title compound (48.3 mg, 41% yield) was obtained as an off- white solid analogous to the method described in example 256:
    [1427] HPLC / LCMS (RT): 5.16 min:
    [1428] MS (+ ve ESI): 504 (M + H) &lt; + &gt;.
    [1429] Example 288 - Preparation of compound No. 288 from Table 10
    [1430] Starting with N, N-dimethyl-ethylenediamine (88 mg, 1.00 mmol), the title compound (55.8 mg, 48% yield) was obtained as an off- white solid analogous to the method described in example 256:
    [1431]
    [1432] Example 289 - Preparation of compound No. 289 from Table 10
    [1433] Starting with N, N-diethyl-ethylenediamine (116 mg, 1.00 mmol), the title compound (86.5 mg, 71% yield) was obtained as an off- white solid analogous to the method described for Example 256:
    [1434]
    [1435] Example 290 - Preparation of compound No. 290 in Table 10
    [1436] Starting with 2-methoxyethyl-amine (75 mg, 1.00 mmol), the title compound (70.7 mg, 62% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1437]
    [1438] Example 291 - Preparation of compound No. 291 in Table 10
    [1439] Starting with 2- (2-amino-ethoxy) ethanol (105 mg, 1.00 mmol), the title compound (70.3 mg, yield 59%) was obtained as an off-white solid analogous to the method described in example 256:
    [1440]
    [1441] Example 292 - Preparation of compound No. 292 of Table 10
    [1442] Starting with ethanolamine (61 mg, 1.00 mmol), the title compound (51.3 mg, 46% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1443] HPLC / LCMS (RT): 1.48 min:
    [1444] MS (+ ve ESI): 474 (M + H) &lt; + &gt;.
    [1445] Example 293 - Preparation of compound No. 293 in Table 10
    [1446] Starting with 2-mercapto-ethylamine hydrochloride (77 mg, 1.00 mmol), the title compound (72.7 mg, yield 64%) was obtained as an off-white solid analogous to the method described in example 256:
    [1447]
    [1448] Example 294 - Preparation of compound No. 294 in Table 10
    [1449] Starting with 2- (ethylthio) ethylamine (105 mg, 1.00 mmol), the title compound (85.9 mg, 72% yield) was obtained as an off-white solid analogous to the method described in example 256:
    [1450]
    [1451] Example 295 - Preparation of compound No. 295 of Table 10
    [1452] Starting with 3-ethoxypropylamine (103 mg, 1.00 mmol), the title compound (67.1 mg, 56% yield) was obtained as an off-white solid analogous to the method described in Example 256:
    [1453]
    [1454] Example 296 - Preparation of compound No. 296 in Table 10
    [1455] Starting with 3-butoxypropylamine (131 mg, 1.00 mmol), the title compound (51.9 mg, 42% yield) was obtained as an off-white solid analogous to the method described in Example 256:
    [1456]
    [1457] Example 297 - Preparation of compound No. 297 in Table 10
    [1458] Starting from 3-amino-1-propanol (75 mg, 1.00 mmol), the title compound (58.1 mg, 51% yield) was obtained as an off- white solid analogous to the method described in example 256:
    [1459]
    [1460] Example 298 - Preparation of compound No. 298 from Table 10
    [1461] Starting with 5-amino-1-pentanol (103 mg, 1.00 mmol), the title compound (66 mg, 55% yield) was obtained as an off- white solid analogous to the method described for Example 256:
    [1462]
    [1463] Example 299 - Preparation of compound No. 299 from Table 10
    [1464] Starting from 2-amino-1-methoxypropane (89 mg, 1.00 mmol), the title compound (30.8 mg, yield 26%) was obtained as an off- white solid analogous to the method described in example 256:
    [1465]
    [1466] MS (+ ve ESI): 502 (M + H) &lt; + & gt ; .
    [1467] Example 300 - Preparation of compound No. 300 in Table 10
    [1468] Starting with 4-amino-1-butanol (89 mg, 1.00 mmol), the title compound (58.4 mg, yield 50%) was obtained as an off-white solid analogous to the method described in example 256:
    [1469]
    [1470] Example 301 - Preparation of compound No. 301 in Table 10
    [1471] Starting with 3-amino-5-methyl-pyrazole (97 mg, 1.00 mmol), the title compound (40.6 mg, 34% yield) was obtained as an off- white solid analogous to the method described in example 256:
    [1472] HPLC / LCMS (RT): 5.63 min:
    [1473] MS (+ ve ESI): 510 (M + H) &lt; + &gt;.
    [1474] Example 302 - Preparation of compound No. 302 in Table 10
    [1475] Starting with 1- (3-aminopropyl) -4-methylpiperazine (157 mg, 1.00 mmol), the title compound (58.6 mg, 45% yield) was obtained as an off- white solid analogous to the method described in example 256 :
    [1476]
    [1477] Example 303 - Preparation of compound No. 303 in Table 10
    [1478] Starting from ethyl 4-amino-1-piperidinecarboxylate (172 mg, 1.00 mmol), the title compound (191.8 mg, 144% yield) was obtained as an off- white solid analogous to the method described in example 256 :
    [1479]
    [1480] Example 304 - Preparation of compound No. 304 in Table 10
    [1481] Starting with 2-dibutylaminoethylamine (172 mg, 1.00 mmol), analogously to the method described in example 256, the title compound (123.6 mg, 93% yield) was obtained as an off-white solid:
    [1482] HPLC / LCMS (RT): 1.40 min:
    [1483] MS (+ ve ESI): 586 (M + H) &lt; + &gt;.
    [1484] Example 305 - Preparation of compound No. 305 in Table 10
    [1485] Starting with 2-di-n-propylaminoethylamine (144 mg, 1.00 mmol), the title compound (123.4 mg, 97% yield) was obtained as an off- white solid analogous to the method described in example 256:
    [1486]
    [1487] Example 306 - Preparation of compound No. 306 in Table 10
    [1488] Starting with 1-aminomethyl-1-cyclohexanol hydrochloride (129 mg, 1.00 mmol), the title compound (80 mg, yield 64%) was obtained as an off-white solid analogous to the method described in example 256:
    [1489] HPLC / LCMS (RT): 1.61 min:
    [1490] MS (+ ve ESI): 542 (M + H) &lt; + &gt;.
    [1491] Example 307 - Preparation of compound No. 307 in Table 10
    [1492] Starting with 2-thiophenethylamine (127 mg, 1.00 mmol), the title compound (107.9 mg, yield 87%) was obtained as an off-white solid analogous to the method described in example 256:
    [1493]
    [1494] Example 308 - Preparation of compound No. 308 from Table 10
    [1495] The title compound (115.2 mg, 94% yield) was obtained as an off-white solid starting from 2-amino-1-hexanol (117 mg, 1.00 mmol), analogous to the method described for Example 256:
    [1496]
    [1497] Example 309 - Preparation of compound No. 309 in Table 10
    [1498] The title compound (111.7 mg, 89% yield) was obtained as an off-white solid starting from 1-methionine (135 mg, 1.00 mmol), analogous to the method described in example 256:
    [1499] HPLC / LCMS (RT): 1.53 min:
    [1500] MS (+ ve ESI): 548 (M + H) &lt; + &gt;.
    [1501] Example 310 - Preparation of compound No. 310 in Table 10
    [1502] The title compound (65.2 mg, 52% yield) was obtained as an off-white solid starting with 2- (2-aminoethyl) -l-methylpyrrolidine (128 mg, 1.00 mmol) Obtained:
    [1503] HPLC / LCMS (RT): 5.04 min:
    [1504] MS (+ ve ESI): 541 (M + H) &lt; + &gt;.
    [1505] Example 311 - Preparation of compound No. 311 in Table 10
    [1506] Starting with 5-methyl-2-furanmethanamine (111 mg, 1.00 mmol), the title compound (61.1 mg, 51% yield) was obtained as an off- white solid analogous to the method described in example 256:
    [1507]
    [1508] Example 312 - Preparation of compound No. 312 in Table 10
    [1509] The title compound (53.7 mg, 43% yield) was obtained as an off-white solid starting from the tetrahydro-3-thiophenamine 1, 1-dioxide (135 mg, 1.00 mmol), analogous to the method described in example 256:
    [1510] HPLC / LCMS (RT): 1.45 min:
    [1511] MS (+ ve ESI): 548 (M + H) &lt; + &gt;.
    [1512] Example 313 - Preparation of compound No. 313 in Table 10
    [1513] Starting with 3-amino-2,2-dimethyl-1-propanol (103 mg, 1.00 mmol), the title compound (69.2 mg, yield 58%) was obtained as an off- white solid analogous to the method described in example 256:
    [1514]
    [1515] Example 314 - Preparation of compound No. 314 in Table 10
    [1516] The title compound (122.5 mg, yield 100%) was obtained as an off-white solid starting from 3- (aminomethyl) -thiophene dihydrochloride (113 mg, 1.00 mmol), analogous to the method described for Example 256:
    [1517] HPLC / LCMS (RT): 1.56 min:
    [1518] MS (+ ve ESI): 526 (M + H) &lt; + &gt;.
    [1519] Example 315 - Preparation of compound No. 315 in Table 10
    [1520] Starting with thiomorpholine (0.10 ml, 1.0 mmol), the title compound (21 mg, 20% yield) was obtained as a white solid analogous to the method described in example 256:
    [1521]
    [1522] MS (+ ve ESI): 515.7 (M + H) &lt; + &gt;.
    [1523] Example 316 - Preparation of compound No. 316 in Table 10
    [1524] The title compound (59 mg, 49% yield) was prepared starting from N- (2-hydroxyethyl) -1- (2- aminoethyl) morpholine (50 mg, 0.26 mmol), analogous to the method described in example 256, Obtained as a white solid:
    [1525]
    [1526] Example 317 - Preparation of compound No. 317 in Table 10
    [1527] Starting with diethanolamine (0.097 ml, 1.00 mmol), the title compound (49 mg, 47% yield) was obtained as a white solid analogous to the method described for Example 256:
    [1528]
    [1529] Example 318 - Preparation of compound No. 318 from Table 10
    [1530] Analogous to the procedure described in example 256 but starting with piperidine (0.10 ml, 1.00 mmol), by flash chromatography on silica gel (eluting with 0-5% methanol in dichloromethane containing 2% ammonia) After purification, the title compound (34 mg, 68% yield) was obtained as a white solid:
    [1531]
    [1532] Example 319 - Preparation of compound No. 319 in Table 10
    [1533] The title compound (62.5 mg, 60% yield) was obtained as an off-white solid starting with 4- (aminomethyl) -pyridine (108 mg, 1.0 mmol), analogous to the method described for Example 256:
    [1534] HPLC / LCMS (RT): 5.27 min:
    [1535] MS (+ ve ESI): 521 (M + H) &lt; + &gt;.
    [1536] Example 320 - Preparation of compound No. 320 in Table 10
    [1537] The title compound (45 mg, 45% yield) was obtained as a white solid starting from 2-amino-1,3-propanediol (91 mg, 1.00 mmol), analogous to the method described for Example 256:
    [1538]
    [1539] Example 321 - Preparation of compound No. 321 in Table 10
    [1540] Analogous to the method described in example 256 but starting with a solution of methylamine in tetrahydrofuran (40.5 ml of a 2.0 N solution, 81 mmol) and flash chromatography on silica gel (eluting with 1-5% methanol in dichloromethane) to give , The title compound (2.20 g, yield 61%) was obtained as a white solid:
    [1541]
    [1542] Example 322 - Preparation of compound No. 322 in Table 10
    [1543] Methanesulfonyl chloride (58 mg, 0.51 mmol) was added to a solution of 4 - ((4- (N-benzoyl) -amino) anilino) -6- -Aminoethoxy) quinazoline (150 mg, 0.34 mmol) and triethylamine (34 mg, 0.34 mmol) and the reaction was stirred at ambient temperature for 3 hours. The resulting precipitate was collected by vacuum filtration and washed with i) water (10 ml), ii) saturated sodium hydrogencarbonate solution (10 ml) and iii) brine (10 ml) . After purification by flash chromatography on silica gel (eluting with 5-10% methanol in dichloromethane), the title compound (76 mg, 43% yield) was obtained as a pale yellow solid:
    [1544]
    [1545] Example 323 - Preparation of compound No. 323 in Table 10
    [1546] Starting with diethylamine (73 mg, 1.00 mmol), the title compound (28 mg, 29% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1547] HPLC / LCMS (RT): 3.27 min:
    [1548] MS (+ ve ESI): 486 (M + H) &lt; + &gt;.
    [1549] Example 324 - Preparation of compound No. 324 in Table 10
    [1550] Starting with hexamethylene-imine (99 mg, 1.00 mmol), the title compound (50 mg, 49% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1551] HPLC / LCMS (RT): 3.41 min:
    [1552] MS (+ ve ESI): 512 (M + H) &lt; + &gt;.
    [1553] Example 325 - Preparation of compound No. 325 of Table 10
    [1554] Starting with N-methylethanolamine (75 mg, 1.00 mmol), the title compound (45 mg, 46% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1555] HPLC / LCMS (RT): 3.13 min:
    [1556] MS (+ ve ESI): 488 (M + H) &lt; + &gt;.
    [1557] Example 326 - Preparation of compound No. 326 from Table 10
    [1558] Starting with 3-pyrroline (69 mg, 1.00 mmol), the title compound (16 mg, yield 16%) was obtained as an off-white solid analogous to the method described in example 256:
    [1559]
    [1560] Example 327 - Preparation of compound No. 327 in Table 10
    [1561] Starting with N, N, N'-trimethylethylenediamine (102 mg, 1.00 mmol), the title compound (41 mg, 40% yield) was obtained as an off- white solid analogous to the method described in Example 256:
    [1562] HPLC / LCMS (RT): 3.04 min:
    [1563] MS (+ ve ESI): 515 (M + H) &lt; + &gt;.
    [1564] Example 328 - Preparation of compound No. 328 from Table 10
    [1565] Starting with N-methylpiperazine (100 mg, 1.00 mmol), the title compound (43 mg, 42% yield) was obtained as a white solid analogous to the method described in example 256:
    [1566] HPLC / LCMS (RT): 3.11 min:
    [1567] MS (+ ve ESI): 513 (M + H) &lt; + &gt;.
    [1568] Example 329 - Preparation of compound No. 329 from Table 10
    [1569] Starting with N-cyclopropylpiperazine (126 mg, 1.00 mmol), the title compound (16 mg, 14% yield) was obtained as a white solid analogous to the method described in example 256:
    [1570] HPLC / LCMS (RT): 3.24 min:
    [1571] MS (+ ve ESI): 539 (M + H) &lt; + &gt;.
    [1572] Example 330 - Preparation of compound No. 330 in Table 10
    [1573] Starting with S-propolinol (101 mg, 1.00 mmol), the title compound (56 mg, 55% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1574] HPLC / LCMS (RT): 3.21 min:
    [1575] MS (+ ve ESI): 514 (M + H) &lt; + &gt;.
    [1576] Example 331 - Preparation of compound No. 331 in Table 10
    [1577] Starting with 4-hydroxypiperidine (101 mg, 1.00 mmol), the title compound (61 mg, 59% yield) was obtained as a white solid analogous to the method described for Example 256:
    [1578]
    [1579] Example 332 - Preparation of compound No. 332 in Table 10
    [1580] Starting from N- (2- (1-morpholino) ethyl) piperazine (199 mg, 1.00 mmol), by analogy with the method described in example 256, the title compound (19 mg, yield 16% Obtained:
    [1581] HPLC / LCMS (RT): 3.09 min:
    [1582] MS (+ ve ESI): 612 (M + H) &lt; + &gt;.
    [1583] Example 333 - Preparation of compound No. 333 in Table 10
    [1584] Starting with N- (3-hydroxypropyl) piperazine (144 mg, 1.00 mmol), the title compound (53 mg, 48% yield) was obtained as an off- white solid analogous to the method described in example 256:
    [1585] HPLC / LCMS (RT): 3.11 min:
    [1586] MS (+ ve ESI): 557 (M + H) &lt; + &gt;.
    [1587] Example 334 - Preparation of compound No. 334 in Table 10
    [1588] Starting with N-ethyl ethanolamine (89 mg, 1.00 mmol), the title compound (36 mg, 36% yield) was obtained as an off-white solid analogous to the method described in example 256:
    [1589] HPLC / LCMS (RT): 3.20 min:
    [1590] MS (+ ve ESI): 502 (M + H) &lt; + &gt;.
    [1591] Example 335 - Preparation of compound No. 335 in Table 10
    [1592] Starting with 3-hydroxypyrrolidine (87 mg, 1.00 mmol), the title compound (35 mg, 35% yield) was obtained as a white solid analogous to the method described in example 256:
    [1593]
    [1594] Example 336 - Preparation of compound No. 336 in Table 10
    [1595] Starting with N-methyl 2-cyano-ethylamine (84 mg, 1.00 mmol), the title compound (75 mg, yield 75%) was obtained as an off-white solid analogous to the method described in example 256:
    [1596]
    [1597] Example 337 - Preparation of compound No. 337 in Table 10
    [1598] Starting from 4-piperidinopiperidine (168 mg, 1.00 mmol), by analogy with the method described in example 256, the title compound (57 mg, 49% yield) was obtained as a white solid:
    [1599] HPLC / LCMS (RT): 3.13 min:
    [1600] MS (+ ve ESI): 581 (M + H) &lt; + &gt;.
    [1601] Example 338 - Preparation of compound No. 338 from Table 10
    [1602] Starting with 2,6-dimethylmorpholine (115 mg, 1.00 mmol), the title compound (37 mg, 35% yield) was obtained as a white solid analogous to the method described in example 256:
    [1603] HPLC / LCMS (RT): 3.36 min:
    [1604] MS (+ ve ESI): 528 (M + H) &lt; + &gt;.
    [1605] Example 339 - Preparation of compound No. 339 from Table 10
    [1606] Starting with N-acetylpiperazine (128 mg, 1.00 mmol), the title compound (60 mg, 55% yield) was obtained as a white solid analogous to the method described in example 256:
    [1607] HPLC / LCMS (RT): 3.16 min:
    [1608] MS (+ ve ESI): 541 (M + H) &lt; + &gt;.
    [1609] Example 340: Preparation of compound No. 340 in Table 10
    [1610] Starting with N-methylallylamine (71 mg, 1.00 mmol), the title compound (38 mg, 39% yield) was obtained as an off-white solid analogous to the method described in example 256:
    [1611] HPLC / LCMS (RT): 3.29 min:
    [1612] MS (+ ve ESI): 484 (M + H) &lt; + &gt;.
    [1613] Example 341 - Preparation of compound No. 341 in Table 10
    [1614] Starting with 2-methyl-pyrrolidine (85 mg, 1.00 mmol), the title compound (80 mg, 80% yield) was obtained as a white solid analogous to the method described in example 256:
    [1615] HPLC / LCMS (RT): 3.31 min:
    [1616] MS (+ ve ESI): 498 (M + H) &lt; + &gt;.
    [1617] Example 342 - Preparation of compound No. 342 in Table 10
    [1618] Starting with N-ethylisopropylamine (87 mg, 1.00 mmol), the title compound (29 mg, 29% yield) was obtained as an off-white solid analogous to the method described in example 256:
    [1619] HPLC / LCMS (RT): 3.36 min:
    [1620] MS (+ ve ESI): 500 (M + H) &lt; + &gt;.
    [1621] Example 343 - Preparation of compound No. 343 in Table 10
    [1622] Starting with N-ethyl 2-cyano-ethylamine (98 mg, 1.00 mmol), the title compound (51 mg, yield 50%) was obtained as an off-white solid analogous to the method described for Example 256:
    [1623] HPLC / LCMS (RT): 3.27 min:
    [1624] MS (+ ve ESI): 511 (M + H) &lt; + &gt;.
    [1625] Example 344 - Preparation of compound No. 344 in Table 10
    [1626] Starting with N-methyl 2-methyl-propylamine (87 mg, 1.00 mmol), the title compound (25 mg, 25% yield) was obtained as an off-white solid analogous to the method described in example 256:
    [1627] HPLC / LCMS (RT): 3.44 min:
    [1628] MS (+ ve ESI): 500 (M + H) &lt; + &gt;.
    [1629] Example 345 - Preparation of compound No. 345 in Table 10
    [1630] Starting with N-ethylpiperazine (114 mg, 1.00 mmol), the title compound (91 mg, 86% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1631]
    [1632] Example 346 - Preparation of compound No. 346 in Table 10
    [1633] Starting with N- (4-fluorophenyl) piperazine (180 mg, 1.00 mmol), the title compound (87 mg, yield 72%) was obtained as an off-white solid analogous to the method described in example 256:
    [1634]
    [1635] Example 347 - Preparation of compound No. 347 in Table 10
    [1636] Starting with thiazoline-2-carboxylic acid (133 mg, 1.00 mmol), the title compound (48 mg, 44% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1637] HPLC / LCMS (RT): 3.39 min:
    [1638] MS (+ ve ESI): 546 (M + H) &lt; + &gt;.
    [1639] Example 348 - Preparation of compound No. 348 from Table 10
    [1640] Starting with 4- (2-hydroxyethyl) -piperidine (129 mg, 1.00 mmol), the title compound (75 mg, 69% yield) was obtained as an off- white solid analogous to the method described in example 256:
    [1641]
    [1642] Example 349 - Preparation of compound No. 349 in Table 10
    [1643] Starting from N-methyl-3- (aminomethyl) pyridine (122 mg, 1.00 mmol), the title compound (21 mg, 20% yield) was obtained as an off- white solid analogous to the method described in example 256:
    [1644] HPLC / LCMS (RT): 3.13 min:
    [1645] MS (+ ve ESI): 535 (M + H) &lt; + &gt;.
    [1646] Example 350 - Preparation of compound No. 350 in Table 10
    [1647] Starting from N-methyl-2- (aminomethyl) pyridine (122 mg, 1.00 mmol), the title compound (62 mg, yield 58%) was obtained as an off-white solid analogous to the method described in example 256:
    [1648]
    [1649] Example 351 - Preparation of compound No. 351 in Table 10
    [1650] Starting with 2,5-dimethyl-pyrrolidine (99 mg, 1.00 mmol), the title compound (36 mg, 35% yield) was obtained as a white solid analogous to the method described for Example 256:
    [1651] HPLC / LCMS (RT): 3.39 min:
    [1652] MS (+ ve ESI): 512 (M + H) &lt; + &gt;.
    [1653] Example 352 - Preparation of compound No. 352 in Table 10
    [1654] Starting with 1,2,3,6-tetrahydro-piperidine (183 mg, 1.00 mmol), the title compound (29 mg, 29% yield) was obtained as a white solid analogous to the method described in example 256:
    [1655] HPLC / LCMS (RT): 3.27 min:
    [1656] MS (+ ve ESI): 496 (M + H) &lt; + &gt;.
    [1657] Example 353 - Preparation of compound No. 353 in Table 10
    [1658] Starting from 4-methylpiperidine (99 mg, 1.00 mmol), the title compound (15 mg, 14% yield) was obtained as an off-white solid analogous to the method described for Example 256:
    [1659] HPLC / LCMS (RT): 3.46 min:
    [1660] MS (+ ve ESI): 512 (M + H) &lt; + &gt;.
    [1661] Example 354 - Preparation of compound No. 354 in Table 10
    [1662] Starting with N- (2-hydroxyethyl) -piperazine (130 mg, 1.00 mmol), the title compound (75 mg, yield 70%) was obtained as an off-white solid analogous to the method described in example 256:
    [1663]
    [1664] MS (+ ve ESI): 484 (M + H) &lt; + & gt ; .
    [1665] Example 355 - Preparation of compound No. 355 of Table 10
    [1666] Starting with 2- (2-hydroxyethyl) -piperidine (129 mg, 1.00 mmol), the title compound (48 mg, 44% yield) was obtained as an off-white solid analogous to the method described in example 256:
    [1667] HPLC / LCMS (RT): 3.30 min:
    [1668] MS (+ ve ESI): 542 (M + H) &lt; + &gt;.
    [1669] Example 356 - Preparation of compound No. 356 in Table 10
    [1670] To a solution of 4 - ((4- (N-benzoyl) amino) anilino) -6-methoxy-7- (2-bromoethoxy) quinazoline (100 mg, 0.202 mmol) in DMF (5 ml) Was heated with excess 2-ethylimidazoline at 100 &lt; 0 &gt; C for 2 hours. The solvent was evaporated in vacuo, water was added to the reaction mixture, the pH was adjusted to 4 with hydrochloric acid (2.0 N) and the solid was collected by vacuum filtration. Purification by flash chromatography on silica gel (eluting with 5% methanol in dichloromethane) gave the title compound (48 mg, 46% yield) as a white solid:
    [1671]
    [1672] Example 357 - Preparation of compound No. 357 of Table 10
    [1673] The title compound (150 mg, 44% yield) was obtained as a white solid, starting from imidazoline (460 mg, 2.13 mmol)
    [1674]
    [1675] Example 358 - Preparation of compound No. 358 in Table 11
    [1676] A solution of 4 - ((4- (N-benzoyl) amino) anilino) -6-methoxy-7- (3-chloropropoxy) quinazoline (92.5 mg, 0.20 mmol) in dimethylacetamide Was added sodium iodide (15.0 mg, 0.10 mmol) and N-acetylethylenediamine (102 mg, 1.00 mmol) and the reaction was heated at 100 &lt; 0 &gt; C for 24 h. The reaction was cooled, methanol (0.50 ml) was added and the reaction mixture was absorbed into normal silica gel. Purification by flash chromatography on silica gel (eluting with 0-20% methanol in dichloromethane (containing 1% aqueous ammonia)) afforded the title compound (45.6 mg, 43% yield) as a white solid:
    [1677] HPLC / LCMS (RT): 5.21 min:
    [1678] MS (+ ve ESI): 529.4 (M + H) &lt; + &gt;.
    [1679] Example 359 - Preparation of compound No. 359 of Table 11
    [1680] Analogous to the procedure described in example 358 but starting with L-alaninamide hydrochloride (88 mg, 1.0 mmol), the title compound (18.7 mg, 18% yield) was obtained as a white solid:
    [1681] HPLC / LCMS (RT): 5.27 min:
    [1682] MS (+ ve ESI): 515.4 (M + H) &lt; + &gt;.
    [1683] Example 360 - Preparation of compound No. 360 in Table 11
    [1684] Starting with cyclopropylamine (57 mg, 1.00 mmol), the title compound (15.5 mg, yield 16%) was obtained as a white solid, analogous to the procedure described in example 358,
    [1685] HPLC / LCMS (RT): 5.42 min:
    [1686] MS (+ ve ESI): 484.3 (M + H) &lt; + &gt;.
    [1687] Example 361 - Preparation of compound No. 361 in Table 11
    [1688] Starting with cyclopropane-methylamine (71 mg, 1.00 mmol), the title compound (64.3 mg, 65% yield) was obtained as a white solid analogous to the method described in example 358:
    [1689] HPLC / LCMS (RT): 5.56 min:
    [1690] MS (+ ve ESI): 498.4 (M + H) &lt; + &gt;.
    [1691] Example 362 - Preparation of compound No. 362 of Table 11
    [1692] Starting with cyclobutylamine (71 mg, 1.00 mmol), the title compound (17.5 mg, 18% yield) was obtained as a white solid analogous to the method described in example 358:
    [1693] HPLC / LCMS (RT): 5.40 min:
    [1694] MS (+ ve ESI): 498.4 (M + H) &lt; + &gt;.
    [1695] Example 363 - Preparation of compound No. 363 in Table 11
    [1696] Starting from cyclopentylamine (85 mg, 1.00 mmol), by analogy with the method described in example 358, the title compound (15.7 mg, yield 15%) was obtained as a white solid:
    [1697] HPLC / LCMS (RT): 5.58 min:
    [1698] MS (+ ve ESI): 512.4 (M + H) &lt; + &gt;.
    [1699] Example 364 - Preparation of compound No. 364 from Table 11
    [1700] Analogously to the procedure described in example 358, starting with l- (3-aminopropyl) -imidazole (125 mg, 1.0 mmol), the title compound (113.8 mg, yield 103%) was obtained as a white solid:
    [1701] HPLC / LCMS (RT): 4.90 min:
    [1702] MS (+ ve ESI): 552.7 (M + H) &lt; + &gt;.
    [1703] Example 365 - Preparation of compound No. 365 in Table 11
    [1704] Starting with cyclohexylamine (99 mg, 1.00 mmol), the title compound (158.2 mg, 150% yield) was obtained as a white solid analogous to the method described in example 358:
    [1705] HPLC / LCMS (RT): 5.55 min:
    [1706] MS (+ ve ESI): 526.4 (M + H) &lt; + &gt;.
    [1707] Example 366 - Preparation of compound No. 366 from Table 11
    [1708] Starting with 4-aminocyclohexanol (115 mg, 1.00 mmol), the title compound (52.6 mg, 49% yield) was obtained as a white solid analogous to the method described in example 358:
    [1709] HPLC / LCMS (RT): 5.24 min:
    [1710] MS (+ ve ESI): 542.4 (M + H) &lt; + &gt;.
    [1711] Example 367 - Preparation of compound No. 367 of Table 11
    [1712] Analogously to the procedure described in example 358, but starting with cyclohexane-methylamine (113 mg, 1.00 mmol) the title compound (126.5 mg, 117% yield) was obtained as a white solid:
    [1713] HPLC / LCMS (RT): 5.76 min:
    [1714] MS (+ ve ESI): 540.4 (M + H) &lt; + &gt;.
    [1715] Example 368 - Preparation of compound No. 368 from Table 11
    [1716] Analogously to the procedure described in example 358, starting with 2-amino-2-methyl-1,3-propanediol (105 mg, 1.00 mmol) the title compound (52 mg, yield 49%) was obtained as a white solid:
    [1717] HPLC / LCMS (RT): 5.21 min:
    [1718] MS (+ ve ESI): 532.3 (M + H) &lt; + &gt;.
    [1719] Example 369 - Preparation of compound No. 369 from Table 11
    [1720] Starting with tris (hydroxymethyl) -methylamine (121 mg, 1.00 mmol), the title compound (27 mg, 25% yield) was obtained as a white solid analogous to the method described in example 358,
    [1721] HPLC / LCMS (RT): 5.14 min:
    [1722] MS (+ ve ESI): 548.3 (M + H) &lt; + &gt;.
    [1723] Example 370 - Preparation of compound No. 370 in Table 11
    [1724] Analogously to the procedure described in example 358, starting with 2-amino-2-ethyl-1,3-propanediol (119 mg, 1.00 mmol), the title compound (55.5 mg, yield 51%) was obtained as a white solid :
    [1725] HPLC / LCMS (RT): 5.20 min:
    [1726] MS (+ ve ESI): 546.4 (M + H) &lt; + &gt;.
    [1727] Example 371 - Preparation of compound No. 371 in Table 11
    [1728] Starting with (S) -yluccinol (117 mg, 1.00 mmol), the title compound (75 mg, 69% yield) was obtained as a white solid analogous to the method described in example 358:
    [1729] HPLC / LCMS (RT): 5.46 min:
    [1730] MS (+ ve ESI): 544.4 (M + H) &lt; + &gt;.
    [1731] Example 372 - Preparation of compound No. 372 of Table 11
    [1732] The title compound (73.8 mg, 70% yield) was obtained as a white solid, analogous to the procedure described in example 358, but starting from tetrahydrofurfurylamine (101 mg, 1.00 mmol)
    [1733] HPLC / LCMS (RT): 5.43 min:
    [1734] MS (+ ve ESI): 528.4 (M + H) &lt; + &gt;.
    [1735] Example 373 - Preparation of compound No. 373 in Table 11
    [1736] Starting from isonipecotamide (128 mg, 1.00 mmol), the title compound (109.8 mg, yield 99%) was obtained as a white solid analogous to the method described for example 358:
    [1737] HPLC / LCMS (RT): 5.18 min:
    [1738] MS (+ ve ESI): 555.4 (M + H) &lt; + &gt;.
    [1739] Example 374 - Preparation of compound No. 374 in Table 11
    [1740] Starting with 4- (2-aminoethyl) -morpholine (130 mg, 1.00 mmol), the title compound (79.4 mg, 71% yield) was obtained as a white solid analogous to the method described in example 358:
    [1741] HPLC / LCMS (RT): 5.08 min:
    [1742] MS (+ ve ESI): 557.4 (M + H) &lt; + &gt;.
    [1743] Example 375 - Preparation of compound No. 375 of Table 11
    [1744] Analogously to the procedure described in example 358, starting with 2-amino-2-methyl-1-propanol (89 mg, 1.00 mmol), the title compound (59.2 mg, yield 57%) was obtained as a white solid:
    [1745] HPLC / LCMS (RT): 5.33 min:
    [1746] MS (+ ve ESI): 516.4 (M + H) &lt; + &gt;.
    [1747] Example 376 - Preparation of compound No. 376 of Table 11
    [1748] Starting with 3-amino-3-methyl-1-butanol (103 mg, 1.00 mmol), the title compound (47.7 mg, 45% yield) was obtained as a white solid analogous to the method described in example 358:
    [1749] HPLC / LCMS (RT): 5.27 min:
    [1750] MS (+ ve ESI): 530.4 (M + H) &lt; + &gt;.
    [1751] Example 377 - Preparation of compound No. 377 of Table 11
    [1752] Starting with isopropylamine (59 mg, 1.00 mmol), by analogy with the method described in example 358, the title compound (65.4 mg, 67% yield) was obtained as a white solid:
    [1753] HPLC / LCMS (RT): 5.32 min:
    [1754] MS (+ ve ESI): 486.3 (M + H) &lt; + &gt;.
    [1755] Example 378 - Preparation of compound No. 378 of Table 11
    [1756] Analogously to the procedure described in example 358, starting with 2-amino-1-propanol (75 mg, 1.00 mmol), the title compound (63.8 mg, yield 64%) was obtained as a white solid:
    [1757] HPLC / LCMS (RT): 5.18 min:
    [1758] MS (+ ve ESI): 502.4 (M + H) &lt; + &gt;.
    [1759] Example 379 - Preparation of compound No. 379 of Table 11
    [1760] Starting with D-2-amino-1-butanol (89 mg, 1.00 mmol), the title compound (70.7 mg, 69% yield) was obtained as a white solid analogous to the method described in example 358:
    [1761] HPLC / LCMS (RT): 5.22 min:
    [1762] MS (+ ve ESI): 516.4 (M + H) &lt; + &gt;.
    [1763] Example 380 - Preparation of compound No. 380 in Table 11
    [1764] Analogously to the procedure described in example 358, starting with 3-amino-1,2-propanediol (91 mg, 1.00 mmol), the title compound (22.1 mg, yield 21%) was obtained as a white solid:
    [1765] HPLC / LCMS (RT): 1.66 min:
    [1766] MS (+ ve ESI): 518.4 (M + H) &lt; + &gt;.
    [1767] Example 381 - Preparation of compound No. 381 of Table 11
    [1768] The title compound (67.1 mg, 67% yield) was obtained as a white solid starting from 2-methoxyethyl-amine (75 mg, 1.00 mmol), analogous to the method described for Example 358:
    [1769] HPLC / LCMS (RT): 5.47 min:
    [1770] MS (+ ve ESI): 502.4 (M + H) &lt; + &gt;.
    [1771] Example 382 - Preparation of compound No. 382 from Table 11
    [1772] Analogously to the procedure described in example 358, starting with 2- (2-aminoethoxy) -ethanol (105 mg, 1.00 mmol), the title compound (75.8 mg, yield 71%) was obtained as a white solid:
    [1773] HPLC / LCMS (RT): 5.24 min:
    [1774] MS (+ ve ESI): 532.4 (M + H) &lt; + &gt;.
    [1775] Example 383 - Preparation of compound No. 383 in Table 11
    [1776] Starting with 2-mercaptoethyl-amine hydrochloride (77 mg, 1.00 mmol), by analogy with the method described in example 358, the title compound (31.8 mg, 33% yield) was obtained as a white solid:
    [1777] HPLC / LCMS (RT): 1.81 min:
    [1778] MS (+ ve ESI): 488.3 (M + H) &lt; + &gt;.
    [1779] Example 384 - Preparation of compound No. 384 from Table 11
    [1780] The title compound (194.4 mg, 193% yield) was obtained as a white solid starting with 2- (ethylthio) ethylamine (105 mg, 1.00 mmol), analogous to the method described in example 358:
    [1781] HPLC / LCMS (RT): 1.92 min:
    [1782] MS (+ ve ESI): 504.3 (M + H) &lt; + &gt;.
    [1783] Example 385 - Preparation of compound No. 385 of Table 11
    [1784] Starting with 3-diethylaminopropylamine (130 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (25.3 mg, 24% yield) was obtained as a white solid:
    [1785] HPLC / LCMS (RT): 5.02 min:
    [1786] MS (+ ve ESI): 532.2 (M + H) &lt; + &gt;.
    [1787] Example 386 - Preparation of compound No. 386 from Table 11
    [1788] Starting with 3-ethoxypropylamine (103 mg, 1.00 mmol), by analogy with the method described in example 358, the title compound (15.9 mg, 14% yield) was obtained as a white solid:
    [1789] HPLC / LCMS (RT): 5.44 min:
    [1790] MS (+ ve ESI): 557.4 (M + H) &lt; + &gt;.
    [1791] Example 387 - Preparation of compound No. 387 of Table 11
    [1792] Starting with 3-amino-1-propanol (75 mg, 1.00 mmol), the title compound (112.7 mg, yield 106%) was obtained as a white solid analogous to the method described in example 358:
    [1793] HPLC / LCMS (RT): 5.23 min:
    [1794] MS (+ ve ESI): 530.4 (M + H) &lt; + &gt;.
    [1795] Example 388 - Preparation of compound No. 388 from Table 11
    [1796] Starting from 5-amino-1-pentanol (103 mg, 1.00 mmol), the title compound (11.9 mg, 12% yield) was obtained as a white solid analogous to the method described in example 358:
    [1797] HPLC / LCMS (RT): 5.37 min:
    [1798] MS (+ ve ESI): 502.4 (M + H) &lt; + &gt;.
    [1799] Example 389 - Preparation of compound No. 389 of Table 11
    [1800] Starting with D-proline amide (114 mg, 1.00 mmol), the title compound (15.4 mg, 15% yield) was obtained as a white solid analogous to the method described in example 358:
    [1801] HPLC / LCMS (RT) 5.: 34 min
    [1802] MS (+ ve ESI): 530.4 (M + H) &lt; + &gt;.
    [1803] Example 390 - Preparation of compound No. 390 in Table 11
    [1804] Analogously to the procedure described in example 358, starting with 3-amino-5-methylpyrazole (97 mg, 1.00 mmol), the title compound (150.6 mg, yield 139%) was obtained as a white solid:
    [1805] HPLC / LCMS (RT): 5.52 min:
    [1806] MS (+ ve ESI): 541.3 (M + H) &lt; + &gt;.
    [1807] Example 391 - Preparation of compound No. 391 of Table 11
    [1808] Starting with 1-aminomethyl-1-cyclohexanol hydrochloride (129 mg, 1.00 mmol), the title compound (153.9 mg, yield 147%) was obtained as a white solid analogous to the method described in example 358:
    [1809] HPLC / LCMS (RT): 5.54 min:
    [1810] MS (+ ve ESI): 524.4 (M + H) &lt; + &gt;.
    [1811] Example 392 - Preparation of compound No. 392 in Table 11
    [1812] Analogously to the procedure described in example 358, starting with 2-amino-1-hexanol (117 mg, 1.00 mmol), the title compound (52.6 mg, 47% yield) was obtained as a white solid:
    [1813] HPLC / LCMS (RT): 5.53 min:
    [1814] MS (+ ve ESI): 556.7 (M + H) &lt; + &gt;.
    [1815] Example 393 - Preparation of compound No. 393 in Table 11
    [1816] Starting with 5-methyl-2-furanmethanamine (111 mg, 1.00 mmol), the title compound (63.1 mg, 58% yield) was obtained as a white solid analogous to the method described in example 358:
    [1817] HPLC / LCMS (RT): 5.58 min:
    [1818] MS (+ ve ESI): 544.4 (M + H) &lt; + &gt;.
    [1819] Example 394 - Preparation of compound No. 394 in Table 11
    [1820] Analogously to the procedure described in example 358, starting with 3-amino-2,2-dimethyl-1-propanol (103 mg, 1.00 mmol) the title compound (151 mg, yield 140%) was obtained as a white solid:
    [1821] HPLC / LCMS (RT): 5.38 min:
    [1822] MS (+ ve ESI): 538.3 (M + H) &lt; + &gt;.
    [1823] Example 395 - Preparation of compound No. 395 of Table 11
    [1824] Analogously to the procedure described in example 358, starting with 3-aminomethyl-thiophene dihydrochloride (113 mg, 1.00 mmol), the title compound (113.4 mg, yield 107%) was obtained as a white solid:
    [1825] HPLC / LCMS (RT): 5.64 min:
    [1826] MS (+ ve ESI): 530.4 (M + H) &lt; + &gt;.
    [1827] Example 396 - Preparation of compound No. 396 in Table 11
    [1828] Starting with ethanolamine (61 mg, 1.00 mmol), the title compound (46.1 mg, 43% yield) was obtained as a white solid, analogous to the procedure described in example 358,
    [1829] HPLC / LCMS (RT): 5.19 min:
    [1830] MS (+ ve ESI): 540.3 (M + H) &lt; + &gt;.
    [1831] Example 397 - Preparation of compound No. 397 in Table 11
    [1832] Analogously to the procedure described in example 358, starting with thiophene-2-methylamine (113 mg, 1.0 mmol), the title compound (10.8 mg, yield 10%) was obtained as a white solid:
    [1833] HPLC / LCMS (RT): 5.64 min:
    [1834] MS (+ ve ESI): 540.3 (M + H) &lt; + &gt;.
    [1835] Example 398 - Preparation of compound No. 398 of Table 11
    [1836] Starting with piperidine (0.11 ml, 1.1 mmol) and omitting the sodium iodide catalyst, t, the title compound (18.7 mg, 18% yield) was obtained as a white solid analogous to the method described in example 358:
    [1837]
    [1838] Example 399 - Preparation of compound No. 399 of Table 11
    [1839] Starting with pyrrolidine (0.09 ml, 1.1 mmol), analogously to the method described in example 358, the title compound (38 mg, 36% yield) was obtained as a white solid:
    [1840]
    [1841] Example 400 - Preparation of compound No. 400 in Table 11
    [1842] Analogous to the procedure described in example 358, but starting with N-methylpiperazine (0.12 ml, 1.1 mmol), the title compound (47 mg, 41% yield) was obtained as a white solid:
    [1843]
    [1844] Example 401 - Preparation of compound No. 401 in Table 11
    [1845] The title compound (49 mg, 43% yield) was obtained as a white solid, starting with diethylamine (0.11 ml, 1.1 mmol), analogous to the method described in example 358:
    [1846]
    [1847] Example 402 - Preparation of compound No. 402 in Table 11
    [1848] Starting with diethanolamine (0.10 ml, 1.1 mmol), analogous to the procedure described in example 358, the title compound (24 mg, 27% yield) was obtained as a white solid:
    [1849]
    [1850] Example 403 - Preparation of compound No. 403 in Table 11
    [1851] Starting from N, N'-dimethyl-3-aminopyrrolidine (114 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (85 mg, yield 78%) was obtained as a white solid:
    [1852] HPLC / LCMS (RT): 5.08 min:
    [1853] MS (+ ve ESI): 541 (M + H) &lt; + &gt;.
    [1854] Example 404 - Preparation of compound No. 404 in Table 11
    [1855] The title compound (30 mg, 28% yield) was obtained as a white solid starting from 2- (N-methylamino) -N-methylacetamide (102 mg, 1.0 mmol), analogous to the method described in example 358:
    [1856] HPLC / LCMS (RT): 5.44 min:
    [1857] MS (+ ve ESI): 529 (M + H) &lt; + &gt;.
    [1858] Example 405 - Preparation of compound No. 405 in Table 11
    [1859] Starting from 2-oxopiperazine (100 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (80 mg, 76% yield) was obtained as a white solid:
    [1860] HPLC / LCMS (RT): 5.35 min:
    [1861] MS (+ ve ESI): 527 (M + H) &lt; + &gt;.
    [1862] Example 406 - Preparation of compound No. 746 from Table 11
    [1863] Analogously to the procedure described in example 358, starting with 3-amino-4-hydroxytetrahydrofuran (103 mg, 1.0 mmol), the title compound (18 mg, yield 17%) was obtained as a white solid:
    [1864] HPLC / LCMS (RT): 5.30 min:
    [1865] MS (+ ve ESI): 530 (M + H) &lt; + &gt;.
    [1866] Example 407 - Preparation of compound No. 407 in Table 11
    [1867] Analogously to the procedure described in example 358, starting with 4-methylpiperidine (99 mg, 1.0 mmol), the title compound (96 mg, 91% yield) was obtained as a white solid:
    [1868] HPLC / LCMS (RT): 5.59 min:
    [1869] MS (+ ve ESI): 526 (M + H) &lt; + &gt;.
    [1870] Example 408 - Preparation of compound No. 408 from Table 11
    [1871] Starting with 3,5-dimethyl-piperidine (113 mg, 1.0 mmol), the title compound (85 mg, 79% yield) was obtained as a white solid, analogous to the procedure described in example 358,
    [1872] HPLC / LCMS (RT): 5.68 min:
    [1873] MS (+ ve ESI): 540 (M + H) &lt; + &gt;.
    [1874] Example 409 - Preparation of compound No. 409 in Table 11
    [1875] Analogously to the procedure described in example 358, starting with N-methyl 3-amino-4-hydroxy-4-methyltetrahydropyran (145 mg, 1.0 mmol), the title compound (11 mg, yield 10% Obtained as a solid:
    [1876] HPLC / LCMS (RT): 5.52 min:
    [1877] MS (+ ve ESI): 572 (M + H) &lt; + &gt;.
    [1878] Example 410 - Preparation of compound No. 410 in Table 11
    [1879] Starting with 3-aminocyclopent-1-ene (83 mg, 1.0 mmol), the title compound (76 mg, 75% yield) was obtained as a white solid analogous to the method described in example 358:
    [1880] HPLC / LCMS (RT): 5.64 min:
    [1881] MS (+ ve ESI): 510 (M + H) &lt; + &gt;.
    [1882] Example 411 - Preparation of compound No. 411 of Table 11
    [1883] 4-hydroxypyrrolidine (117 mg, 1.0 mmol), the title compound (80 mg, 74% yield), was obtained in analogy to the method described in example 358 but starting from (2S, 4R) -2- (hydroxymethyl) -4- ) As a white solid:
    [1884] HPLC / LCMS (RT): 5.26 min:
    [1885] MS (+ ve ESI): 544 (M + H) &lt; + &gt;.
    [1886] Example 412 - Preparation of compound No. 412 in Table 11
    [1887] Analogously to the procedure described in example 358, starting with trans-N-methyl-3-hydroxy-4-amino-tetrahydropyran (131 mg, 1.0 mmol), the title compound (58 mg, yield 52% Obtained as a solid:
    [1888] HPLC / LCMS (RT): 5.38 min:
    [1889] MS (+ ve ESI): 558 (M + H) &lt; + &gt;.
    [1890] Example 413 - Preparation of compound No. 413 in Table 11
    [1891] Starting with N-methylcyclobutylmethylamine (99 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (83 mg, 79% yield) was obtained as a white solid:
    [1892] HPLC / LCMS (RT): 5.60 min:
    [1893] MS (+ ve ESI): 526 (M + H) &lt; + &gt;.
    [1894] Example 414 - Preparation of compound No. 414 in Table 11
    [1895] Starting with 3-hydroxyazetidine (73 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (19 mg, 19% yield) was obtained as a white solid:
    [1896] HPLC / LCMS (RT): 5.40 min:
    [1897] MS (+ ve ESI): 500 (M + H) &lt; + &gt;.
    [1898] Example 415 - Preparation of compound No. 415 of Table 11
    [1899] Starting with N-methyl 3-cyano-methylamine (84 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (63 mg, 62% yield) was obtained as a white solid:
    [1900] HPLC / LCMS (RT): 5.33 min:
    [1901] MS (+ ve ESI): 511 (M + H) &lt; + &gt;.
    [1902] Example 416 - Preparation of compound No. 416 in Table 11
    [1903] Starting with N-methyl 1- (2-aminoethyl) morpholine (144 mg, 1.0 mmol), the title compound (91 mg, yield 80%) was obtained as a white solid analogous to the method described in example 358:
    [1904] HPLC / LCMS (RT): 5.38 min:
    [1905] MS (+ ve ESI): 571 (M + H) &lt; + &gt;.
    [1906] Example 417 - Preparation of compound No. 417 in Table 11
    [1907] Starting with 1- (2-methoxy-ethyl) piperazine (144 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (52 mg, yield 46%) was obtained as a white solid:
    [1908] HPLC / LCMS (RT): 5.44 min:
    [1909] MS (+ ve ESI): 571 (M + H) &lt; + &gt;.
    [1910] Example 418 - Preparation of compound No. 418 from Table 11
    [1911] Starting from 2,6-dimethylmorpholine (115 mg, 1.0 mmol), the title compound (38 mg, 35% yield) was obtained as a white solid analogous to the procedure described in example 358,
    [1912] HPLC / LCMS (RT): 5.47 min:
    [1913] MS (+ ve ESI): 542 (M + H) &lt; + &gt;.
    [1914] Example 419 - Preparation of compound No. 419 from Table 11
    [1915] Analogously to the procedure described in example 358, starting with thiomorpholine (103 mg, 1.0 mmol), the title compound (69 mg, 65% yield) was obtained as a white solid:
    [1916] HPLC / LCMS (RT): 5.52 min:
    [1917] MS (+ ve ESI): 530 (M + H) &lt; + &gt;.
    [1918] Example 420 - Preparation of compound No. 420 in Table 11
    [1919] Analogously to the procedure described in example 358, starting with 2-methylpiperidine (99 mg, 1.0 mmol), the title compound (103 mg, 98% yield) was obtained as a white solid:
    [1920] HPLC / LCMS (RT): 5.46 min:
    [1921] MS (+ ve ESI): 526 (M + H) &lt; + &gt;.
    [1922] Example 421 - Preparation of compound No. 421 in Table 11
    [1923] Starting with 2,6-dimethylpiperidine (113 mg, 1.0 mmol), the title compound (69 mg, yield 64%) was obtained as a white solid analogous to the method described in example 358,
    [1924] HPLC / LCMS (RT): 5.60 min:
    [1925] MS (+ ve ESI): 540 (M + H) &lt; + &gt;.
    [1926] Example 422 - Preparation of compound No. 422 from Table 11
    [1927] Analogously to the procedure described in example 358, starting with 2-piperidin-methanol (115 mg, 1.0 mmol), the title compound (66 mg, yield 61%) was obtained as a white solid:
    [1928] HPLC / LCMS (RT): 5.46 min:
    [1929] MS (+ ve ESI): 542 (M + H) &lt; + &gt;.
    [1930] Example 423 - Preparation of compound No. 423 in Table 11
    [1931] Starting from 3-hydroxy-piperidine (101 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (89 mg, 84% yield) was obtained as a white solid:
    [1932] HPLC / LCMS (RT): 5.31 min:
    [1933] MS (+ ve ESI): 528 (M + H) &lt; + &gt;.
    [1934] Example 424 - Preparation of compound No. 424 from Table 11
    [1935] Analogously to the procedure described in example 358, starting with 3-pyrroline (69 mg, 1.0 mmol), the title compound (33 mg, 33% yield) was obtained as a white solid:
    [1936] HPLC / LCMS (RT): 6.46 min:
    [1937] MS (+ ve ESI): 494 (M + H) &lt; + &gt;.
    [1938] Example 425 - Preparation of compound No. 425 of Table 11
    [1939] Starting with bis- (2-methoxyethyl) amine (133 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (43 mg, yield 38%) was obtained as a white solid:
    [1940] HPLC / LCMS (RT): 5.50 min:
    [1941] MS (+ ve ESI): 560 (M + H) &lt; + &gt;.
    [1942] Example 426 - Preparation of compound No. 426 in Table 11
    [1943] Starting from 4-hydroxy-piperidine (101 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (90 mg, 85% yield) was obtained as a white solid:
    [1944] HPLC / LCMS (RT): 5.25 min:
    [1945] MS (+ ve ESI): 528 (M + H) &lt; + &gt;.
    [1946] Example 427 - Preparation of compound No. 427 of Table 11
    [1947] Starting with L-proline amide (114 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (87 mg, 81% yield) was obtained as a white solid:
    [1948] HPLC / LCMS (RT): 5.40 min:
    [1949] MS (+ ve ESI): 541 (M + H) &lt; + &gt;.
    [1950] Example 428 - Preparation of compound No. 428 from Table 11
    [1951] Starting with 1-isopropyl-piperazine (128 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (22 mg, 20% yield) was obtained as a white solid:
    [1952] HPLC / LCMS (RT): 5.44 min:
    [1953] MS (+ ve ESI): 555 (M + H) &lt; + &gt;.
    [1954] Example 429 - Preparation of compound No. 429 from Table 11
    [1955] Starting with N-methyltetrahydrofurfurylamine (115 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (106 mg, yield 98%) was obtained as a white solid:
    [1956] HPLC / LCMS (RT): 5.52 min:
    [1957] MS (+ ve ESI): 542 (M + H) &lt; + &gt;.
    [1958] Example 430 - Preparation of compound No. 430 in Table 11
    [1959] Analogously to the procedure described in example 358, starting with 4-acetylpiperidine hydrochloride (163 mg, 1.0 mmol), the title compound (55 mg, yield 50%) was obtained as a white solid:
    [1960] HPLC / LCMS (RT): 5.59 min:
    [1961] MS (+ ve ESI): 554 (M + H) &lt; + &gt;.
    [1962] Example 431 - Preparation of compound No. 431 in Table 11
    [1963] Starting with (R) -3-pyridinol (87 mg, 1.0 mmol), the title compound (100 mg, 97% yield) was obtained as a white solid analogous to the method described in example 358,
    [1964] HPLC / LCMS (RT): 5.34 min:
    [1965] MS (+ ve ESI): 514 (M + H) &lt; + &gt;.
    [1966] Example 432 - Preparation of compound No. 432 of Table 11
    [1967] Starting from l-methyl-4- (methylamino) piperidine (128 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (83 mg, yield 75%) was obtained as a white solid:
    [1968] HPLC / LCMS (RT): 5.10 min:
    [1969] MS (+ ve ESI): 555 (M + H) &lt; + &gt;.
    [1970] Example 433 - Preparation of compound No. 433 in Table 11
    [1971] Starting from 4- (1-pyrrolidinyl) -piperidine (154 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (103 mg, 89% yield) was obtained as a white solid:
    [1972] HPLC / LCMS (RT): 5.07 min:
    [1973] MS (+ ve ESI): 581 (M + H) &lt; + &gt;.
    [1974] Example 434 - Preparation of compound No. 434 in Table 11
    [1975] Starting with 1-methyl homo-piperazine (114 mg, 1.0 mmol), the title compound (63 mg, 58% yield) was obtained as a white solid analogous to the method described in example 358:
    [1976] HPLC / LCMS (RT): 5.03 min:
    [1977] MS (+ ve ESI): 541 (M + H) &lt; + &gt;.
    [1978] Example 435 - Preparation of compound No. 435 of Table 11
    [1979] Analogously to the procedure described in example 358, starting with 4-amino-2,2-dimethyltetrahydropyran (126 mg, 1.0 mmol), the title compound (63 mg, yield 57%) was obtained as a white solid:
    [1980] HPLC / LCMS (RT): 5.44 min:
    [1981] MS (+ ve ESI): 556 (M + H) &lt; + &gt;.
    [1982] Example 436 - Preparation of compound No. 436 in Table 11
    [1983] Starting from N- (2-hydroxyethyl) piperazine (128 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (91 mg, 82% yield) was obtained as a white solid:
    [1984] HPLC / LCMS (RT): 5.25 min:
    [1985] MS (+ ve ESI): 557 (M + H) &lt; + &gt;.
    [1986] Example 437 - Preparation of compound No. 437 in Table 11
    [1987] Analogous to the procedure described in example 358 but starting with 2- (methylamino) -ethanol (75 mg, 1.0 mmol), the title compound (81 mg, 81% yield) was obtained as a white solid:
    [1988] HPLC / LCMS (RT): 5.24 min:
    [1989] MS (+ ve ESI): 502 (M + H) &lt; + &gt;.
    [1990] Example 438 - Preparation of compound No. 438 from Table 11
    [1991] Starting with (S) -pyrrolidine methanol (101 mg, 1.0 mmol), by analogy with the method described in example 358, the title compound (87 mg, 83% yield) was obtained as a white solid:
    [1992] HPLC / LCMS (RT): 5.39 min:
    [1993] MS (+ ve ESI): 528 (M + H) &lt; + &gt;.
    [1994] Example 439 - Preparation of compound No. 439 in Table 11
    [1995] The title compound (105 mg, 97% yield) was obtained as a white solid starting from 3-piperidinemethanol (115 mg, 1.0 mmol), analogous to the procedure described in example 358:
    [1996] HPLC / LCMS (RT): 5.34 min:
    [1997] MS (+ ve ESI): 542 (M + H) &lt; + &gt;.
    [1998] Example 440 - Preparation of compound No. 440 in Table 11
    [1999] Starting with cis-2,5-dimethyl-piperazine (114 mg, 1.0 mmol), the title compound (91 mg, 84% yield) was obtained as a white solid analogous to the method described in example 358:
    [2000] HPLC / LCMS (RT): 5.16 min:
    [2001] MS (+ ve ESI): 541 (M + H) &lt; + &gt;.
    [2002] Example 441 - Preparation of compound No. 441 from Table 11
    [2003] Analogously to the procedure described in example 358, starting with a solution of methylamine in tetrahydrofuran (2.ON solution 60 ml, 120 mmol) and flash chromatography on silica gel (eluting with 5-10% methanol in dichloromethane) , The title compound (2.6 g, yield 38%) was obtained as a white solid:
    [2004]
    [2005] Example 442 - Preparation of compound No. 442 from Table 12
    [2006] (88 mg, 0.2 mmol) was added to a solution of N (N, N-dimethylamino) anilino) -6-methoxy-7- (glycidyl) quinazoline , N-dimethylethylenediamine (88 mg, 1.00 mmol) in dichloromethane (5 ml) and the reaction was stirred at 50 &lt; 0 &gt; C for 24 h. The reaction was cooled to ambient temperature, diluted with methanol (5 ml) and absorbed onto silica gel for chromatography. After purification by flash chromatography on silica gel (eluting with 0-10% methanol in dichloromethane), the title compound (36 mg, 34% yield) was obtained as an off-white solid:
    [2007] HPLC / LCMS (RT): 4.93 min:
    [2008] MS (+ ve ESI): 531 (M + H) &lt; + &gt;.
    [2009] Example 443 - Preparation of compound No. 443 from Table 12
    [2010] The title compound (102 mg, 91% yield) was prepared in analogy to the procedure described in example 442, but starting from N, N-diethyl-ethylenediamine (116 mg, 1.00 mmol) and the S enantiomer of the starting epoxide Obtained as a solid:
    [2011] HPLC / LCMS (RT): 4.98 min:
    [2012] MS (+ ve ESI): 559 (M + H) &lt; + &gt;.
    [2013] Example 444 - Preparation of compound No. 444 from Table 12
    [2014] The title compound (71 mg, 67% yield) was obtained as an off-white solid starting with 2- (2-aminoethoxy) -ethanol (105 mg, 1.00 mmol), analogous to the method described in example 442:
    [2015] HPLC / LCMS (RT): 5.17 min:
    [2016] MS (+ ve ESI): 548 (M + H) &lt; + &gt;.
    [2017] Example 445 - Preparation of compound No. 445 from Table 12
    [2018] Starting with ethanolamine (62 mg, 1.00 mmol), the title compound (33 mg, 33% yield) was obtained as an off-white solid analogous to the method described in example 442,
    [2019] HPLC / LCMS (RT): 5.18 min:
    [2020] MS (+ ve ESI): 504 (M + H) &lt; + &gt;.
    [2021] Example 446 - Preparation of compound No. 446 from Table 12
    [2022] The title compound (28 mg, 26% yield) was obtained as an off-white solid, starting with 2- (ethylthio) ethylamine (106 mg, 1.00 mmol), analogous to the method described in example 442:
    [2023] HPLC / LCMS (RT): 5.51 min:
    [2024] MS (+ ve ESI): 548 (M + H) &lt; + &gt;.
    [2025] Example 447 - Preparation of compound No. 447 of Table 12
    [2026] Starting with 3- (diethylamino) -propylamine (130 mg, 1.00 mmol), the title compound (29 mg, yield 26%) was obtained as an off-white solid analogous to the method described in example 442:
    [2027] HPLC / LCMS (RT): 4.97 min:
    [2028] MS (+ ve ESI): 573 (M + H) &lt; + &gt;.
    [2029] Example 448 - Preparation of compound No. 448 from Table 12
    [2030] The title compound (68 mg, 62% yield) was obtained as an off-white solid starting from 3-ethoxypropylamine (104 mg, 1.00 mmol), analogous to the method described in example 442:
    [2031] HPLC / LCMS (RT): 5.41 min:
    [2032] MS (+ ve ESI): 546 (M + H) &lt; + &gt;.
    [2033] Example 449 - Preparation of compound No. 449 from Table 12
    [2034] Starting with 3-amino-1-propylamine (75 mg, 1.00 mmol), the title compound (35 mg, 34% yield) was obtained as an off- white solid analogous to the method described in example 442:
    [2035] HPLC / LCMS (RT): 5.20 min:
    [2036] MS (+ ve ESI): 518 (M + H) &lt; + &gt;.
    [2037] Example 450 - Preparation of compound No. 450 in Table 12
    [2038] Starting with 5-amino-1-pentylamine (103 mg, 1.00 mmol), the title compound (67 mg, yield 62%) was obtained as an off-white solid analogous to the method described in example 442,
    [2039] HPLC / LCMS (RT): 5.26 min:
    [2040] MS (+ ve ESI): 546 (M + H) &lt; + &gt;.
    [2041] Example 451 - Preparation of compound No. 451 of Table 12
    [2042] 4-amino-1-butanol (89 mg, 1.00 mmol), the title compound (47 mg, 44% yield) was obtained as an off- white solid analogous to the method described in example 442:
    [2043] HPLC / LCMS (RT): 5.16 min:
    [2044] MS (+ ve ESI): 532 (M + H) &lt; + &gt;.
    [2045] Example 452 - Preparation of compound No. 452 of Table 12
    [2046] Starting from 3-amino-5-methylpyrazole (98 mg, 1.00 mmol), the title compound (35 mg, yield 32%) was obtained as an off- white solid analogous to the method described in example 442:
    [2047] HPLC / LCMS (RT): 5.44 min:
    [2048] MS (+ ve ESI): 540 (M + H) &lt; + &gt;.
    [2049] Example 453 - Preparation of compound No. 453 in Table 12
    [2050] The title compound (36 mg, yield 32%) was obtained as an off-white solid, starting with 1- (aminomethyl) -1-cyclohexanol hydrochloride (167 mg, 1.00 mmol), analogous to the method described in example 442:
    [2051] HPLC / LCMS (RT): 5.50 min:
    [2052] MS (+ ve ESI): 572 (M + H) &lt; + &gt;.
    [2053] Example 454 - Preparation of compound No. 454 in Table 12
    [2054] Starting with thiophen-2-ethylamine (128 mg, 1.00 mmol), the title compound (24 mg, yield 21%) was obtained as an off-white solid analogous to the method described in example 442:
    [2055] HPLC / LCMS (RT): 5.68 min:
    [2056] MS (+ ve ESI): 570 (M + H) &lt; + &gt;.
    [2057] Example 455 - Preparation of compound No. 455 of Table 12
    [2058] Starting from 2-amino-1-hexanol (118 mg, 1.00 mmol), the title compound (66 mg, 59% yield) was obtained as an off- white solid analogous to the method described in example 442:
    [2059] HPLC / LCMS (RT): 5.55 min:
    [2060] MS (+ ve ESI): 560 (M + H) &lt; + &gt;.
    [2061] Example 456 - Preparation of compound No. 456 in Table 12
    [2062] Starting with 2- (2-aminoethyl) -1-methylpyrrolidine (128 mg, 1.00 mmol), the title compound (46 mg, 41% yield) was obtained as an off- white solid analogous to the method described in example 442 :
    [2063] HPLC / LCMS (RT): 5.05 min:
    [2064] MS (+ ve ESI): 571 (M + H) &lt; + &gt;.
    [2065] Example 457 - Preparation of compound No. 457 in Table 12
    [2066] Starting with 5-methyl-2-furan-methylamine (112 mg, 1.00 mmol), the title compound (27 mg, yield 24%) was obtained as an off- white solid analogous to the method described in example 442:
    [2067] HPLC / LCMS (RT): 5.56 min:
    [2068] MS (+ ve ESI): 554 (M + H) &lt; + &gt;.
    [2069] Example 458 - Preparation of compound No. 458 of Table 12
    [2070] The title compound (106 mg, 95% yield) was obtained as an off-white solid starting with 3-amino-2,2-dimethyl- 1 -propanol (104 mg, 1.00 mmol), analogous to the method described in example 442:
    [2071] HPLC / LCMS (RT): 5.34 min:
    [2072] MS (+ ve ESI): 546 (M + H) &lt; + &gt;.
    [2073] Example 459 - Preparation of compound No. 459 of Table 12
    [2074] Starting from 3-aminomethyl-thiophene hydrochloride (150 mg, 1.00 mmol), the title compound (55 mg, yield 50%) was obtained as an off-white solid analogous to the method described in example 443:
    [2075] HPLC / LCMS (RT): 5.54 min:
    [2076] MS (+ ve ESI): 556 (M + H) &lt; + &gt;.
    [2077] Example 460 - Preparation of compound No. 460 in Table 12
    [2078] Starting from 3-aminopropane-l, 2-diol (91 mg, 1.00 mmol), the title compound (11 mg, yield 10%) was obtained as an off- white solid analogous to the method described in example 443:
    [2079] HPLC / LCMS (RT): 5.16 min:
    [2080] MS (+ ve ESI): 534 (M + H) &lt; + &gt;.
    [2081] Example 461 - Preparation of compound No. 461 in Table 12
    [2082] Starting from cyclobutylamine (72 mg, 1.00 mmol), the title compound (58 mg, 56% yield) was obtained as an off-white solid analogous to the method described in example 443:
    [2083] HPLC / LCMS (RT): 5.34 min:
    [2084] MS (+ ve ESI): 514 (M + H) &lt; + &gt;.
    [2085] Example 462 - Preparation of compound No. 462 in Table 12
    [2086] The title compound (74 mg, 71% yield) was obtained as an off-white solid starting with cyclopentylamine (86 mg, 1.00 mmol), analogous to the method described in example 443:
    [2087] HPLC / LCMS (RT): 5.34 min:
    [2088] MS (+ ve ESI): 528 (M + H) &lt; + &gt;.
    [2089] Example 463 - Preparation of compound No. 463 in Table 12
    [2090] The title compound (92 mg, 81% yield) was obtained as an off-white solid starting from 1- (3-aminopropyl) -imidazole (125 mg, 1.00 mmol), analogous to the method described in example 443:
    [2091] HPLC / LCMS (RT): 4.92 min:
    [2092] MS (+ ve ESI): 568 (M + H) &lt; + &gt;.
    [2093] Example 464 - Preparation of compound No. 464 in Table 12
    [2094] Starting with cyclohexylamine (100 mg, 1.00 mmol), by analogy with the method described in example 442, the title compound (58 mg, yield 53%) was obtained as an off-white solid:
    [2095] HPLC / LCMS (RT): 5.51 min:
    [2096] MS (+ ve ESI): 542 (M + H) &lt; + &gt;.
    [2097] Example 465 - Preparation of compound No. 465 of Table 12
    [2098] Starting with 4-aminocyclohexanol (116 mg, 1.00 mmol), the title compound (56 mg, 51% yield) was obtained as an off-white solid analogous to the method described in example 442:
    [2099] HPLC / LCMS (RT): 5.17 min:
    [2100] MS (+ ve ESI): 558 (M + H) &lt; + &gt;.
    [2101] Example 466 - Preparation of compound No. 466 in Table 12
    [2102] Starting with cyclohexanemethylamine (114 mg, 1.00 mmol), the title compound (68 mg, 62% yield) was obtained as an off-white solid analogous to the method described in example 442:
    [2103] HPLC / LCMS (RT): 5.77 min:
    [2104] MS (+ ve ESI): 556 (M + H) &lt; + &gt;.
    [2105] Example 467 - Preparation of compound No. 467 in Table 12
    [2106] The title compound (66 mg, 60% yield) was obtained as an off-white solid, starting with 2-amino-2-methyl-1,3-propanediol (106 mg, 1.00 mmol), analogous to the method described in example 442:
    [2107] HPLC / LCMS (RT): 5.25 min:
    [2108] MS (+ ve ESI): 548 (M + H) &lt; + &gt;.
    [2109] Example 468 - Preparation of compound No. 468 from Table 12
    [2110] Analogously to the method described in example 443, starting with 122 mg (1.00 mmol) of 2-amino-2- (hydroxymethyl) -1,3-propanediol, the title compound (18 mg, yield 16% Obtained as a solid:
    [2111] HPLC / LCMS (RT): 5.21 min:
    [2112] MS (+ ve ESI): 564 (M + H) &lt; + &gt;.
    [2113] Example 469 - Preparation of compound No. 469 in Table 12
    [2114] Starting from 2-amino-2-ethyl-1,3-propanediol (120 mg, 1.00 mmol), the title compound (56 mg, yield 49%) was obtained as an off- white solid analogous to the method described in example 442:
    [2115] HPLC / LCMS (RT): 5.26 min:
    [2116] MS (+ ve ESI): 562 (M + H) &lt; + &gt;.
    [2117] Example 470 - Preparation of compound No. 470 in Table 12
    [2118] The title compound (74 mg, 65% yield) was obtained as an off-white solid starting with 2- (aminoethyl) -1-ethylpyrrolidine (128 mg, 1.00 mmol), analogous to the method described in example 442:
    [2119] HPLC / LCMS (RT): 5.01 min:
    [2120] MS (+ ve ESI): 571 (M + H) &lt; + &gt;.
    [2121] Example 471 - Preparation of compound No. 471 in Table 12
    [2122] The title compound (73 mg, 67% yield) was obtained as an off-white solid, analogously to the method described in Example 442, but starting from tetrahydrofurfurylamine (102 mg, 1.00 mmol)
    [2123] HPLC / LCMS (RT): 5.41 min:
    [2124] MS (+ ve ESI): 544 (M + H) &lt; + &gt;.
    [2125] Example 472 - Preparation of compound No. 472 in Table 12
    [2126] Starting from isonipecotamide (128 mg, 1.00 mmol), the title compound (86 mg, 75% yield) was obtained as an off-white solid analogous to the method described in example 442,
    [2127] HPLC / LCMS (RT): 5.18 min:
    [2128] MS (+ ve ESI): 571 (M + H) &lt; + &gt;.
    [2129] Example 473 - Preparation of compound No. 473 in Table 12
    [2130] Starting with 4- (2-aminoethyl) -morpholine (130 mg, 1.00 mmol), the title compound (112 mg, yield 98%) was obtained as an off-white solid analogous to the method described in example 442:
    [2131] HPLC / LCMS (RT): 5.04 min:
    [2132] MS (+ ve ESI): 573 (M + H) &lt; + &gt;.
    [2133] Example 474 - Preparation of compound No. 474 from Table 12
    [2134] Analogously to the method described in example 442, starting with 2-amino-2-methyl-1-propanol (89 mg, 1.00 mmol), the title compound (75 mg, yield 71%) was obtained as an off-white solid:
    [2135] HPLC / LCMS (RT): 5.22 min:
    [2136] MS (+ ve ESI): 532 (M + H) &lt; + &gt;.
    [2137] Example 475 - Preparation of compound No. 475 of Table 12
    [2138] Starting with 3-amino-3-methyl-1-butanol (103 mg, 1.00 mmol), the title compound (48 mg, 44% yield) was obtained as an off- white solid analogous to the method described in example 442:
    [2139] HPLC / LCMS (RT): 5.28 min:
    [2140] MS (+ ve ESI): 546 (M + H) &lt; + &gt;.
    [2141] Example 476 - Preparation of compound No. 476 in Table 12
    [2142] Starting with isopropylamine (59 mg, 1.00 mmol), the title compound (73 mg, 73% yield) was obtained as an off-white solid analogous to the method described in example 442:
    [2143] HPLC / LCMS (RT): 5.17 min:
    [2144] MS (+ ve ESI): 502 (M + H) &lt; + &gt;.
    [2145] Example 477 - Preparation of compound No. 477 of Table 12
    [2146] Starting from 2-amino-1-propanol (75 mg, 1.00 mmol), the title compound (59 mg, 57% yield) was obtained as an off- white solid analogous to the method described in example 442,
    [2147] HPLC / LCMS (RT): 5.18 min:
    [2148] MS (+ ve ESI): 518 (M + H) &lt; + &gt;.
    [2149] Example 478 - Preparation of compound No. 478 from Table 12
    [2150] The title compound (59 mg, 59% yield) was obtained as an off-white solid starting with cyclopropylamine (57 mg, 1.00 mmol), analogous to the method described in example 442:
    [2151] HPLC / LCMS (RT): 5.24 min:
    [2152] MS (+ ve ESI): 500 (M + H) &lt; + &gt;.
    [2153] Example 479 - Preparation of compound No. 479 from Table 12
    [2154] Starting with thiophene-2-methylamine (113 mg, 1.00 mmol), the title compound (14 mg, 13% yield) was obtained as an off- white solid analogous to the method described in example 442:
    [2155] HPLC / LCMS (RT): 5.50 min:
    [2156] MS (+ ve ESI): 556 (M + H) &lt; + &gt;.
    [2157] Example 480 - Preparation of compound No. 480, Table 12
    [2158] Starting with N-acetylethylenediamine (102 mg, 1.00 mmol), by analogy with the method described in example 442, the title compound (73 mg, 67% yield) was obtained as an off- white solid:
    [2159] HPLC / LCMS (RT): 5.21 min:
    [2160] MS (+ ve ESI): 545 (M + H) &lt; + &gt;.
    [2161] Example 481 - Preparation of compound No. 481 in Table 12
    [2162] The title compound (51 mg, 48% yield) was obtained as an off-white solid starting with 2- (methylthio) ethylamine (92 mg, 1.00 mmol), analogous to the method described in example 442:
    [2163] HPLC / LCMS (RT): 5.34 min:
    [2164] MS (+ ve ESI): 534 (M + H) &lt; + &gt;.
    [2165] Example 482 - Preparation of compound No. 482 from Table 12
    [2166] The title compound (99 mg, 87% yield) was obtained as an off-white solid starting with N- (2-aminoethyl) -piperidine (128 mg, 1.00 mmol), analogous to the method described in example 442:
    [2167] HPLC / LCMS (RT): 4.92 min:
    [2168] MS (+ ve ESI): 571 (M + H) &lt; + & gt ; .
    [2169] Example 483 - Preparation of compound No. 483 in Table 12
    [2170] Starting with L-proline amide (114 mg, 1.00 mmol), the title compound (112 mg, 99% yield) was obtained as an off-white solid analogous to the method described in example 443:
    [2171] HPLC / LCMS (RT): 5.38 min:
    [2172] MS (+ ve ESI): 557 (M + H) &lt; + & gt ; .
    [2173] Example 484 - Preparation of compound No. 484 in Table 12
    [2174] Starting with S-leucinol (117 mg, 1.00 mmol), the title compound (76 mg, 68% yield) was obtained as an off-white solid analogous to the method described in example 443:
    [2175] HPLC / LCMS (RT): 5.44 min:
    [2176] MS (+ ve ESI): 560 (M + H) &lt; + & gt ; .
    [2177] Example 485 - Preparation of compound No. 485 of Table 12
    [2178] Starting with D-2-amino-1-butanol (75 mg, 1.00 mmol), the title compound (78 mg, yield 73%) was obtained as an off- white solid analogous to the method described in example 443:
    [2179] HPLC / LCMS (RT): 5.27 min:
    [2180] MS (+ ve ESI): 532 (M + H) &lt; + & gt ; .
    [2181] Example 486 - Preparation of compound No. 486 in Table 12
    [2182] Starting with L-proline amide (114 mg, 1.00 mmol), the title compound (109 mg, 96% yield) was obtained as an off-white solid analogous to the method described in example 442:
    [2183] HPLC / LCMS (RT): 5.28 min:
    [2184] MS (+ ve ESI): 557 (M + H) &lt; + & gt ; .
    [2185] Example 487 - Preparation of compound No. 487 in Table 12
    [2186] Starting with S-leucinol (117 mg, 1.00 mmol), the title compound (71 mg, yield 64%) was obtained as an off-white solid analogous to the method described in example 442:
    [2187] HPLC / LCMS (RT): 5.26 min:
    [2188] MS (+ ve ESI): 560 (M + H) &lt; + & gt ; .
    [2189] Example 488 - Preparation of compound No. 488 from Table 12
    [2190] Starting with D-2-amino-1-butanol (75 mg, 1.00 mmol), the title compound (59 mg, yield 57%) was obtained as an off- white solid analogous to the method described in example 442:
    [2191] HPLC / LCMS (RT): 5.24 min:
    [2192] MS (+ ve ESI): 518 (M + H) &lt; + & gt ; .
    [2193] Example 489 - Preparation of compound No. 489 in Table 12
    [2194] Starting with N, N-dimethylethylenediamine (88 mg, 1.00 mmol), the title compound (38 mg, yield 36%) was obtained as an off-white solid analogous to the method described in example 443:
    [2195] HPLC / LCMS (RT): 4.92 min:
    [2196] MS (+ ve ESI): 531 (M + H) &lt; + & gt ; .
    [2197] Example 490 - Preparation of compound No. 490 from Table 12
    [2198] The title compound (73 mg, 67% yield) was obtained as an off-white solid starting with 2- (2-aminoethoxy) -ethanol (105 mg, 1.00 mmol), analogous to the method described in example 443:
    [2199] HPLC / LCMS (RT): 5.19 min:
    [2200] MS (+ ve ESI): 548 (M + H) &lt; + &gt;.
    [2201] Example 491 - Preparation of compound No. 491 of Table 12
    [2202] The title compound (63 mg, 63% yield) was obtained as an off-white solid, starting with ethanolamine (61 mg, 1.00 mmol), analogous to the method described in example 443:
    [2203] HPLC / LCMS (RT): 5.17 min:
    [2204] MS (+ ve ESI): 504 (M + H) &lt; + &gt;.
    [2205] Example 492 - Preparation of compound No. 492 from Table 12
    [2206] Starting with 2- (ethylthio) ethylamine (105 mg, 1.00 mmol), the title compound (28 mg, 25% yield) was obtained as an off-white solid analogous to the method described in example 443:
    [2207] HPLC / LCMS (RT): 5.53 min:
    [2208] MS (+ ve ESI): 548 (M + H) &lt; + &gt;.
    [2209] Example 493 - Preparation of compound No. 493 of Table 12
    [2210] The title compound (40 mg, 35% yield) was obtained as an off-white solid, starting with 3- (diethylamino) -propylamine (130 mg, 1.00 mmol), analogous to the method described in example 443:
    [2211] HPLC / LCMS (RT): 5.02 min:
    [2212] MS (+ ve ESI): 573 (M + H) &lt; + &gt;.
    [2213] Example 494 - Preparation of compound No. 494 from Table 12
    [2214] The title compound (84 mg, 77% yield) was obtained as an off-white solid starting with 3-ethoxypropylamine (103 mg, 1.00 mmol), analogous to the method described in example 443:
    [2215] HPLC / LCMS (RT): 5.43 min:
    [2216] MS (+ ve ESI): 546 (M + H) &lt; + &gt;.
    [2217] Example 495 - Preparation of compound No. 495 of Table 12
    [2218] Starting from 3-amino-1-propanol (75 mg, 1.00 mmol), the title compound (61 mg, 59% yield) was obtained as an off- white solid analogous to the method described in example 443:
    [2219] HPLC / LCMS (RT): 5.16 min:
    [2220] MS (+ ve ESI): 518 (M + H) &lt; + &gt;.
    [2221] Example 496 - Preparation of compound No. 496 in Table 12
    [2222] Starting from 5-amino-1-pentanol (103 mg, 1.00 mmol), the title compound (65 mg, 60% yield) was obtained as an off- white solid analogous to the method described in example 443:
    [2223] HPLC / LCMS (RT): 5.21 min:
    [2224] MS (+ ve ESI): 546 (M + H) &lt; + &gt;.
    [2225] Example 497 - Preparation of compound No. 497 of Table 12
    [2226] Starting from 4-amino-1-butanol (89 mg, 1.00 mmol), the title compound (45 mg, 42% yield) was obtained as an off- white solid analogous to the method described in example 443:
    [2227] HPLC / LCMS (RT): 5.24 min:
    [2228] MS (+ ve ESI): 532 (M + H) &lt; + &gt;.
    [2229] Example 498 - Preparation of compound No. 498 from Table 12
    [2230] Starting from 3-amino-5-methyl-pyrazole (98 mg, 1.00 mmol), the title compound (38 mg, yield 35%) was obtained as an off- white solid analogous to the method described in example 443:
    [2231] HPLC / LCMS (RT): 5.48 min:
    [2232] MS (+ ve ESI): 540 (M + H) &lt; + &gt;.
    [2233] Example 499 - Preparation of compound No. 499 from Table 12
    [2234] The title compound (108 mg, 95% yield) was obtained as an off-white solid starting with 1- (aminomethyl) -1-cyclohexanol (129 mg, 1.00 mmol), analogous to the method described in example 443:
    [2235] HPLC / LCMS (RT): 5.52 min:
    [2236] MS (+ ve ESI): 572 (M + H) &lt; + &gt;.
    [2237] Example 500 - Preparation of compound No. 500 in Table 12
    [2238] Starting with thiophen-2-ethyl-amine (127 mg, 1.00 mmol), the title compound (62 mg, 54% yield) was obtained as an off- white solid analogous to the method described in example 443:
    [2239] HPLC / LCMS (RT): 5.70 min:
    [2240] MS (+ ve ESI): 570 (M + H) &lt; + &gt;.
    [2241] Example 501 - Preparation of compound No. 501 in Table 12
    [2242] Starting from 2-amino-1-hexanol (117 mg, 1.00 mmol), the title compound (88 mg, 79% yield) was obtained as an off- white solid analogous to the method described in example 443:
    [2243] HPLC / LCMS (RT): 5.56 min:
    [2244] MS (+ ve ESI): 560 (M + H) &lt; + &gt;.
    [2245] Example 502 - Preparation of compound No. 502 in Table 12
    [2246] The title compound (108 mg, 95% yield) was obtained as an off-white solid starting with 2- (2-aminoethyl) -1-methylpyrrolidine (128 mg, 1.00 mmol), analogous to the method described in example 443 :
    [2247] HPLC / LCMS (RT): 4.98 min:
    [2248] MS (+ ve ESI): 571 (M + H) &lt; + &gt;.
    [2249] Example 503 - Preparation of compound No. 503 in Table 12
    [2250] Starting with 5-methyl-2-furanmethylamine (111 mg, 1.00 mmol), the title compound (55 mg, yield 50%) was obtained as an off-white solid analogous to the method described in example 443:
    [2251] HPLC / LCMS (RT): 5.51 min:
    [2252] MS (+ ve ESI): 554 (M + H) &lt; + &gt;.
    [2253] Example 504 - Preparation of compound No. 504 from Table 12
    [2254] Starting from 3-amino-2,2-dimethyl-1-propanol (103 mg, 1.00 mmol), the title compound (56 mg, yield 50%) was obtained as an off- white solid analogous to the method described in example 443:
    [2255] HPLC / LCMS (RT): 5.48 min:
    [2256] MS (+ ve ESI): 556 (M + H) &lt; + &gt;.
    [2257] Example 505 - Preparation of compound No. 505 of Table 12
    [2258] Starting with 3-aminomethylthiophene hydrochloride (150 mg, 1.00 mmol), the title compound (105 mg, 97% yield) was obtained as an off-white solid analogous to the method described in example 442:
    [2259] HPLC / LCMS (RT): 5.34 min:
    [2260] MS (+ ve ESI): 546 (M + H) &lt; + &gt;.
    [2261] Example 506 - Preparation of compound No. 506 from Table 12
    [2262] Starting from cyclobutylamine (71 mg, 1.00 mmol), by analogy with the method described in example 442, the title compound (80 mg, 78% yield) was obtained as an off-white solid:
    [2263] HPLC / LCMS (RT): 5.36 min:
    [2264] MS (+ ve ESI): 514 (M + H) &lt; + &gt;.
    [2265] Example 507 - Preparation of compound No. 507 of Table 12
    [2266] Starting from cyclopentylamine (85 mg, 1.00 mmol), by analogy with the method described in example 442, the title compound (83 mg, yield 78%) was obtained as an off-white solid:
    [2267] HPLC / LCMS (RT): 5.37 min:
    [2268] MS (+ ve ESI): 528 (M + H) &lt; + &gt;.
    [2269] Example 508 - Preparation of compound No. 508 from Table 12
    [2270] Starting with cyclohexylamine (99 mg, 1.00 mmol), the title compound (77 mg, 71% yield) was obtained as an off-white solid analogous to the method described in example 443:
    [2271] HPLC / LCMS (RT): 5.50 min:
    [2272] MS (+ ve ESI): 542 (M + H) &lt; + &gt;.
    [2273] Example 509 - Preparation of compound No. 509 from Table 12
    [2274] Starting with 4-aminocyclohexanol (115 mg, 1.00 mmol), the title compound (35 mg, 31% yield) was obtained as an off-white solid analogous to the method described in example 443:
    [2275] HPLC / LCMS (RT): 5.35 min:
    [2276] MS (+ ve ESI): 558 (M + H) &lt; + &gt;.
    [2277] Example 510 - Preparation of compound No. 510 in Table 12
    [2278] Starting with cyclohexanemethylamine (113 mg, 1.00 mmol), the title compound (97 mg, 87% yield) was obtained as an off-white solid analogous to the method described in example 443:
    [2279] HPLC / LCMS (RT): 5.66 min:
    [2280] MS (+ ve ESI): 556 (M + H) &lt; + &gt;.
    [2281] Example 511 - Preparation of compound No. 511 of Table 12
    [2282] The title compound (105 mg, 96% yield) was obtained as an off-white solid, starting with 2-amino-2-methyl-1,3-propanediol (105 mg, 1.00 mmol), analogous to the method described in example 443:
    [2283] HPLC / LCMS (RT): 5.17 min:
    [2284] MS (+ ve ESI): 548 (M + H) &lt; + &gt;.
    [2285] Example 512 - Preparation of compound No. 512 in Table 12
    [2286] Analogously to the procedure described in example 443, starting with 2-amino-2-ethyl-1,3-propanediol (119 mg, 1.00 mmol) the title compound (112 mg, yield 99%) was obtained as an off-white solid:
    [2287] HPLC / LCMS (RT): 5.24 min:
    [2288] MS (+ ve ESI): 562 (M + H) &lt; + &gt;.
    [2289] Example 513 - Preparation of compound No. 513 in Table 12
    [2290] The title compound (108 mg, 95% yield) was obtained as an off-white solid starting with 2- (aminomethyl) -1-ethylpyrrolidine (128 mg, 1.00 mmol), analogous to the method described in example 443:
    [2291] HPLC / LCMS (RT): 4.95 min:
    [2292] MS (+ ve ESI): 571 (M + H) &lt; + &gt;.
    [2293] Example 514 - Preparation of compound No. 514 in Table 12
    [2294] The title compound (92 mg, 84% yield) was obtained as an off-white solid, analogous to the procedure described in Example 443, but starting from tetrahydrofurfurylamine (102 mg, 1.00 mmol)
    [2295] HPLC / LCMS (RT): 5.44 min:
    [2296] MS (+ ve ESI): 544 (M + H) &lt; + &gt;.
    [2297] Example 515 - Preparation of compound No. 515 of Table 12
    [2298] Starting with isonipecotamide (128 mg, 1.00 mmol), the title compound (94 mg, 82% yield) was obtained as an off-white solid analogous to the method described in example 443:
    [2299] HPLC / LCMS (RT): 5.24 min:
    [2300] MS (+ ve ESI): 571 (M + H) &lt; + &gt;.
    [2301] Example 516 - Preparation of compound No. 516 from Table 12
    [2302] Starting from 4- (2-aminoethyl) morpholine (128 mg, 1.00 mmol), the title compound (77 mg, 67% yield) was obtained as an off- white solid analogous to the method described in example 443:
    [2303] HPLC / LCMS (RT): 5.02 min:
    [2304] MS (+ ve ESI): 573 (M + H) &lt; + &gt;.
    [2305] Example 517 - Preparation of compound No. 517 in Table 12
    [2306] Analogously to the method described in example 443, starting with 2-amino-2-methyl-l-propanol (89 mg, 1.00 mmol) the title compound (71 mg, yield 67%) was obtained as an off- white solid:
    [2307] HPLC / LCMS (RT): 5.21 min:
    [2308] MS (+ ve ESI): 532 (M + H) &lt; + &gt;.
    [2309] Example 518 - Preparation of compound No. 518 from Table 12
    [2310] Starting with 3-amino-3-methyl-1-butanol (103 mg, 1.00 mmol), the title compound (68 mg, yield 62%) was obtained as an off- white solid analogous to the method described in example 443:
    [2311] HPLC / LCMS (RT): 5.26 min:
    [2312] MS (+ ve ESI): 546 (M + H) &lt; + &gt;.
    [2313] Example 519 - Preparation of compound No. 519 from Table 12
    [2314] Starting with isopropylamine (59 mg, 1.00 mmol), the title compound (76 mg, 76% yield) was obtained as an off-white solid analogous to the method described in example 443:
    [2315] HPLC / LCMS (RT): 5.26 min:
    [2316] MS (+ ve ESI): 502 (M + H) &lt; + &gt;.
    [2317] Example 520 - Preparation of compound No. 520 in Table 12
    [2318] Analogously to the procedure described in example 443, starting with 2-amino-1-propanol (75 mg, 1.00 mmol), the title compound (56 mg, yield 54%) was obtained as an off-white solid:
    [2319] HPLC / LCMS (RT): 5.17 min:
    [2320] MS (+ ve ESI): 518 (M + H) &lt; + &gt;.
    [2321] Example 521 - Preparation of compound No. 521 in Table 12
    [2322] The title compound (58 mg, 58% yield) was obtained as an off-white solid starting with cyclopropylamine (57 mg, 1.00 mmol), analogous to the method described in example 443:
    [2323] HPLC / LCMS (RT): 5.26 min:
    [2324] MS (+ ve ESI): 500 (M + H) &lt; + &gt;.
    [2325] Example 522 - Preparation of compound No. 522 from Table 12
    [2326] Starting with thiophene-2-methylamine (114 mg, 1.00 mmol), the title compound (55 mg, yield 50%) was obtained as an off-white solid analogous to the method described in example 443:
    [2327] HPLC / LCMS (RT): 5.48 min:
    [2328] MS (+ ve ESI): 556 (M + H) &lt; + &gt;.
    [2329] Example 523 - Preparation of compound No. 523 in Table 12
    [2330] The title compound (98 mg, 90% yield) was obtained as an off-white solid, starting with N-acetylethylenediamine (102 mg, 1.00 mmol), analogous to the method described for Example 443:
    [2331] HPLC / LCMS (RT): 5.21 min:
    [2332] MS (+ ve ESI): 545 (M + H) &lt; + &gt;.
    [2333] Example 524 - Preparation of compound No. 524 from Table 12
    [2334] The title compound (76 mg, 71% yield) was obtained as an off-white solid starting from 2- (methylthio) -ethylamine (92 mg, 1.00 mmol), analogous to the method described in example 443:
    [2335] HPLC / LCMS (RT): 5.32 min:
    [2336] MS (+ ve ESI): 534 (M + H) &lt; + &gt;.
    [2337] Example 525 - Preparation of compound No. 525 in Table 12
    [2338] The title compound (16 mg, 16% yield) was obtained as an off-white solid, starting with diethanolamine (0.5 ml), analogous to the method described in example 442:
    [2339]
    [2340] MS (+ ve ESI): 548 (M + H) &lt; + &gt;.
    [2341] Example 526 - Preparation of compound No. 526 in Table 13
    [2342] Di- t -butyl-N, N-diethylphosphoramide (0.42 ml, 1.51 mmol) was added to a solution of 4 - ((4- (N-benzoyl) amino) anilino) -6 methoxy (500 mg, 1.16 mmol) and tetrazole (244 mg, 0.348 mmol) was added dropwise over 2 minutes at ambient temperature. The reaction was stirred at ambient temperature for 1 hour, then di-t-butyl-N, N-diethylphosphoramide (0.42 ml, 1.51 mmol) was further added and stirred for a further 5 hours. (0.727 g of 70% active, 2.32 mmol) was added and the reaction stirred at ambient temperature for 30 minutes and then poured into water.
    [2343] The aqueous phase was extracted with dichloromethane (3 x 25 ml), then the solvent was evaporated in vacuo and the resulting yellow solid was triturated with diethyl ether to give the title compound (163 mg, yield 23%) as a light yellow solid:
    [2344]
    [2345] Example 527 - Preparation of compound No. 527 in Table 13
    [2346] Starting from dibenzyl-N, N-diethylphosphoramide (0.27 ml, 0.91 mmol), by analogy with the method described in example 526, the title compound (69 mg, yield 14%) was obtained as a pale yellow solid:
    [2347]
    [2348] Example 528 - Preparation of compound No. 528 from Table 13
    [2349] Trimethylsilyl bromide (0.325 ml, 2.46 mmol) was added to a solution of 4 - ((4- (N-benzoyl) amino) anilino) -6-methoxy- 7- (2- (dibenzyloxy) Phosphino) ethoxy) quinazoline (170 mg, 0.246 mmol) in dichloromethane (5 ml) and the reaction was stirred at ambient temperature for 16 h. The solvent was evaporated in vacuo, methanol (10 ml) was added and it was evaporated in vacuo.
    [2350] The residue was triturated with diethyl ether to give the title compound (125 mg, yield 100%) as a pale yellow solid after prolonged drying in vacuo:
    [2351]
    [2352] Example 529 - Preparation of compound No. 529 from Table 14
    [2353] (1 g, 3.45 mmol) was added to a solution of 4-amino (4-methylthio) (3.66 g, 17.2 mmol). After purification by flash chromatography on silica gel (elution with 5-10% methanol in dichloromethane), the title compound (850 mg, yield 54%) was obtained as a white solid:
    [2354]
    [2355] (4- (N-benzoyl) amino) anilino) -6-methoxy-7- (3-carboxyprop-1-enyl)) quinazoline used as a starting material was obtained in the following manner :
    [2356] A mixture of 4 - ((4- (N-benzoyl) amino) anilino) -6-methoxy-7- (trifluoromethanesulfonyloxy) quinazoline (3.04 g, 8.21 mmol), methyl acrylate 0.23 mmol), triethylamine (1.26 ml, 9.03 mmol) and palladium acetate (46 mg, 0.2 mmol) were dissolved in dimethylformamide (36 ml, ) At 100 &lt; 0 &gt; C for 1.5 hours under argon. The mixture was cooled, the solvent was evaporated in vacuo and hydrochloric acid (2.0 N) was added. The aqueous phase was extracted with dichloromethane, the organic phase was washed with brine, dried over magnesium sulfate and the solvent was evaporated in vacuo. Purification by flash chromatography on silica gel (eluting with 4% methanol in dichloromethane) afforded 4- (methylthio) -6-methoxy-7- (3-carbomethoxyprop- 1-enyl)) quinazoline 1.82 g, yield 76%) as a white solid:
    [2357]
    [2358] Example 530 - Preparation of compound No. 530 in Table 14
    [2359] A solution of sodium hydroxide (26mg, 0.66mmol) in water (0.5ml) was added to a solution of 4 - ((4- (N-benzoyl) amino) anilino) -6-methoxy- 7- (3-carbomethoxy) 1-enyl)) quinazoline (150 mg, 0.33 mmol) in tetrahydrofuran at 80 &lt; 0 &gt; C over 45 min. The solvent was evaporated in vacuo, water was added and the mixture was acidified to pH 2 with hydrochloric acid (2.ON). Collection of the solid by filtration under reduced pressure gave the title compound (135 mg, 93%) as a white solid:
    [2360]
    [2361] Example 531 - Preparation of compound No. 531 in Table 14
    [2362] 4- (Methylthio) -6-methoxy-7- (3-hydroxyprop-l-enyl) quinazoline (100 mg, 0.38 mmol) was added to a solution of 4- aminobenzanilide (405 mg, 1.91 mmol). The residue was purified by flash chromatography on silica gel (eluting with 5-10% methanol in dichloromethane) to give the title compound (66 mg, 40% yield) as a white solid:
    [2363]
    [2364] 4- (Methylthio) -6-methoxy-7- (3-hydroxyprop-1-enyl) quinazoline used as starting material was obtained by the following method:
    [2365] a) A solution of 6-methoxy-7-benzyloxy-3,4-dihydroquinazolin-4-one (50 g, 0.177 mol) in phosphorus oxychloride (95 g, 0.213 mol) in pyridine (2 L) Lt; / RTI &gt; The mixture was cooled, poured into water (6000 ml), solid roll filtered and washed with water. The solid was put into an aqueous sodium hydroxide solution (6N), the insoluble matter was removed by filtration, and the solution was acidified with hydrochloric acid (6N) to bring the pH to 2. The precipitate was filtered, washed with water and methanol, and dried over phosphorus pentoxide under vacuum to give 6-methoxy-7-benzyloxy-3,4-dihydroquinazoline-4-thione (42.8 g, yield 81%) .
    [2366]
    [2367] b) Sodium hydroxide (1.0 N, 200 ml) was added to a solution of 6-methoxy-7 benzyloxy-3,4-dihydroquinazolin-4-thione (30 g, 0.1 mol) in tetrahydrofuran , And methyl iodide (7.5 ml, 0.12 mol) were slowly added over 30 minutes at ambient temperature. The pH of the solution was then adjusted to 7 with hydrochloric acid (2.0 N), the reaction was diluted with water, and the solid was collected by vacuum filtration. Vacuum drying afforded 4- (methylthio) -6-methoxy-7-benzyloxyquinazoline (29.5 g, 94% yield)
    [2368]
    [2369] c) A solution of 4- (methylthio) -6-methoxy-7-benzyloxyquinazoline (29.5 g, 0.095 mol) in trifluoroacetic acid (250 ml) was heated to reflux for 3 hours. The mixture was cooled, water was added, and the pH was adjusted to 5 with sodium hydroxide (2.0 N). The solid was filtered, washed with water and diethyl ether, and dried in vacuo. The solids were redissolved in methanol (2000 ml) and water (500 ml), the pH was adjusted to 7 with sodium hydroxide (2.0 N) and the precipitated solids were collected by reduced pressure filtration. Vacuum drying afforded 4- (methylthio) -6-methoxy-7-hydroxy-quinazoline (19.18 g, yield 91%):
    [2370]
    [2371] d) To a solution of 4- (methylthio) -6-methoxy-7-hydroxyquinazoline (2.28 g, 10.3 mmol) and pyridine (0.91 ml) in dichloromethane (20 ml) was added triflic acid Was added slowly at 0 &lt; 0 &gt; C to a solution of the anhydride (1.9 ml, 11.3 mmol). The mixture was stirred at 0 &lt; 0 &gt; C for 40 min, then hydrochloric acid (0.5 N, 50 ml) was added and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and evaporated in vacuo.
    [2372] Purification by flash chromatography on silica gel (eluting with 1: 1 isohexane: ethyl acetate) afforded 4- (methylthio) -6-methoxy-7- (trifluoromethanesulfonyloxy) -quinazoline , Yield: 80%):
    [2373]
    [2374] e) A mixture of 4- (methylthio) -6-methoxy-7- (trifluoromethanesulfonyloxy) quinazoline (1.1 g, 3.1 mmol), E-3- (tributylstannyl A suspension of 1.12 g (3.23 mmol) bisdichloro (triphenylphosphine) palladium (44 mg, 0.06 mmol) and lithium chloride (395 mg, 9.32 mmol) Lt; / RTI &gt; The mixture was cooled to ambient temperature and the solid was recovered by vacuum filtration and washed with ether. Dried to obtain 4- (methylthio) -6-methoxy-7- (3-hydroxyprop-1-enyl) quinazoline (355 mg, yield 44%
    [2375]
    [2376] Example 532 - Preparation of compound No. 532 in Table 14
    [2377] Diisopropylethylamine (0.07 ml, 0.38 mmol) was added to a solution of 4 ((4- (N-benzoyl) amino) anilino) -6-methoxy- 7- (3- 1-enyl)) quinazoline (120 mg, 0.27 mmol), 1- (2-aminoethyl) piperidine (0.039 ml, 0.27 mmol) and 1- (3- dimethylaminopropyl) -3-ethylcarbodiimide Chloride (73 mg, 0.38 mmol) and the reaction was stirred at ambient temperature for 16 hours. The solvent was evaporated in vacuo to give the title compound (60 mg, 40% yield) after purification by reverse phase hplc:
    [2378]
    [2379] Example 533 - Preparation of compound No. 533 in Table 14
    [2380] 10% palladium supported on carbon (30 mg) was added to a solution of 4 - ((4- (N-benzoyl) amino) -anilino) -6- Was added to a solution of methoxy-7- (3-hydroxyprop-1-enyl) quinazoline (120 mg, 0.28 mmol) and the reaction stirred under hydrogen atmosphere (50 psi) And the solvent was evaporated in vacuo. Purification by flash chromatography on silica gel (eluting with 15% methanol in dichloromethane) gave the title compound (90 mg, 75% yield) as a white solid:
    [2381]
    [2382] Example 534 - Preparation of compound No. 534 from Table 14
    [2383] Starting with 1- (2-dimethylaminoethyl) piperazine (76 mg, 0.28 mmol) and purification by reverse phase preparative hplc, the title compound (41 mg, yield 25 %) As a white solid:
    [2384]
    [2385] Example 535 - Preparation of compound No. 535 of Table 14
    [2386] 4- (methylthio) -7- (3-hydroxy-3-methylbut-1-ynyl) quinazoline (240 mg, 0.93 mmol) was reacted with 4- aminobenzanilide g, 6.51 mmol). Purification by flash chromatography on silica gel (eluting with 5-15% methanol in dichloromethane) gave the title compound (344 mg, 88% yield) as a white solid:
    [2387]
    [2388] 4- (Methylthio) -7- (3-hydroxy-3-methylbut-1-ynyl) quinazoline used as starting material was obtained by the following method:
    [2389] a) Trifluoromethanesulfonic anhydride (0.96 ml, 5.73 mmol) and pyridine (0.46 ml, 5.73 mmol) were added to a solution of 7-benzyloxy-3,4-dihydroquinazoline-4-thione (1.0 g, 5.21 mmol) in DMF (5 mL) at O &lt; 0 &gt; C for 1.5 h. Then hydrochloric acid (0.5 N) was added to the mixture, which was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and the solvent removed in vacuo. 7- (methylthio) -7- (trifluoromethanesulfonyloxy) quinazoline (800 mg, yield 50%) was obtained as a colorless oil by purification by flash chromatography on silica gel (eluting with isohexane / ethyl acetate (1: Lt; / RTI &gt;
    [2390]
    [2391] b) Bisdichloro (triphenylphosphine) palladium (64 mg, 0.091 mmol) was added to a solution of 4- (methylthio) -7- (trifluoromethanesulfonyloxy) quinazoline (592 mg, 1.82 mmol) in dimethylformamide Methyl-3-butyn-2-ol (0.53 ml, 0.54 mmol) in the presence of copper (I) iodide . The solvent was removed in vacuo, an aqueous solution of hydrochloric acid (2N) was added, and the mixture was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate and the solvent was evaporated in vacuo. Purification by flash chromatography on silica gel eluting with isohexane / ethyl acetate (55:45) afforded 4- (methylthio) -7- (3-hydroxy-3-methylbut- 1 -yl) quinazoline 243 mg, yield 51%):
    [2392]
    [2393] Example 536 - Preparation of compound No. 536 from Table 14
    [2394] 4- (methylthio) -6-methoxy-7- (3-hydroxyprop-1-ynyl) quinazoline (120 mg, 0.461 mmol) was added in the absence of solvent at 140 &lt; 0 &gt; C for 1.5 h to 4-aminobenzanilide (490 mg, 2.31 mmol). Flash chromatography (elution with 7.5% methanol in dichloromethane) of the residue on silica gel gave the title compound (42 mg, 21% yield) as a white solid:
    [2395]
    [2396] 4- (Methylthio) -6-methoxy-7- (3-hydroxyprop-1-ynyl) quinazoline used as starting material was obtained by the following method:
    [2397] (Methylthio) -6- methoxy-7- (trifluoromethanesulfonyloxy) quinazoline (1.0 g, 2.82 mmol) in dimethylformamide (30 ml) was added to a solution of bisdichloro (triphenylphosphine) palladium Was reacted with propargyl alcohol (0.51 ml, 8.75 mmol) in the presence of copper (I) (40 mg) and triethylamine (1.7 ml, 0.0124 mmol) at 90 ° C under argon for 2.5 hours. The solvent was evaporated in vacuo, water and hydrochloric acid (2.0 N) were added and the mixture was extracted with ethyl acetate. (Methylthio) -6-methoxy-7- (3-hydroxyprop-1-ynyl) quinazoline (122 mg, Yield 17%): &lt; RTI ID = 0.0 &gt;
    [2398]
    [2399] Example 537 - Preparation of compound No. 537 from Table 14
    [2400] Iron powder (325 mesh, 730mg, 13mmol) was added to a solution of 4 - ((4- (N-benzoyl) amino) anilino) -7-nitroquinazoline , 1.3 mmol) was added several times at reflux for 1 h. The mixture was cooled to 50 &lt; 0 &gt; C and ammonia solution (28%, 5 ml) was added. The precipitate was collected by vacuum filtration, washed with warm ethanol and the solvent was evaporated in vacuo. (4- (N-benzoyl) amino) anilino) -7-aminoquinazoline (461 mg, yield 100%) was obtained by flash chromatography on silica gel (eluting with 5% methanol in dichloromethane) :
    [2401]
    [2402] 4 - ((4- (N-benzoyl) amino) anilino) -7-nitroquinazoline used as a starting material was obtained by the following method:
    [2403] A solution of 4-chloro-7-nitroquinazoline (500 mg, 2.38 mmol) in isopropanol (15 ml) was reacted with 4-aminobenzanilide (607 mg, 2.86 mmol) under reflux for 2 hours. The solid precipitated upon cooling was collected to give 4 - ((4- (N-benzoyl) amino) anilino) -7-nitroquinazoline (920 mg, yield 100%):
    [2404]
    [2405] Example 538 - Preparation of compound No. 538 from Table 14
    [2406] Isonicotinoyl chloride hydrochloride (95 mg, 0.507 mmol) was added to a solution of 4 - ((4- (N-benzoyl) amino) anilino) -7-aminoquinazoline (150 mg, 0.422 mmol) Amine (0.5ml) and the reaction was stirred at ambient temperature for 3 hours. The solvent was evaporated, water was added to the residue, the precipitate was filtered, washed with water and dried under vacuum.
    [2407] The resulting solid was triturated with methanol to give the title compound (66 mg, 33% yield) as a pale yellow solid:
    [2408]
    [2409] Example 539 - Preparation of compound No. 539 from Table 14
    [2410] The title compound (18 mg, yield 9%) was obtained as a white solid after purification by reverse phase preparative hplc, starting from 3- (1-piperidine) propionyl chloride (0.84 mmol) Obtained:
    [2411]
    [2412] Example 540 - Preparation of compound No. 540 in Table 14
    [2413] 7- (Methylthio) -7- (N-2-acetoxyacetyl) quinazoline (78 mg, 0.268 mmol) was heated with 4-aminobenzanilide at 150 <0> C for 1.5 h (without any additional solvent).
    [2414] Purification by flash chromatography on silica gel (eluting with 5% methanol in dichloromethane) gave the title compound (40 mg, 32% yield) as a white solid:
    [2415]
    [2416] 4- (Methylthio) -7- (N-2-acetoxyacetyl) quinazoline used as a starting material was obtained by the following method:
    [2417] a) Iron powder (325 mesh, 1.35 g, 52 mmol) was added to a solution of 4- (methylthio) -7-nitroquinazoline (1.44 g, 6.52 mmol) in ethanol (130 ml), water (65 ml) and acetic acid To the stirred solution was added several times over 1.5 hours under reflux. The mixture was cooled to 50 &lt; 0 &gt; C and ammonia solution (28%, 5 ml) was added. The precipitate was collected by vacuum filtration, washed with warm ethanol and the solvent was evaporated in vacuo. Purification by flash chromatography on silica gel (eluting with 5% methanol in dichloromethane) gave 4- (methylthio) -7-aminoquinazoline (1.17 g, 94% yield)
    [2418]
    [2419] b) Acetoxyacetyl chloride (0.093 ml, 0.864 mmol) was added to a solution of 4- (methylthio) -7-aminoquinazoline (150 mg, 0.785 mmol) and triethylamine (150 mg, 1.49 mmol) in pyridine At 0 &lt; 0 &gt; C, and the reaction was stirred for 1 hour. The solvent was evaporated in vacuo, water was added to the residue, the mixture was extracted with dichloromethane and evaporated in vacuo. (Methylthio) -7- (N-2-acetoxyacetyl) quinazoline (78 mg, yield 34%) was obtained as a white solid by flash chromatography on silica gel (eluting with 5% methanol in dichloromethane) Obtained:
    [2420]
    [2421] Example 541 - Preparation of compound No. 541 from Table 15
    [2422] The title compound (198 mg, 45% yield) was obtained as a beige solid starting from N- (4-hydroxyphenyl) benzenesulfonamide (299 mg, 1.20 mmol), analogous to the method described in example 99:
    [2423]
    [2424] The N- (4-hydroxyphenyl) benzenesulfonamide used as the starting material was obtained in the following manner:
    [2425] A solution of benzenesulfonyl chloride (2.54 ml, 20.0 mmol) in tetrahydrofuran (10 ml) was added dropwise at ambient temperature to a solution of 4-aminophenol (1.09 g, 10.0 mmol) in pyridine (20 ml) Stir for 18 hours. The reaction was poured into 2.ON hydrochloric acid (125 ml) and the aqueous phase was extracted with diethyl ether (3 x 50 ml). The collected organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution (100 ml), dried over magnesium sulfate and evaporated in vacuo. Vacuum drying afforded N- (4-hydroxyphenyl) benzenesulfonamide (694 mg, 28% yield) as a beige solid:
    [2426]
    [2427] Example 542 - Preparation of compound No. 542 from Table 15
    [2428] 4-aminophenyl) methanesulfonamide (128 mg, 0.59 mmol) and 4-chloro-6,7-dimethoxyquinazoline hydrochloride (154 mg, , 0.59 mmol), the title compound (122 mg, 51% yield) was obtained as an off-white solid:
    [2429]
    [2430] Example 543 - Preparation of compound No. 543 in Table 16
    [2431] A solution of n-butyl 4-aminobenzoate (103 mg, 0.535 mmol) in isopropanol (7 ml) was added to 4-chloro-6,7-dimethoxyquinazoline hydrochloride (140 mg, 0.535 mmol) After heating for 2 hours, it was cooled to 5 캜. The precipitated solid was collected by vacuum filtration and washed with diethyl ether (2 x 5 ml). The material was dried to give the title compound (149 mg, 73% yield) as an off-white solid:
    [2432]
    [2433] MS (+ ve ESI): 382 (M + H) &lt; + & gt ; .
    [2434] Example 544 - Preparation of compound No. 544 from Table 16
    [2435] Starting with 4-aminobenzophenone (90 mg, 0.46 mmol), by analogy with the method described in example 543, the title compound (116 mg, 66% yield) was obtained as a white solid:
    [2436]
    [2437] Example 545 - Preparation of compound No. 545 in Table 16
    [2438] (104 mg, 0.60 mmol), the title compound (122 mg, yield 56%) was obtained as a white solid: &lt;
    [2439]
    [2440] Example 546 - Preparation of compound No. 546 from Table 16
    [2441] Starting with 4-nitrophenyl-sulfonyl aniline (164 mg, 0.59 mmol), by analogy with the method described in example 543, the title compound (146 mg, yield 53%) was obtained as a white solid:
    [2442]
    [2443] Example 547 - Preparation of Compound No. 547 in Table 16
    [2444] The title compound (168 mg, 70% yield) was prepared in analogy to the procedure described in example 543, but starting from N- (2-cyanophenyl) -4-amino-2-chlorobenzamide (143 mg, 0.52 mmol) Obtained as a solid:
    [2445]
    [2446] MS (+ ve ESI): 460 (M + H) &lt; + &gt;.
    [2447] The N- (2-cyanophenyl) -4-amino-2-chlorobenzamide used as starting material was obtained by the following method:
    [2448] a) 2-Chloro-4-nitrobenzoic acid (6.00 g, 29.8 mmol) in thionyl chloride (20 ml) was heated to reflux for 2.5 h. The reaction was cooled, excess thionyl chloride was evaporated in vacuo and the residue was made into azeotropic mixture with toluene (2 x 25 ml). The residue was taken up in toluene (35 ml), 2-aminobenzonitrile (1.75 g, 14.8 mmol) was added and the reaction was heated to reflux for 2 hours. The reaction was cooled, the solvent was removed in vacuo and the residue was taken up in silica gel. Purification by flash chromatography on silica gel (elution with dichloromethane) gave N- (2-cyanophenyl) -2-chloro-4-nitrobenzamide (1.30 g, 27% yield) as a pale yellow solid:
    [2449] MS (+ ve CI): 322 (M + H) +.
    [2450] b) To a stirred solution of the tin (II) chloride dihydrate (4.42g, 23mmol) in N- (2-cyanophenyl) -2-chloro-4-nitrobenzamide (1.30g, 4.04mmol) At 0 &lt; 0 &gt; C. The reaction was allowed to warm to ambient temperature over 2 hours and aqueous sodium hydroxide solution was added to bring the pH of the reaction to 10.
    [2451] The aqueous layer was extracted with dichloromethane (3 x 50 ml) and the solvent was evaporated in vacuo to give N- (2-cyanophenyl) -4-amino-2-chlorobenzamide (0.19 g, yield 16%) as a white solid :
    [2452] MS (+ ve CI): 292 (M + H) +.
    [2453] Example 548 - Preparation of compound No. 548 from Table 16
    [2454] (438 mg, 2.00 mmol) and 4-chloro-6,7-dimethoxyquinazoline hydrochloride (458 mg, 2.00 mmol) in analogy to the method described in example 543, mmol), the title compound (389 mg, 46% yield) was obtained as a white solid:
    [2455]
    [2456] Example 549 - Preparation of compound No. 549 from Table 16
    [2457] The title compound (90 mg, yield 38%) was prepared starting from 4-amino-N- (4,5-dimethyl- ) As a white solid:
    [2458]
    [2459] Example 550 - Preparation of compound No. 550 in Table 16
    [2460] A solution of 4-chloro-6,7-dimethoxyquinazoline (224 mg, 1.00 mmol), potassium carbonate (152 mg, 1.10 mmol) and 4-hydroxybenzenesulfonamide (87 mg, 0.50 mmol) in dimethylformamide (4 ml) Was heated to 110 &lt; 0 &gt; C for 2 hours and then the reaction was cooled to ambient temperature. The reaction was poured into water and the precipitated solid was collected by vacuum filtration and washed with a mixture of diethyl ether (10 ml), ethyl acetate (10 ml) and isohexane (10 ml). Drying of the material gave the title compound (48 mg, yield 26%) as a white solid:
    [2461]
    [2462] Example 551 - Preparation of compound No. 551 in Table 16
    [2463] 4-Chloro-6,7-dimethoxyquinazoline (112 mg, 0.50 mmol) and potassium carbonate (69 mg, 0.50 mmol) were added to a solution of 4-hydroxy-2-methoxybenzaldehyde (76 mg, 0.50 mmol ) &Lt; / RTI &gt; The reaction was heated at 100 &lt; 0 &gt; C for 4 hours and then at ambient temperature for an additional 36 hours. Solids were collected by filtration under reduced pressure (the analogous reactants which did not form a solid precipitate were extracted with dichloromethane (2 x 5 ml) and the dichloromethane layer was evaporated under vacuum To obtain a solid product). Vacuum drying afforded the title compound (140 mg, 86% yield) as a white solid:
    [2464]
    [2465] Example 552 - Preparation of compound No. 552 in Table 16
    [2466] Starting with 4- (methylsulfonyl) -phenol (86 mg, 0.50 mmol), the title compound (143 mg, 82% yield) was obtained as a white solid analogous to the method described in example 551:
    [2467]
    [2468] Example 553 - Preparation of compound No. 553 in Table 16
    [2469] Starting with 4-hydroxybenzophenone (99 mg, 0.50 mmol), by analogy with the method described in example 551, the title compound (156 mg, 81% yield) was obtained as a white solid:
    [2470]
    [2471] Example 554 - Preparation of compound No. 554 in Table 16
    [2472] Starting with 3-ethoxy-4-hydroxybenzaldehyde (83 mg, 0.50 mmol), the title compound (159 mg, 90% yield) was obtained as a white solid analogous to the method described in example 551:
    [2473]
    [2474] Example 555 - Preparation of compound No. 555 in Table 16
    [2475] To a solution of 4- (4-carboxy) anilino) -6,7-dimethoxyquinazoline (100 mg, 0.28 mmol), 4- (dimethylamino) -pyridine (67 mg, 0.55 mmol) in dimethylacetamide (3.0 ml) A mixture of n-heptylamine (0.045 ml, 0.031 mmol) and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (58 mg, 0.31 mmol) was stirred at ambient temperature for 16 hours . The reaction was acidified by addition of 2.ON hydrochloric acid (7.0 ml, 14.0 mmol) and the precipitated solid was collected by vacuum filtration. Vacuum drying afforded the title compound (114 mg, 90% yield) as a white solid:
    [2476]
    [2477] 4- (4-carboxy) anilino) -6,7-dimethoxyquinazoline used as starting material was obtained by the following method:
    [2478] a) A solution of methyl 4-aminobenzoate (151 mg, 1.00 mmol) and 4-chloro-6,7dimethoxyquinazoline (224 mg, 1.00 mmol) in isopropanol (200 ml) was heated to reflux for 3 hours, And cooled to ambient temperature. The precipitated solid was collected by vacuum filtration and washed with diethyl ether (2 x 50 ml). This material was dried to give 4- (4-carbomethoxy) anilino) -6,7-dimethoxyquinazoline (363 mg, yield 97%) as a white solid:
    [2479]
    [2480] b) A solution of sodium hydroxide (2.ON, 2.0 ml, 4.0 mmol) was added to a solution of 4- (4-carboethoxy) anilino) -6,7-dimethoxyquinazoline (325 mg, 0.87 mmol) And the reaction was heated to reflux for 4 hours. The reaction was cooled to ambient temperature, acidified with 2.ON hydrochloric acid, and the solid material was collected by reduced pressure filtration. The solid was taken up in acetone (20 ml), precipitated by addition of diethyl ether (20 ml), and collected by filtration under reduced pressure. Drying in vacuo afforded 4- (4- (2-carboxy) ethenyl) anilino-6,7-dimethoxyquinazoline (296 mg, 94% yield) as a white solid:
    [2481]
    [2482] MS (+ ve ESI): 326 (M + H) &lt; + &gt;.
    [2483] Example 556 - Preparation of compound No. 556 from Table 16
    [2484] To a solution of (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (63 mg, 0.33 mmol) and 4- (dimethylamino) pyridine (73 mg, 0.60 mmol) in dimethylacetamide The solution was added to 3-methoxypropylamine (29 mg, 0.33 mmol) and 4- (4-carboxy) anilino) -6,7-dimethoxyquinazoline (108 mg, 0.30 mmol). The reaction was stirred at ambient temperature for 48 hours, then heated at 100 &lt; 0 &gt; C for 4 hours and then cooled to ambient temperature. After brine (10 ml) was added and the reaction was allowed to stand for 16 h, the solid was collected by vacuum filtration (similar reactions that failed to obtain solid precipitate were extracted with dichloromethane (2 x 5 ml) and the dichloromethane layer was evaporated in vacuo Solid product was obtained). Vacuum drying afforded the title compound (66.3 mg, 56% yield) as a white solid:
    [2485]
    [2486] Example 557 - Preparation of compound No. 557 in Table 16
    [2487] Starting with 4-fluorobenzylamine (41 mg, 0.33 mmol), by analogy with the method described in example 556, the title compound (117.6 mg, 91% yield) was obtained as a white solid:
    [2488]
    [2489] MS (+ ve ESI): 443 (M + H) &lt; + & gt ; .
    [2490] Example 558 - Preparation of compound No. 558 from Table 16
    [2491] The title compound (127.7 mg, 98% yield) was obtained as a white solid starting from cyclohexenyl ethylamine (41 mg, 0.33 mmol), analogous to the procedure described in example 556:
    [2492]
    [2493] Example 559 - Preparation of compound No. 559 of Table 16
    [2494] The title compound (114.2 mg, 88% yield) was obtained as a white solid starting from 2- (aminoethyl) -thiophene (42 mg, 0.33 mmol), analogous to the procedure described in example 556:
    [2495]
    [2496] Example 560 - Preparation of compound No. 560 in Table 16
    [2497] The title compound (115.7 mg, 95% yield) was obtained as a white solid starting from 2,2,2-trifluoroethylamine hydrochloride (33 mg, 0.33 mmol), analogous to the procedure described in example 556:
    [2498]
    [2499] Example 561 - Preparation of compound No. 561 in Table 16
    [2500] The title compound (101.2 mg, 85% yield) was obtained as a white solid starting from 2- (methylthio) -ethylamine (30 mg, 0.33 mmol), analogous to the procedure described in example 556:
    [2501]
    [2502] Example 562 - Preparation of compound No. 562 from Table 16
    [2503] Analogous to the procedure described in example 556 but starting with 1-aminoindane (44 mg, 0.33 mmol), the title compound (107 mg, 81% yield) was obtained as a white solid:
    [2504]
    [2505] Example 563 - Preparation of compound No. 563 in Table 16
    [2506] Starting with cyclohexylamine (33 mg, 0.33 mmol), by analogy with the method described in example 556, the title compound (81.8 mg, 67% yield) was obtained as a white solid:
    [2507]
    [2508] Example 564 - Preparation of compound No. 564 from Table 16
    [2509] Starting with (aminomethyl) cyclohexane (37 mg, 0.33 mmol), by analogy with the method described in example 556, the title compound (96.7 mg, 77% yield) was obtained as a white solid:
    [2510]
    [2511] Example 565 - Preparation of compound No. 565 of Table 16
    [2512] 556, but starting with 5-amino-2-chloropyridine (42 mg, 0.33 mmol) the title compound (120.8 mg, 92% yield) was obtained as a white solid:
    [2513]
    [2514] Example 566 - Preparation of compound No. 566 from Table 16
    [2515] Starting with 4-nitrobenzylamine hydrochloride (50 mg, 0.33 mmol), by analogy with the method described in example 556, the title compound (134.4 mg, yield 98%) was obtained as a white solid:
    [2516]
    [2517] Example 567 - Preparation of compound No. 567 in Table 16
    [2518] The title compound (112.9 mg, 92% yield) was obtained as a white solid starting from 2-amino-l, 3,4-thiadiazole (33 mg, 0.33 mmol), analogous to the procedure described in example 556:
    [2519]
    [2520] Example 568 - Preparation of compound No. 568 from Table 16
    [2521] Starting from 2-aminopyridine (31 mg, 0.33 mmol), by analogy with the method described in Example 556, the title compound (73.8 mg, yield 61%) was obtained as a white solid:
    [2522]
    [2523] Example 569 - Preparation of compound No. 569 from Table 16
    [2524] Starting from 1-aminoisoquinoline (48 mg, 0.33 mmol), by analogy with the method described in example 556, the title compound (84.1 mg, 62% yield) was obtained as a white solid:
    [2525]
    [2526] Example 570 - Preparation of compound No. 570 in Table 16
    [2527] Starting with 5 amino-2-nitrobenzotrifluoride (68 mg, 0.33 mmol), the title compound (19.9 mg, yield 13%) was obtained as a white solid analogous to the method described in example 556:
    [2528]
    [2529] Example 571 - Preparation of compound No. 571 of Table 16
    [2530] Starting with 1,3-dimethylbutylamine (33 mg, 0.33 mmol), the title compound (66.9 mg, 55% yield) was obtained as a white solid analogous to the method described in example 556:
    [2531]
    [2532] Example 572 - Preparation of compound No. 572 in Table 16
    [2533] (3.90 g, 20.0 mmol) and 4-aminobenzoic acid (2.90 g, 21.2 mmol) in isopropanol (100 ml) &Lt; / RTI &gt; and the reaction was cooled to ambient temperature. The precipitated solid was collected by infected filtration and washed with diethyl ether (2 x 50 ml). This material was dried to give the title compound (9.08 g, 89% yield) as a white solid:
    [2534]
    [2535] Example 573 - Preparation of compound No. 573 in Table 16
    [2536] (3-morpholinopropoxy) quinazoline (168 g, 0.50 mmol) and 4-chloro-6-methoxy-7- (3-morpholinoproxy) quinazoline analogously to the method described in example 543 but using isopropanol , 0.50 mmol), the title compound (231 mg, 98% yield) was obtained as a white solid:
    [2537]
    [2538] Example 574 - Preparation of compound No. 574 in Table 16
    [2539] The title compound (123 mg, yield 85%) was prepared starting from N- (5-methoxypyrimidin-2- yl) -4-aminobenzenesulfonamide (60 mg, 0.24 mmol), analogous to the method described in example 543, ) As a white solid:
    [2540]
    [2541] Example 575 - Preparation of compound No. 575 of Table 16
    [2542] 4-aminobenzenesulfonamide (57 mg, 0.24 mmol), the title compound (138 mg, yield 99%) was obtained in analogy to the method described in example 543, but starting from N- (4,5- %) As a white solid:
    [2543]
    [2544] Example 576 - Preparation of compound No. 576 in Table 1
    [2545] 4-aminobenzenesulfonamide (57 mg, 0.24 mmol), the title compound (45 mg, yield 36%) was obtained as white crystals from N- %) As a white solid:
    [2546]
    [2547] Example 577 - Preparation of compound No. 577 of Table 16
    [2548] After refluxing for 3 hours 4-chloro-6-methoxy-7-benzyloxyquinazoline (150 mg, 0.50 mmol) and 4-aminobenzamide (68 mg, 0.50 mmol) in isopropanol (200 ml) Lt; / RTI &gt; The precipitated solid was collected by vacuum filtration and washed with diethyl ether (2 x 50 ml). This material was dried to give the title compound (196 mg, 90% yield) as an off-white solid:
    [2549]
    [2550] Example 578 - Preparation of compound No. 578 from Table 16
    [2551] (150 mg, 0.50 mmol) and 4-aminobenzophenone (99 mg, 0.50 mmol) in isopropanol (200 ml) were heated to reflux for 3 hours , The reaction was cooled to ambient temperature. The precipitated solid was collected by vacuum filtration and washed with diethyl ether (2 x 50 ml). This material was dried to give the title compound (233 mg, 94% yield) as an off-white solid:
    [2552]
    [2553] Example 579 - Preparation of compound No. 579 in Table 16
    [2554] 4-chloro-4'-fluorobenzophenone (777 mg, 3.11 mmol) and 4-chloro-6-methoxy-7- (2,2,2 -Trifluoroethoxy) quinazoline (932 g, 2.83 mmol), the title compound (1.10 g, 77% yield) was obtained as a white solid:
    [2555]
    [2556] Example 580 - Preparation of compound No. 580 of Table 16
    [2557] N, N, N ', N'-tetramethyluronium hexafluorophosphate (HATU) (192 mg, 0.50 mmol) was dissolved in dimethylformamide (4.5 ml) Was added to a suspension of 4- (4-carboxyphenyl) -6-methoxy-7- (3-morpholinopropoxy) quinazoline (232 mg, 0.50 mmol). After 5 min, cyclopentylamine (42.8 mg, 0.50 mmol) was added and the reaction was heated at 50 &lt; 0 &gt; C for 16 h. The reaction was cooled, poured into water (10 ml) and diethyl ether (5 ml) was added. The precipitated solid was collected by reduced pressure filtration and washed with water (10 ml) and diethyl ether (10 ml). The solid was vacuum dried to give the title compound (63.4 mg, 28% yield) as a white solid:
    [2558]
    [2559] Example 581 - Preparation of compound No. 581 from Table 16
    [2560] Starting from cyclohexylamine (49.8 mg, 0.50 mmol), by analogy with the method described in example 580, the title compound (65.8 mg, 28% yield) was obtained as a white solid:
    [2561]
    [2562] Example 582 - Preparation of compound No. 582 from Table 16
    [2563] Starting with cyclohexylmethylamine (56.9 mg, 0.50 mmol), by analogy with the method described in example 580, the title compound (158.8 mg, 66% yield) was obtained as a white solid:
    [2564]
    [2565] Example 583 - Preparation of compound No. 583 in Table 16
    [2566] Starting with 5-amino-2-chloropyridine (64.6 mg, 0.50 mmol), the title compound (215 mg, 86% yield) was obtained as a white solid analogous to the method described for example 580:
    [2567]
    [2568] Example 584 - Preparation of compound No. 584 from Table 16
    [2569] Starting with furfurylamine (48.8 mg, 0.50 mmol), by analogy with the method described in example 580, the title compound (147 mg, 63% yield) was obtained as a white solid:
    [2570]
    [2571] Example 585 - Preparation of compound No. 585 in Table 16
    [2572] Starting from tetrahydrofurfurylamine (50.8 mg, 0.50 mmol), by analogy with the method described in example 580, the title compound (45.9 mg, 19% yield) was obtained as a white solid:
    [2573]
    [2574] Example 586 - Preparation of compound No. 586 from Table 16
    [2575] Starting from 2-aminopyridine (47.3 mg, 0.50 mmol), by analogy with the method described in example 580, the title compound (72.5 mg, 31% yield) was obtained as a white solid:
    [2576]
    [2577] Example 587 - Preparation of compound No. 587 from Table 16
    [2578] Starting from 3-aminopyridine (47.3 mg, 0.50 mmol), by analogy with the method described in example 580, the title compound (204 mg, 88% yield) was obtained as a white solid:
    [2579]
    [2580] Example 588 - Preparation of compound No. 588 from Table 16
    [2581] Starting with 1,3-dimethylbutylamine (50.9 mg, 0.50 mmol), by analogy with the method described in example 580, the title compound (32.2 mg, yield 14%) was obtained as a white solid:
    [2582]
    [2583] Example 589 - Preparation of compound No. 589 from Table 16
    [2584] Starting with 2,2,2-trifluoroethylamine hydrochloride (67.8 mg, 0.50 mmol), the title compound (173.6 mg, 74% yield) was obtained as a white solid analogous to the procedure described in example 580, :
    [2585]
    [2586] Example 590 - Preparation of compound No. 590 of Table 16
    [2587] Starting with 3-ethoxypropylamine (51.8 mg, 0.50 mmol), by analogy with the method described in example 580, the title compound (31.8 mg, 13% yield) was obtained as a white solid:
    [2588]
    [2589] Example 591 - Preparation of compound No. 591 from Table 16
    [2590] Starting with 3- (methylthio) propylamine (52.9 mg, 0.50 mmol), by analogy with the method described in example 580, the title compound (143 mg, yield 60%) was obtained as a white solid:
    [2591]
    [2592] Example 592 - Preparation of compound No. 592 from Table 16
    [2593] Analogous to the procedure described in example 580 but starting with 2-amino-1-methoxypropane (44.8 mg, 0.50 mmol), the title compound (11.8 mg, yield 5%) was obtained as a white solid:
    [2594]
    [2595] Example 593 - Preparation of compound No. 593 from Table 16
    [2596] Starting with 3-methylcyclohexylamine (56.9 mg, 0.50 mmol), the title compound (160 mg, 66% yield) was obtained as a white solid analogous to the method described in example 580:
    [2597]
    [2598] Example 594 - Preparation of compound No. 594 from Table 16
    [2599] The title compound (222 mg, 88% yield) was obtained as a white solid starting from 2-aminoindane (66.9 mg, 0.50 mmol), analogous to the method described in example 580:
    [2600]
    [2601] Example 595 - Preparation of compound No. 595 in Table 16
    [2602] Starting with cyclohexenyl-ethylamine (62.9 mg, 0.50 mmol), by analogy with the method described in example 580, the title compound (120 mg, 48% yield) was obtained as a white solid:
    [2603]
    [2604] Example 596 - Preparation of compound No. 596 from Table 16
    [2605] Starting with 2-thiophenethylamine (63.9 mg, 0.50 mmol), by analogy with the method described in example 580, the title compound (207 mg, 83% yield) was obtained as a white solid:
    [2606]
    [2607] Example 597 - Preparation of compound No. 597 from Table 1
    [2608] Starting with 5-methyl-2- (aminomethyl) furan (55.9 mg, 0.50 mmol), the title compound (203 mg, 84% yield) was obtained as a white solid analogous to the method described in example 580:
    [2609]
    [2610] Example 598 - Preparation of compound No. 598 from Table 16
    [2611] The title compound (217 mg, 86% yield) was obtained as a white solid (yield: 86%), starting with 3-aminotetrahydrothiophene-S, S-dioxide dihydrochloride (104.5 mg, 0.50 mmol) Lt; / RTI &gt;
    [2612]
    [2613] Example 599 - Preparation of compound No. 599 from Table 16
    [2614] Starting from 2-methylpentylamine (33 mg, 0.33 mmol), by analogy with the method described in example 556, the title compound (59 mg, 43% yield) was obtained as a white solid:
    [2615]
    [2616] Example 600 - Preparation of compound No. 600 in Table 16
    [2617] Analogously to the procedure described in example 556, starting with 3-ethoxypropylamine (34 mg, 0.33 mmol), the title compound (95 mg, yield 70%) was obtained as a white solid:
    [2618]
    [2619] Example 601 - Preparation of compound No. 601 from Table 16
    [2620] Starting from 3- (methylthio) propylamine (35 mg, 0.33 mmol), by analogy with the method described in example 556, the title compound (83 mg, yield 61%) was obtained as a white solid:
    [2621]
    [2622] Example 602 - Preparation of compound No. 602 from Table 16
    [2623] Starting from hexylamine (33 mg, 0.33 mmol), by analogy with the method described in example 556, the title compound (74 mg, yield 54%) was obtained as a white solid:
    [2624]
    [2625] Example 603 - Preparation of compound No. 603 from Table 16
    [2626] A solution of 1.ON hydrochloric acid in ether (0.50ml, 0.50mmol) was added to a solution of 4-aminobenzamide (78mg, 0.50mmol) and 4- chloro-6-methoxy- 7- (3- ) -Quinazoline &lt; / RTI &gt; (168 mg, 0.50 mmol) in tetrahydrofuran. The reaction was heated at 40 &lt; 0 &gt; C for 30 minutes and then at 83 &lt; 0 &gt; C for 12 hours. The reaction was cooled to ambient temperature and the precipitated solids were collected by reduced pressure filtration and washed with diethyl ether (2 x 10 ml). This material was dried to give the title compound (222 mg, 94% yield) as a white solid:
    [2627]
    [2628] Example 604 - Preparation of compound No. 604 from Table 16
    [2629] The title compound (279 mg, 92% yield) was prepared in analogy to the procedure described in example 603 but starting from N- (4,5-dimethyloxazol-2-yl) sulfanylamide (135 mg, 0.50 mmol) Obtained as a solid:
    [2630]
    [2631] Example 605 - Preparation of compound No. 605 of Table 16
    [2632] Starting with 4-amino-2,4'-dichlorobenzophenone (133 mg, 0.50 mmol), the title compound (296 mg, yield 98%) was obtained as a white solid analogous to the method described in example 603:
    [2633]
    [2634] Example 606 - Preparation of compound No. 606 from Table 16
    [2635] The title compound (283 mg, 97% yield) was obtained as a white solid starting from the sulfanilanilide (129 mg, 0.50 mmol), analogous to the procedure described for Example 603:
    [2636]
    [2637] Example 607 - Preparation of compound No. 607 from Table 16
    [2638] Starting from 4-aminobenzophenone (99 mg, 0.50 mmol), by analogy with the method described in example 603, the title compound (244 mg, 91% yield) was obtained as a white solid:
    [2639]
    [2640] MS (+ ve ESI): 499 (M + H) &lt; + &gt;.
    [2641] Example 608 - Preparation of compound No. 608 from Table 16
    [2642] Starting with 4- (4-nitrophenylsulfonyl) aniline (139 mg, 0.50 mmol), the title compound (289 mg, 94% yield) was obtained as a white solid analogous to the method described in example 603:
    [2643]
    [2644] Example 609 - Preparation of compound No. 609 from Table 16
    [2645] A solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI) (106 mg, 0.55 mmol) and 4- (dimethylamino) pyridine (190 mg, 1.55 mmol) in dimethylacetamide Was reacted with 4- (4-carboxyanilino) -6-methoxy-7- (3-morpholinopropoxy) quinazoline dihydrochloride (see Example 29) (256 mg, 0.17 mmol) (0.063 ml, 0.50 mmol) and the reaction was stirred at ambient temperature for 18 hours. The reaction was poured into water (15 ml) and the precipitated solid material was collected by vacuum filtration. Vacuum drying afforded the title compound (247 mg, 85% yield) as a light brown solid:
    [2646]
    [2647] Example 610 - Preparation of compound No. 610 from Table 16
    [2648] (2-methylthio) -ethylamine (40 mg, 0.44 mmol) and 4- (4- carboxy) anilino) -6-methoxy-7- , 2-trifluoroethoxy) -quinazoline (157 mg, 0.4 mmol), the title compound (147 mg, 79% yield) was obtained as a white solid:
    [2649] HPLC / LCMS (RT): 2.11 min:
    [2650] MS (+ ve ESI): 467 (M + H) &lt; + & gt ; .
    [2651] 4 - ((4-carboxy) anilino) -6-methoxy-7- (2,2,2-trifluoroethoxy) quinazoline used as starting material was obtained by the following method:
    [2652] A mixture of 4-chloro-6-methoxy-7- (2,2,2-trifluoroethoxy) quinazoline (3.8 g, 13 mmol) and 4-aminobenzoic acid (1.78 g, 13 mmol) was dissolved in ethylene glycol dimethyl ether (DME) (75 ml) at 60 &lt; 0 &gt; C for 3 hours. The reaction was cooled and the precipitated light yellow solid was collected by reduced pressure filtration. Dried to obtain 4 - ((4-carboxy) anilino) -6-methoxy-7- (2,2,2-trifluoroethoxy) quinazoline (5.37 g, yield 96%) as a pale yellow solid :
    [2653]
    [2654] Example 611 - Preparation of compound No. 611 of Table 16
    [2655] Starting from cyclopentylamine (37 mg, 0.44 mmol), by analogy with the method described in example 610, the title compound (45 mg, 25% yield) was obtained as a white solid:
    [2656] HPLC / LCMS (RT): 2.23 min:
    [2657] MS (+ ve ESI): 461 (M + H) &lt; + & gt ; .
    [2658] Example 612 - Preparation of compound No. 612 from Table 16
    [2659] Starting with cyclohexylamine (44 mg, 0.44 mmol), the title compound (78 mg, 41% yield) was obtained as a white solid analogous to the method described in example 610:
    [2660] HPLC / LCMS (RT): 2.38 min:
    [2661] MS (+ ve ESI): 475 (M + H) &lt; + & gt ; .
    [2662] Example 613 - Preparation of compound No. 613 in Table 16
    [2663] Analogously to the procedure described in example 610, but starting with 5-amino-2-chloropyridine (56 mg, 0.44 mmol), the title compound (188 mg, 94% yield) was obtained as a white solid:
    [2664] HPLC / LCMS (RT): 2.39 min:
    [2665] MS (+ ve ESI): 504 (M + H) &lt; + & gt ; .
    [2666] Example 614 - Preparation of compound No. 614 in Table 16
    [2667] Starting from tetrahydrofurfurylamine (44 mg, 0.44 mmol), by analogy with the method described in example 610, the title compound (140 mg, 74% yield) was obtained as a white solid:
    [2668] HPLC / LCMS (RT): 1.98 min:
    [2669] MS (+ ve ESI): 477 (M + H) &lt; + & gt ; .
    [2670] Example 615 - Preparation of compound No. 615 in Table 16
    [2671] Starting with 4- (2-aminoethyl) -morpholine (57 mg, 0.44 mmol), the title compound (169 mg, 84% yield) was obtained as a white solid analogous to the procedure described in example 610:
    [2672] HPLC / LCMS (RT): 1.51 min:
    [2673] MS (+ ve ESI): 506 (M + H) &lt; + & gt ; .
    [2674] Example 616 - Preparation of compound No. 616 in Table 16
    [2675] Starting from 2-aminopyridine (41 mg, 0.44 mmol), by analogy with the method described in example 610, the title compound (80 mg, 43% yield) was obtained as a white solid:
    [2676] HPLC / LCMS (RT): 2.05 min:
    [2677] MS (+ ve ESI): 470 (M + H) &lt; + & gt ; .
    [2678] Example 617 - Preparation of compound No. 617 in Table 16
    [2679] Analogously to the procedure described in example 610, but starting with 3-aminopyridine (41 mg, 0.44 mmol), the title compound (173 mg, 92% yield) was obtained as a white solid:
    [2680] HPLC / LCMS (RT): 1.83 min:
    [2681] MS (+ ve ESI): 470 (M + H) &lt; + & gt ; .
    [2682] Example 618 - Preparation of compound No. 618 from Table 16
    [2683] Starting with 1,3-dimethylbutylamine (44 mg, 0.44 mmol), by analogy with the method described in example 610, the title compound (47 mg, 25% yield) was obtained as a white solid:
    [2684] HPLC / LCMS (RT): 2.47 min:
    [2685] MS (+ ve ESI): 477 (M + H) &lt; + & gt ; .
    [2686] Example 619 - Preparation of compound No. 619 from Table 16
    [2687] Starting with 2,2,2-trifluoroethylamine hydrochloride (60 mg, 0.44 mmol), the title compound (111 mg, yield 59%) was obtained as a white solid analogous to the method described in example 610:
    [2688] HPLC / LCMS (RT): 2.16 min:
    [2689] MS (+ ve ESI): 475 (M + H) &lt; + & gt ; .
    [2690] Example 620 - Preparation of compound No. 620 in Table 16
    [2691] Starting with 3-amino-1,2-propanediol (40 mg, 0.44 mmol), by analogy with the method described in example 610, the title compound (16 mg, Yield 9%) was obtained as a white solid:
    [2692] HPLC / LCMS (RT): 1.71 min:
    [2693] MS (+ ve ESI): 467 (M + H) &lt; + & gt ; .
    [2694] Example 621 - Preparation of compound No. 621 from Table 16
    [2695] Starting with 2-methyl-1-amyl amine (40 mg, 0.44 mmol), the title compound (78 mg, 41% yield) was obtained as a white solid analogous to the method described in example 610:
    [2696] HPLC / LCMS (RT): 2.53 min:
    [2697] MS (+ ve ESI): 477 (M + H) &lt; + & gt ; .
    [2698] Example 622 - Preparation of compound No. 622 from Table 16
    [2699] Starting from 3-dimethylaminopropylamine (45 mg, 0.44 mmol), by analogy with the method described in example 610, the title compound (14 mg, yield 8%) was obtained as a white solid:
    [2700] HPLC / LCMS (RT): 1.49 min:
    [2701] MS (+ ve ESI): 478 (M + H) &lt; + & gt ; .
    [2702] Example 623 - Preparation of compound No. 623 from Table 16
    [2703] Starting from 3-ethoxypropylamine (45 mg, 0.44 mmol), by analogy with the method described in example 610, the title compound (116 mg, 61% yield) was obtained as a white solid:
    [2704] HPLC / LCMS (RT): 2.16 min:
    [2705] MS (+ ve ESI): 479 (M + H) &lt; + & gt ; .
    [2706] Example 624 - Preparation of compound No. 624 from Table 16
    [2707] Starting with 3-methylcyclohexylamine (50 mg, 0.44 mmol), the title compound (132 mg, 68% yield) was obtained as a white solid analogous to the procedure described in example 610:
    [2708] HPLC / LCMS (RT): 2.59 min: MS (+ ve ESI): 489 (M + H) <+> .
    [2709] Example 625 - Preparation of compound No. 625 from Table 16
    [2710] Analogously to the procedure described in example 610, but starting with 2-aminoindane (59 mg, 0.44 mmol), the title compound (193 mg, 95% yield) was obtained as a white solid:
    [2711] HPLC / LCMS (RT): 2.53 min: MS (+ ve ESI): 509 (M + H) <+> .
    [2712] Example 626 - Preparation of compound No. 626 from Table 16
    [2713] Starting with cyclohexenylethylamine (55 mg, 0.44 mmol), the title compound (180 mg, 90% yield) was obtained as a white solid, analogous to the procedure described in Example 610:
    [2714] HPLC / LCMS (RT): 2.67 min: MS (+ ve ESI): 521 (M + H) + .
    [2715] Example 627 - Preparation of compound No. 627 from Table 16
    [2716] The title compound (131 mg, 65% yield) was obtained as a white solid starting from 2-thiophenethylamine (56 mg, 0.44 mmol), analogous to the procedure described in example 610:
    [2717] HPLC / LCMS (RT): 2.39 min: MS (+ ve ESI): 503 (M + H) <+> .
    [2718] Example 628 - Preparation of compound No. 628 from Table 16
    [2719] Analogously to the procedure described in example 610, starting with 2- (2-aminoethyl) -1-methylpyrrolidine (56 mg, 0.44 mmol), the title compound (50 mg, yield 25%) was obtained as an off- white solid :
    [2720] HPLC / LCMS (RT): 1.48 min: MS (+ ve ESI): 504 (M + H) <+> .
    [2721] Biological data
    [2722] The compounds of the present invention inhibit the serine / threonine kinase activity of Aurora 2 kinase and thus inhibit cell cycle and cell proliferation. These properties can be evaluated, for example, using one or more of the following disclosed procedures:
    [2723] (a) In vivo Aurora-2 kinase inhibition test
    [2724] This assay determines the performance of test compounds for inhibition of serine / threonine kinase activity. Aurora 2 coding DNA can be obtained by total gene synthesis or cloning. The DNA can then be expressed in a suitable expression system to yield a polypeptide having serine / threonine kinase activity. For Aurora 2, the coding sequence was isolated from the cDNA by polymerase chain reaction (PCR) and cloned into the BamHl and Notl restriction endonuclease sites of the baculovirus expression vector pFastBac HTc (GibcoBRL / Life Technologies). The 5 'PCR primer contained a recognition sequence for the restriction enzyme BamHI 5' to the Aurora 2 coding sequence. This allows the Aurora-2 gene to be inserted into the frame with six histidine residues, a spacer region and an rTEV protease cleavage site encoded by the pFastBac HTc vector. The 3'PCR primer replaces the aurora 2 termination codon with an additional coding sequence followed by the termination codon and recognition sequence for the restriction enzyme Notl. This additional coding sequence (5 'TAC CCA TAC GAT GTT CCA GAT TAC GCT TCT TAA 3') encodes the polypeptide sequence YPYDVPDYAS. This sequence derived from the influenza hemagglutin protein is often used as a tag epitope that can be identified using specific monoclonal antibodies. Thus, the recombinant pFastBac vector codes for the Aurora 2 protein, which is 6-histected to the N-terminus and tagged with the influenza hemagglutinin epitope to the C-terminus. A detailed description of methods for assembly of recombinant DNA molecules can be found in standard textbooks such as Sambrook et al., 1989, Molecular Cloning-A Laboratory Manual, 2nd Edition, Cold Spring Harbor Laboratory press and Ausubel et al., 1999, in Molecular Biology, John Wiley and Sons Inc.).
    [2725] Generation of the recombinant virus can be done according to the manufacturer's protocol from GibcoBRL. In summary, the pFastBac-1 vector carrying the aurora 2 gene is transformed into E. coli DH10Bac cells containing the bacmid virus genome, and through the transposition process in the cell, the gentamycin resistance One part of the Aurora 2 gene including the pFastBac vector containing the gene and the baculovirus polyhedrin promoter was directly transferred to the bacmid DNA. By selection for gentamycin, kanamycin, tetracycline and X-gal, the resulting white colonies contain Aurora-2 coding recombinant bacmid DNA. Bacmid DNA was extracted from small scale cultures of several BH10Bac white colonies, and Spodoptera frugiperda grown on TC100 medium (GibcoBRL) containing 10% serum using CellFECTIN reagent (GibcoBRL) according to the manufacturer's instructions. Sf21 cells. After 72 hours of transfection, the cell culture medium was collected to obtain viral particles. 0.5 mls of medium was used to infect 100 ml suspension culture of Sf21s containing 1 x 10 7 cells / ml. Cell culture medium was obtained 48 hours after infection and viral titers were determined using standard plaque assay methods. Virus stocks were used to infect Sf9 and " High 5 " cells at multiplicity of infection (MOI) 3 to confirm the expression of recombinant Aurora 2 protein.
    [2726] For large scale expression of Aurora 2 kinase activity, Sf21 infected cells were cultured in TC100 medium supplemented with 10% fetal bovine serum (Viralex) and 0.2% F68 Pluronic on Wheaton roller rig at 3 rpm 0.0 &gt; 28 C. &lt; / RTI &gt; When the cell density reached 1.2 x 106 cells ml -1 , it was infected with a multiplicity of infection 1 with a plaque-pure Aurora 2 recombinant virus and was obtained after 48 hours. All subsequent purification steps were performed at 4 &lt; 0 &gt; C. The frozen infected cell pellet containing 2.0 x 10 &lt; 8 &gt; total cells was thawed and lysed in a lysis buffer (25 mM HEPES (N- [2-hydroxyethyl] piperazine-N '- [2- ethanesulfonic acid]) pH7 .4 (4 ℃), 100mM KCl , 25mM NaF, 1mM Na 3 VO 4, 1mM PMSF ( phenylmethylsulfonyl fluoride), 2mM 2- mercaptoethanol, 2mM imidazole, 1㎍ / ml aprotinin, 1㎍ / ml pepstatin, and diluted using 1㎍ / ml leupeptin} to cell 3 x 10 7 1.0ml per. After cell lysis using a dounce homogenizer, the cell lysate was centrifuged at 41,000 g for 35 minutes. The supernatant was pumped into a 5 mm diameter chromatography column containing 500 μl Ni NTA (nitrilo-tri-acetic acid) agarose (Qiagen, Product No. 30250) equilibrated in the cell lysate. The column was washed with 12 ml of cell lysate and then washed with 7 ml of washing buffer (25 mM HEPES pH 7.4, 4 캜, 100 mM KCl, 20 mM imidazole, 2 mM 2-mercaptoethanol) and reached the baseline of UV absorption for the eluent Respectively. Bound Aurora 2 protein was eluted from the column using elution buffer (25 mM HEPES pH 7.4 (4 C), 100 mM KCl, 400 mM imidazole, 2 mM 2-mercaptoethanol). Elution fractions (2.5 ml) corresponding to the peak in the UV absorbance were collected. The eluted fractions containing active Aurora-2 kinase were dialyzed against dialysis buffer (25 mM HEPES pH 7.4 (4 캜), 45% glycerol (v / v), 100 mM KCl, 0.25% Nonidet P40 Toll) was thoroughly dialyzed.
    [2727] Each new batch of Aurora-2 enzyme was diluted with enzyme dilution (25 mM Tris-HCl pH 7.5, 12.5 mM KCl, 0.6 mM DTT) and titrated in the assay. For one exemplary batch, the stock enzyme was diluted 666 to 1 in enzyme dilution and 20 [mu] l of dilution enzyme was used for each assay well. The test compound (10 mM in dimethylsulfoxide (DMSO)) was diluted with water and 10 ul of the diluted compound transferred to the wells in the assay plate. The " total " and " blank " control wells contained 2.5% DMSO instead of compound. 20 microliters of freshly diluted enzyme was removed from the " blank " well and added to all wells. 20 mg of enzyme dilution was added to the " blank " well. (25 mM Tris-HCl pH 7.5, 78.4 mM KCl, 2.5 mM NaF, 0.6 mM dithiothreitol, 6.25 mM (pH 7.4) containing 0.2 μCi [γ 33 P] ATP (Amersham Pharmacia, intrinsic activity ≥ 2500 Ci / mmol) 20 μl of MnCl 2 , 6.25 mM ATP, 7.5 μM peptide substrate [biotin-LRRWSLGLRRWSLGLRRWSLGLRRWSLG]) was added to all test wells to initiate the reaction. The plate was incubated at room temperature for 60 minutes. To terminate the reaction, 100 μl of 20% v / v orthophosphoric acid was added to all wells. To the peptide substrate by using the positive 96-well plate collector (harvester) (TomTek) - charged nitrocellulose P30 filter mat; captured and then, analyzes the introduction of 33 P with a beta plate counter (counter) on (filtermat Whatman) Respectively. The "blank" (no enzyme) and "total" (no compound) control values were used to determine the dilution range of the test compound to provide 50% inhibition of enzyme activity.
    [2728] In this test, Compound 1 of Table 1 provided 50% inhibition of enzyme activity at a concentration of 0.374 μM and Compound 101 of Table 4 provided 50% inhibition of enzyme activity at a concentration of 0.0193 μM. In this test, compound 557 of Table 16 provided 50% inhibition of enzyme activity at a concentration of 0.519 μM.
    [2729] (b) In vivo cell proliferation assay
    [2730] This assay and other assays can be used to determine the ability of a test compound to inhibit the growth of an adherent mammalian cell line, e. G., The human tumor cell line MCF7.
    [2731] Analysis 1 : MCF-7 (ATCC HTB-22) or other adherent cells were cultured in 96 well tissue culture-treated clean plates in the presence of 10% fetal bovine serum, 1% L-glutamine and 1% penicillin / streptomycin, And sparged with 1 x 10 3 cells per well (excluding surrounding wells) in DMEM (Sigma Aldrich). On the following day (Day 1), the medium was removed from untreated control plates and the plates were stored at -80 ° C. The remaining plates were dosed with compound diluted from 10 mM of stock solution in DMSO, using DMEM (10% FCS, 1% L-glutamine, 1% penicillin / streptomycin, no phenol red). Untreated control wells were placed on each plate. The medium was removed after 3 days (4 days) in the presence / absence of the compound and the plate was stored at -80 ° C. After 24 hours, the plates were thawed at room temperature and cell density was determined using the CyQUANT cell proliferation assay kit (c-7026 / c-7027 Molecular Probes Inc.) according to the manufacturer's instructions. To summarize, 200 쨉 l of a cell lysis / dye mixture (10 쨉 l of 20X cell lysate B, 190 쨉 l of sterile water, 0.25 쨉 l of CYQUANT GR dye) was added to each well and the plate was incubated for 5 minutes at room temperature and darkness. Fluorescence of the wells was then measured using a fluorescence microplate reader (gain 70,2 reads per well, CytoFluor platereader (PerSeptive Biosystems Inc.) at excitation 485 nm and emission 530 nm 1 cycle). Values of 1 day and 4 days (compound treatment) with values from untreated cells were used to determine the dilution range of the test compound to provide 50% inhibition of cell proliferation. Compound No. 1 in Table 1 was effective at 8.03 μM in this test and Compound No. 101 in Table 4 was effective at 1.06 μM in this test. Compound 557 of Table 16 was effective at 1.57 [mu] M in this test. These values can also be used to calculate the dilution range of the test compound where the cell density drops below the control value per day. This indicates the cytotoxicity of the compound.
    [2732] Assay 2 : This assay determines the performance of test compounds that inhibit the introduction of the thymidine analog, 5'-bromo-2'-deoxy-uridine (BrdU) into cellular DNA. In addition to 10% fetal bovine serum, 1% L-glutamine and 1% penicillin / streptomycin (50 [mu] l / well) in 96 well tissue culture treated 96 well plates (Costar), MCF- (Sigma Aldrich) in 0.8 x 10 4 cells per well and allowed to attach overnight. The following day cells were dosed with compound {DMEM (10% FCS, 1% L-glutamine, 1% penicillin / streptomycin, no phenol red) diluted from 10 mM stock solution in DMSO}. Untreated control wells and wells containing compounds known to provide 100% inhibition of BrdU incorporation were placed on each plate. The ability of the cells to introduce BrdU over a 2 hour labeling period after 48 hours in the presence / absence of the test compound was determined using the Boehringer (Roche) cell proliferation BrDU ELISA kit (cat. No. 1647 229) And measured according to the manufacturer's instructions. Briefly, 15 Br of BrDU labeling reagent (diluted 1: 100 in dilution 1: 100 medium-DMEM 10% FCS, 1% L-glutamine, 1% penicillin / streptomycin, no phenol red) Again humidified (+ 5% CO 2 ) was placed in a 37 ° C incubator for 2 hours. After 2 hours, the labeling reagent was decanted and the plate was tapped on a paper towel to remove it. The FixDenat solution (50 占 퐇 per well) was added and the plate was incubated for 45 minutes while shaking at room temperature. The FixDenate solution was removed by tilting and inverting the plate on a paper towel. Plates were then washed once with phosphate buffered saline (PBS) and 100 ㎕ / well of anti-BrdU-POD antibody solution (in diluted 1: 100 antibody dilution buffer) was added. The plates were then incubated for 90 minutes with shaking at room temperature. Branched and the plate was washed 5 times with PBS before staining to remove unbound anti-BrdU-POD antibody. TMB substrate solution was added (100 [mu] L / well) and incubated at room temperature for about 10 minutes with shaking until the color change became apparent. The optical density of the wells was then measured at a wavelength of 690 nm using a Titertek Multiscan plate reader. Values from the treated, untreated and 100% inhibitory control compounds were used to determine the dilution range of the test compound to provide 50% inhibition of BrdU incorporation. Compound 1 of Table 1 was effective at 1.245 μM in this test and Compound 101 of Table 4 was effective at 0.159 to 0.209 μM.
    [2733] (c) In vivo cell circulation assay test
    [2734] This assay determines the performance of test compounds that confine cells to specific phases of the cell cycle. A number of different mammalian cell lines can be used in this assay, and MCF7 cells are introduced herein as examples. MCF-7 cells DMEM (10% FCS, 1% L- glutamine, 1% penicillin / streptomycin, phenol red No) sprinkled with 5ml of 3 x 10 5 cells per T25 flask (Costar). The flask was then incubated overnight in a humidified 37 ° C incubator with 5% CO 2 . The following day, 1 ml of DMEM (10% FCS, 1% L-glutamine, 1% penicillin / streptomycin, no phenol red) with the appropriate concentration of test compound was added to the flask. Contrast treatment without compound was also included (0.5% DMSO). The cells were then incubated with the compound for a limited time (generally 24 hours). After this time, the medium was inhaled from the cells, washed with 5 ml of pre-warmed (37 ° C) sterile PBSA and incubated in trypsin followed by reconstitution in 10 ml of 1% bovine serum albumin (BSA, Sigma-Aldrich Co.) And then separated from the flask. The samples were then centrifuged at 2200 rpm for 10 minutes. The supernatant was aspirated and the cell pellet was resuspended in 200 μl of nonidet NP40 [H 7.6] with 0.1% (w / v) sodium trisodium citrate, 0.0564% (w / v) NaCl, 0.03% (v / v). Pro-iodide (Sigma Aldrich Co.) was added at 40 / / ml and RNAase A (Sigma Aldrich Co.) was added at 100 / / ml. The cells were then incubated at 37 DEG C for 30 minutes. The samples were centrifuged at 2200 rpm for 10 min, the supernatant was removed and the residual pellet (nucleus) was resuspended in 200 μl of sterile PBSA. Each sample was then injected 10 times using a 21 gauge needle. The samples were then transferred to LPS tubes and DNA content per cell was analyzed by fluorescence activated cell sorting (FACS) using a FACScan flow cytometer (Becton Dickinson). In general, 25000 events were counted and recorded using CellQuest v1.1 software (Verity Software). Cellular distribution of the population was calculated using Modfit software (Verity Software) and expressed as the percentage of cells in the GO / G1, S and G2 / M phases of the cell cycle. Treatment of MCF7 for 24 hours with 25 μM of the compound of Table 1 or 2.12 μM of Compound 101 of Table 4 leads to the following changes in the cell circulation distribution:
    [2735] processCells in G1%Cells in S%Cells in G2 / M% DMSO (Control - Compound 1)49.939.210.9 25 [mu] M Compound 125.8217.7156.47 DMSO (Control-Compound 101)57.531.9510.55 2.12 [mu] M Compound 10119.6912.468.21
    权利要求:
    Claims (31)
    [1" claim-type="Currently amended] Use of a compound of formula (I), or a salt, ester, amide or prodrug thereof, for the manufacture of a medicament for the inhibition of aurora 2 kinase:
    (I)

    Wherein X is O, S, S (O) or S (O) 2 or NH or NR 12 wherein R 12 is hydrogen or C 1-6 alkyl;
    R 5 is NHC (O) OR 9, NHC (O) R 9, NHS (O) 2 R 9, C (O) R 9, C (O) OR 9, S (O) R 9, S (O) oR 9, S (O) 2 oR 9, C (O) NR 10 R 11, S (O) NR 10 R 11, S (O) ONR 10 R 11 ( wherein, R 9, R 10 or R 11 is hydrogen , Optionally substituted hydrocarbyl and optionally substituted heterocyclyl, and R 10 and R 11 , together with the nitrogen atom to which they are attached, &Lt; / RTI &gt;
    R &lt; 6 &gt; is hydrogen, optionally substituted hydrocarbyl or optionally substituted heterocyclyl;
    R 7 and R 8 are independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxymethyl, di (C 1-4 alkoxy) methyl, C 1-4 alkanoyl, trifluoromethyl A 5 to 6 membered heteroaromatic ring having 1 to 3 heteroatoms (independently selected from O, S and N), optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, C 2-5 alkenyl, C 2-5 alkynyl, phenyl, Cyclic group wherein said heterocyclic group may be aromatic or non-aromatic and may be saturated (linked through a ring carbon or nitrogen atom) or unsaturated (linked via a ring carbon atom), said phenyl, benzyl or hetero cyclic group is hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro, C 2-4 alkanoylamino, C 1 -4 alkanoylamino, C 1-4 alkoxycarbonyl, C 1-4 alkyl sulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, carbamoyl, NC 1-4 alkyl carbamoyl , N, N-di (C ( C1-4 alkyl) carbamoyl, aminosulfonyl, NC 1-4 alkylaminosulfonyl, N, N-di (C 1-4 alkyl) aminosulfonyl, C 1-4 alkylsulfonylamino, Saturated saturated heterocyclic group selected from oxo, hydroxy, halogeno, C &lt; RTI ID = 0.0 &gt; 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, can possess a trifluoromethyl, methyl, cyano, amino, nitro and C 1-4 alkoxy group by one or two substituents selected from carbonyl) &Lt; / RTI &gt; may be on one or more ring carbon atoms;
    R 1, R 2, R 3 , R 4 is a halogeno, cyano, nitro, C 1-3 alkyl sulfanyl, -N (OH) R 13 - ( wherein, R 13 is hydrogen or C 1-3 alkyl Or R 15 X 1 - wherein X 1 is a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, -S-, -SO-, -SO 2 -, -NR 16 CO -, -CONR 16 -, -SO 2 NR 16 -, -NR 17 SO 2 - or -NR 18 -, wherein R 16 , R 17 and R 18 are each independently hydrogen, C 1-3 alkyl or C 1 -3 alkoxy C 2-3 alkyl, and R 15 is hydrogen, optionally substituted hydrocarbyl, optionally substituted heterocyclyl or optionally substituted alkoxy.
    [2" claim-type="Currently amended] The compound of formula (I) according to claim 1, wherein the compound of formula (I) is a compound wherein at least one group R 1 , R 2 , R 3 and R 4 is R 15 X 1 - and R 15 is hydrogen or an alkyl, Or an optionally substituted hydrocarbyl group selected from aryl, aralkyl, cycloalkyl, cycloalkenyl, or cycloalkynyl, or a combination thereof, or a 4- to 20-membered ring (of which at least one is heteroatom such as oxygen, atom), an optionally substituted heterocyclyl group-{wherein having, optional substituents are nitro, cyano, halo, oxo, = CR 78 R 79, C (O) x R 77, OR 77, S (O) y R 77 , NR 78 R 79 , C (O) NR 78 R 79 , OC (O) NR 78 R 79 , -NOR 77 , -NR 77 C (O) x R 78 , -NR 77 CONR 78 R 79 , -N = CR 78 R 79, S (O ) y NR 78 R 79 or -NR 77 S (O) y R 78 ( wherein, R 77, R 78 and R 79 is hydrogen, optionally substituted hydrocarbyl, an optionally substituted heteroaryl heterocyclyl or optionally independently selected from substituted alkoxy, R 78 and R 79 And with oxygen, nitrogen, S, S (O) or S (O) forming an optionally substituted ring further includes a heteroatom optionally, such as 2, and x is an integer of 1 or 2, y is 0 or 1 to 3 (Wherein R &lt; 1 &gt;
    [3" claim-type="Currently amended] The compound of claim 2 wherein the rings formed by hydrocarbyl, heterocyclyl or alkoxy groups R 77 , R 78 and R 79 , and R 78 and R 79 are selected from halo, perhaloalkyl, mercapto, alkylthio, Alkoxy, alkoxy, alkoxy, aryloxy, wherein the aryl group is optionally substituted by halo, nitro or hydroxy, or a pharmaceutically acceptable salt, ester, Optionally substituted by cyano, nitro, amino, mono- or di-alkylamino, oximino or S (O) y R 90 , wherein y is as defined above and R 90 is alkyl Uses that are.
    [4" claim-type="Currently amended] Article according to any one of the preceding claims, wherein in the compound of Formula (I), one group R 1, R 2, R 3 or R 4 is a X 1 R 15 above, R 15 is to 22 One of the uses:
    1) C 1-5 alkyl which is unsubstituted or may be substituted with at least one functional group, or hydrogen;
    2) -R a X 2 C (O) R 19 wherein X 2 represents -O- or -NR 20 - (wherein R 20 represents hydrogen or alkyl optionally substituted by one functional group) R 19 is C 1-3 alkyl, -NR 21 R 22 or -OR 23 wherein R 21 , R 22 and R 23 may be the same or different and are each hydrogen or alkyl optionally substituted with one functional group );
    3) -R b X 3 R 24 { wherein, X 3 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 25 C (O) s -, -C ( O) NR 26 -, -SO 2 NR 27 -, -NR 28 SO 2 - or -NR 29 - (wherein, R 25, R 26, R 27, R 28 and R 29 Are each independently hydrogen or alkyl optionally substituted by one functional group and s is 1 or 2 and R 24 represents hydrogen, hydrocarbyl (as defined herein) or a saturated heterocyclic group, Wherein said hydrocarbyl or heterocyclic group may be optionally substituted by one or more functional groups and said heterocyclic group may be further substituted by one hydrocarbyl group;
    4) -R c X 4 R c ' X 5 R 30 wherein X 4 and X 5 may be the same or different and are each -O-, -C (O) -, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 31 C (O) s -, -C (O) x NR 32 -, -SO 2 NR 33 -, -NR 34 SO 2 - or -NR 35 - (Wherein R 31 , R 32 , R 33 , R 34 and R 35 are each independently hydrogen or alkyl optionally substituted by one functional group and s is 1 or 2), R 30 represents hydrogen , Or alkyl optionally substituted by one functional group;
    5) R 36 wherein R 36 is a C 3-6 cycloalkyl or a saturated heterocyclic ring connected via carbon or nitrogen and wherein the cycloalkyl or heterocyclic group may be substituted by one or more functional groups, Which may be substituted by one hydrocarbyl or heterocyclyl group which may be optionally substituted by one or more functional groups;
    6) -R d R 36 , wherein R 36 is as defined above;
    7) -R e R 36 wherein R 36 is as defined above;
    8) -R f R 36 wherein R 36 is as defined above;
    9) R 37 wherein R 37 represents a pyridone group, an aryl group, or an aromatic heterocyclic group having 1 to 3 hetero atoms selected from O, N and S (connected via carbon or nitrogen) The donor, aryl or aromatic heterocyclic group may be substituted by one or more functional groups, or may be substituted by one hydrocarbyl group optionally substituted by one or more functional groups or heterocyclyl groups, or may be substituted by one or more functional groups or hydrocarbons Which may be substituted by one heterocyclyl group optionally substituted by a bicyclic group;
    10) -R g R 37 wherein R 37 is as defined above;
    11) -R h R 37 wherein R 37 is as defined above;
    12) -R i R 37 wherein R 37 is as defined above;
    13) -R j X 6 R 37 wherein X 6 is -O-, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 42 C (O) NR 43 -, -SO 2 NR 44 -, -NR 45 SO 2 - or -NR 46 -, wherein R 42 , R 43 , R 44 , R 45 and R 46 are each independently hydrogen or one And R &lt; 37 &gt; is the same as defined above;
    14) -R k X 7 R 37 { wherein, X 7 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 47 C (O) -, -C (O ) NR 48 -, -SO 2 NR 49 -, -NR 50 SO 2 - or -NR 51 - (wherein, R 47, R 48, R 49, R 50 and R 51 is Each independently represent hydrogen or alkyl optionally substituted by one functional group, and R 37 is as defined above;
    15) -R m X 8 R 37 { wherein, X 8 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 52 C (O) -, -C (O ) NR 53 -, -SO 2 NR 54 -, -NR 55 SO 2 - or -NR 56 - (wherein, R 52, R 53, R 54, R 55 and R 56 is Each independently represent hydrogen or alkyl optionally substituted by one functional group, and R 37 is as defined above;
    16) -R n X 9 R n ' R 37 wherein X 9 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -OC NR 57 C (O) -, -C (O) NR 58 -, -SO 2 NR 59 -, -NR 60 SO 2 - or -NR 61 - (wherein, R 57, R 58, R 59, R 60 , and R 61 independently represents hydrogen or alkyl optionally substituted by one functional group, and R 37 is as defined above;
    17) -R p X 9 R p ' R 36 wherein X 9 and R 36 are as defined above;
    18) C 2-5 alkenyl which is unsubstituted or may be substituted with at least one functional group;
    19) C 2-5 alkynyl which is unsubstituted or may be substituted with at least one functional group;
    20) -R t X 9 R t ' R 36 wherein X 9 and R 36 are as defined above;
    21) -R u X 9 R u ' R 36 wherein X 9 and R 36 are as defined above; And
    22) -R v R 62 (R v ') q (X 9) r R 63 { wherein, X 9 is as defined above, q is 0 or 1, r is 0 or 1, R 62 is C 1 -3 alkylene group, a divalent cycloalkyl or a heterocyclic group (wherein the C 1-3 alkylene group may be substituted by at least one functional group, and the cyclic group may be substituted with at least one functional group Or by one hydrocarbyl group optionally substituted by at least one functional group or heterocyclyl group or by one heterocyclyl group optionally substituted by at least one functional group or hydrocarbyl group, And R 63 is hydrogen or C 1-3 alkyl or a cyclic group selected from a cycloalkyl or a heterocyclic group wherein the C 1-3 alkyl group may be substituted by at least one functional group, The cyclic group may be substituted by at least one functional group Or may be substituted by one hydrocarbyl group optionally substituted by at least one functional group or heterocyclyl group or by one heterocyclyl group optionally substituted by at least one functional group or hydrocarbyl group }
    [In the above groups, R a, R b, R c, R c ', R d, R g, R j, R n, R n', R p, R p ', R t', R u ', R v and R v ' are independently selected from a C 1-8 alkylene group optionally substituted by one or more substituent functional groups,
    R e , R h , R k and R t are independently selected from C 2-8 alkenylene groups optionally substituted by one or more functional groups,
    R f , R i , R m and R u are independently selected from C 2-8 alkynylene groups optionally substituted by one or more functional groups.
    [5" claim-type="Currently amended] 5. The compound of claim 4, wherein in the compound of formula (I), at least one group R 1 , R 2 , R 3 or R 4 is X 1 R 15 and R 15 is selected from one of the following 22 groups: Usage:
    1) C 1-5 alkyl which is unsubstituted or substituted with one or more groups selected from hydroxy, oxiranyl, fluoro, chloro, bromo and amino (including C 1-3 alkyl and trifluoromethyl), Or hydrogen;
    2) -R a X 2 C (O) R 19 wherein X 2 is -O- or -NR 20 - wherein R 20 is hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 And R 19 represents C 1-3 alkyl, -NR 21 R 22 or -OR 23 (wherein R 21 , R 22 and R 23 may be the same or different and each represents hydrogen, C 1-5 alkyl, hydroxyC 1-5 alkyl or C 1-3 alkoxyC 2-3 alkyl;
    3) -R b X 3 R 24 { wherein, X 3 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 25 C (O) s -, -NR 25 C (O) NR 26 -, -C (O) NR 26 -, -SO 2 NR 27 -, -NR 28 SO 2 - or -NR 29 - (wherein, R 25, R 26 , R 27 , R 28 and R 29 are each independently hydrogen, C 1-3 alkyl, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl, and s is 1 or 2, And R 24 is hydrogen, C 1-6 alkyl or C 2-6 alkenyl, or is a cyclic group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, or independently from O, S and N Wherein said C 1-6 alkyl group is selected from the group consisting of oxo, hydroxy, halogeno, cyclopropyl, amino, C 1-4 alkylamino, di -C 1-4 alkylamino, C 1-4 alkylthio, and can have one, two or three substituents selected from C 1-4 alkoxy, wherein the cyclic groups are oxo, hydroxy When, halogeno, cyano, C 1-4 cyanoalkyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1- 4 alkylsulfonyl C 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 aminoalkyl, C 1-4 alkylamino, di (C 1-4 alkyl) amino, C 1-4 alkylamino C 1 -4 alkyl, di (C 1-4 alkyl) amino C 1-4 alkyl, C 1-4 alkanoyl, C 1-4 alkylamino, C 1-4 alkoxy, di (C 1-4 alkyl) amino C 1- 4 alkoxy and - (- O-) f and (R b ') g D group (where, f is 0 or 1, g is 0 or 1 and ring D is a C 3-6 alkyl group or a cycloalkyl or aryl, O, S and N, wherein said cyclic group may be optionally substituted with one or more substituents selected from halo or C 1-4 alkyl, wherein said cyclic group is optionally substituted with one or more substituents selected from halo, C 1-4 alkyl, Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt;
    4) -R c X 4 R c ' X 5 R 30 wherein X 4 and X 5 may be the same or different and are each -O-, -C (O) -, -S-, -SO-, -SO 2 -, -NR 31 C ( O) s -, -C (O) x NR 32 -, -SO 2 NR 33 -, -NR 34 SO 2 - or -NR 35 - represents a (wherein, R 31 , R 32 , R 33 , R 34 and R 35 are each independently hydrogen, C 1-3 alkyl, hydroxy C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl, s is 1 or 2 ), R 30 represents hydrogen, C 1-3 alkyl, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl;
    5) R 36 wherein R 36 is a 4 to 6 membered cycloalkyl or a saturated heterocyclic ring (linked via carbon or nitrogen) having one or two heteroatoms independently selected from O, S and N, In this case, the cycloalkyl or heterocyclic group, oxo, hydroxy, halogeno, cyano, C 1-4 alkyl, hydroxy C 1-4 alkyl, cyano C 1-4 alkyl, cyclopropyl, C 1-4 alkylsulfonyl C 1-4 alkyl, C 1-4 alkoxycarbonyl, carboxamide not shown, C 1-4 aminoalkyl, C 1-4 alkylamino, di (C 1-4 alkyl) amino, C 1-4 alkyl (C 1-4 alkyl) aminoC 1-4 alkyl, C 1-4 alkylaminoC 1-4 alkoxy, di (C 1-4 alkyl) aminoC 1-4 alkyl, aminoC 1-4 alkyl, C 1-4 alkanoyl, di C 1-4 alkoxy, nitro, amino, C 1-4 alkoxy, C 1-4 hydroxy alkoxy, carboxy, trifluoromethyl, -C (O) NR 38 R 39, -NR 40 C (O) R 41 (wherein, R 38, R 39, R 40 and R 41 may be the same or different and each Cattle, C 1-4 alkyl, hydroxy C 1-4 alkyl, or represents a C 1-3 alkoxy C 2-3 alkyl), and - (- O-) f (C 1-4 alkyl) g D group (wherein , f is 0 or 1, g is 0 or 1, and ring D is C 3-6 cycloalkyl, aryl, or a 5 or 6 membered saturated or unsaturated ring having 1 or 2 heteroatoms independently selected from O, S and N Or an unsaturated heterocyclic group, and the cyclic group may have one or more substituents selected from halo or C 1-4 alkyl;
    6) -R d R 36 , wherein R 36 is as defined above;
    7) -R e R 36 wherein R 36 is as defined above;
    8) -R f R 36 wherein R 36 is as defined above;
    9) R 37 wherein R 37 represents a pyridone group, a phenyl group, or a 5 or 6 membered aromatic heterocyclic group (connected via carbon or nitrogen) having 1 to 3 heteroatoms selected from O, N and S Wherein said pyridone, phenyl or aromatic heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, nitro, halogeno, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C C 1-4 alkyl, C 1-4 hydroxyalkoxy, oxo, cyano C 1-4 alkyl, cyclopropyl, C 1-4 alkylsulfonyl C 1-4 alkyl, C 1-4 alkoxycarbonyl, di C 1-4 alkyl) amino, C 1-4 alkylaminoC 1-4 alkyl, C 1-4 alkanoyl, di (C 1-4 alkyl) aminoC 1-4 alkyl, C 1-4 alkylaminoC 1 -4 alkoxy, di (C 1-4 alkyl) amino C 1-4 alkoxy, carboxy, carboxamide not shown, trifluoromethyl, cyano, -C (O) NR 38 R 39, -NR 40 C (O) R 41 (wherein, R 38, R 39, R 40 and R 41 may be the same or different and each Cattle, C 1-4 alkyl, hydroxy C 1-4 alkyl, or represents a C 1-3 alkoxy C 2-3 alkyl), and - (- O-) f (C 1-4 alkyl) g D group (wherein , f is 0 or 1, g is 0 or 1, ring D is a C 3-6 cycloalkyl group, aryl, or a 5 or 6 membered saturated or unsaturated ring having 1 or 2 heteroatoms independently selected from O, S and N Or an unsaturated heterocyclic group, and the cyclic group may have at least one substituent selected from halo or C 1-4 alkyl);
    10) -R g R 37 wherein R 37 is as defined above;
    11) -R h R 37 wherein R 37 is as defined above;
    12) -R i R 37 wherein R 37 is as defined above;
    13) -R j X 6 R 37 wherein X 6 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 42 C (O) -, -C (O ) NR 43 -, -SO 2 NR 44 -, -NR 45 SO 2 - or -NR 46 - (wherein, R 42, R 43, R 44, R 45 and R 46 is Each independently represents hydrogen, C 1-3 alkyl, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl, and R 37 is as defined above;
    14) -R k X 7 R 37 wherein X 7 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -NR 47 C (O) NR 48 -, -SO 2 NR 49 -, -NR 50 SO 2 - or -NR 51 - (wherein, R 47, R 48, R 49, R 50 and R 51 are independently hydrogen, C 1 each -3 alkyl, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl, and R 37 is as defined above;
    15) -R m X 8 R 37 wherein X 8 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -NR 52 C (O) NR 53 -, -SO 2 NR 54 -, -NR 55 SO 2 - or -NR 56 - wherein R 52 , R 53 , R 54 , R 55 and R 56 are each independently hydrogen, C 1 -3 alkyl, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl, and R 37 is as defined above;
    16) -R n X 9 R n ' R 37 wherein X 9 is -O-, -C (O) -, -S-, -SO-, -SO 2 -, -NR 57 C , -C (O) NR 58 - , -SO 2 NR 59 -, -NR 60 SO 2 - or -NR 61 - (wherein, R 57, are each independently hydrogen, R 58, R 59, R 60 and R 61 , C 1-3 alkyl, hydroxyC 1-3 alkyl or C 1-3 alkoxyC 2-3 alkyl), and R 37 is as defined above;
    17) -R p X 9 R p ' R 36 wherein X 9 and R 36 are as defined above;
    18) is optionally substituted, hydroxy, fluoro, amino, C 1-4 alkylamino, carboxyl (and in particular its alkyl ester), N, N- di (C 1-4 alkyl) amino, aminosulfonyl, NC 1 -4-alkyl aminosulfonyl and N, N- di (C 1-4 alkyl) aminosulfonyl C 2-5 alkenyl which may be substituted with one or more selected from;
    19) a is optionally substituted, hydroxy, fluoro, amino, C 1-4 alkylamino, N, N- di (C 1-4 alkyl) amino, aminosulfonyl, NC 1-4 alkylamino, sulfonyl and N, C 2-5 alkynyl which may be substituted with one or more groups selected from N-di (C 1-4 alkyl) aminosulfonyl;
    20) -R t X 9 R t ' R 36 wherein X 9 and R 36 are as defined above;
    21) -R u X 9 R u ' R 36 wherein X 9 and R 36 are as defined above; And
    22) -R v R 62 (R v ') q (X 9) r R 63 { wherein, X 9 is as defined above, q is 0 or 1, r is 0 or 1, R 62 is C 1 3 alkylene group or a 5 or 6 membered saturated heterocyclic group having 1 or 2 heteroatoms independently selected from O, S and N, selected from cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, Wherein said C 1-3 alkylene group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy, said cyclic group being optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, halo C 1-4 haloalkyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1-4 alkyl C 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 aminoalkyl, C 1-4 alkylamino, di (C 1-4 alkyl) amino, C 1-4 alkylamino C 1-4 alkyl , Di (C 1-4 alkyl) aminoC 1-4 alkyl, C 1-4 alkyl Kill amino C 1-4 alkoxy, di (C 1-4 alkyl) amino C 1-4 alkoxy and - (- O-) f (C 1-4 alkyl) g D group (this time, and f is 0 or 1, g is 0 or 1, and ring D is selected from a C 3-6 cycloalkyl group, aryl, or a 5 or 6 membered saturated or unsaturated heterocyclic group having 1 or 2 heteroatoms independently selected from O, S and N And the cyclic group may have one or more substituents selected from halo or C 1-4 alkyl, and R 63 is hydrogen or C 1-3 alkyl, A cyclic group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or a 5 or 6 membered saturated or unsaturated heterocyclic group having one or two heteroatoms independently selected from O, S and N, The C 1-3 alkyl group may be substituted by oxo, hydroxy, halogeno, C 1-4 alkoxy, And wherein said cyclic group is optionally substituted with one or two substituents selected from the group consisting of oxo, hydroxy, halogeno, cyano, C 1-4 cyanoalkyl, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1 -4 alkoxy, C 1-4 alkoxy C 1-4 alkyl, C 1-4 alkylsulfonyl C 1-4 alkyl, C 1-4 alkoxycarbonyl, C 1-4 aminoalkyl, C 1-4 alkylamino, Di (C 1-4 alkyl) amino, C 1-4 alkylamino C 1-4 alkyl, di (C 1-4 alkyl) aminoC 1-4 alkyl, C 1-4 alkylaminoC 1-4 alkoxy, di (C 1-4 alkyl) aminoC 1-4 alkoxy and - (-O-) f (C 1-4 alkyl) g D wherein f is 0 or 1, g is 0 or 1, and ring D Is a C 3-6 cycloalkyl, aryl, or a cyclic group selected from a 5 or 6 membered saturated or unsaturated heterocyclic group having one or two heteroatoms independently selected from O, S and N, halo or C 1-4 selected from the substituents that may have more selected from alkyl), or 1 Which may have two substituents.
    [In the group, R a, R b, R b ', R c, R c', R d, R g, R j, R n, R n ', R p, R p', R t ', R u ' , R v and R v' are independently selected from C 1-8 alkylene groups optionally substituted by one or more substituents selected from hydroxy, halogeno, amino,
    R e , R h , R k and R t are independently selected from C 2-8 alkenylene groups optionally substituted by one or more substituents selected from hydroxy, halogeno, amino, and R t may additionally be a bond ,
    R f , R i , R m and R u are independently selected from C 2-5 alkynylene groups optionally substituted by one or more substituents selected from hydroxy, halogeno, amino.
    [6" claim-type="Currently amended] 6. Compounds of formula I according to any one of claims 1 to 5, wherein R 1 , R 2 , R 3 or R 4 is halo, cyano, nitro, trifluoromethyl, C 1- 3 alkyl, -NR 13 R 14 , wherein R 13 and R 14 , which may be the same or different, each represent hydrogen or C 1-3 alkyl, or -X 1 R 15 , X 1 is a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, -S-, -SO-, -SO 2 -, -NR 16 CO-, -CONR 16 -, -SO 2 NR 16 -, - NR 17 SO 2 - or - NR 18 -, wherein R 16 , R 17 and R 18 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl) And R &lt; 15 &gt; is selected from one of the following groups:
    1 &apos;) C 1-5 alkyl which is unsubstituted or may be substituted with one or more groups selected from hydroxy, fluoro or amino, or hydrogen;
    2 ') C 1-5 alkyl X 2 COR 19 wherein X 2 is -O- or -NR 20 - wherein R 20 is hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl , R 19 represents C 1-3 alkyl, -NR 21 R 22 or -OR 23 wherein R 21 , R 22 and R 23 may be the same or different and each represents hydrogen, C 1 -3 alkyl or C 1-3 alkoxyC 2-3 alkyl;
    3 ') C 1-5 alkyl X 3 R 24 wherein X 3 is -O-, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 25 CO-, -C (O) NR 26 -, -SO 2 NR 27 -, -NR 28 SO 2 - or -NR 29 - wherein R 25 , R 26 , R 27 , R 28 and R 29 are each independently hydrogen, C 1 3 alkyl or C 1-3 alkoxy C 2-3 alkyl, and R 24 represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl, or one or two independently selected from O, S and N Wherein the C 1-3 alkyl group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy, and wherein the C 1-3 alkyl group may be substituted with one or two substituents selected from the group consisting of The cyclic group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy;
    4 ') C 1-5 alkyl X 4 C 1-5 alkyl X 5 R 30 wherein X 4 and X 5 may be the same or different and are each -O-, -S-, -SO-, -SO 2 -, -NR 31 CO-, -CONR 32 -, -SO 2 NR 33 -, -NR 34 SO 2 - or -NR 35 - represents a (wherein, R 31, R 32, R 33, R 34 and R 35 each independently represent hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl), and R 30 represents hydrogen or C 1-3 alkyl;
    5 ') R 36 wherein R 36 is a 5 or 6 membered saturated heterocyclic ring (linked via carbon or nitrogen) having 1 or 2 heteroatoms independently selected from O, S and N, The heterocyclic group may be optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl and C 1-4 alkylsulfonyl Lt; / RTI &gt; alkyl optionally substituted with one or two substituents selected from C1-4 alkyl;
    6 ') C 1-5 alkyl R 36 wherein R 36 is as defined in 5'above;
    7 ') C 2-5 alkenyl R 36 wherein R 36 is as defined in 5'above;
    8 ') C 2-5 alkynyl R 36 wherein R 36 is as defined in 5'above;
    9 ') R 37 wherein R 37 is a pyridone group, a phenyl group, or a 5 or 6 membered aromatic heterocyclic group (linked via carbon or nitrogen) having 1 to 3 heteroatoms selected from O, N and S Wherein said pyridone, phenyl or aromatic heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogeno, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1 -4 alkylamino, C 1-4 hydroxy alkoxy, carboxy, trifluoromethyl, cyano, -C (O) NR 38 R 39, and -NR 40 C (O) R 41 ( wherein, R 38, R 39 , R 40 and R 41 , which may be the same or different, each represent hydrogen, C 1-4 alkyl or C 1-3 alkoxy C 2-3 alkyl) may be substituted on any possible carbon atom You can have}};
    10 ') C 1-5 alkyl R 37 wherein R 37 is as defined in 9'above;
    11 ') C 2-5 alkenyl R 37 wherein R 37 is as defined in 9'above;
    12 ') C 2-5 alkynyl R 37 wherein R 37 is as defined in 9'above;
    13 ') C 1-5 alkyl X 6 R 37 wherein X 6 is -O-, -S-, -SO-, -SO 2 -, -NR 42 CO-, -CONR 43 -, -SO 2 NR 44 -, -NR 45 SO 2 - or -NR 46 - (wherein, R 42, R 43, R 44, R 45 and R 46 are independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2 each -3 alkyl, and R 37 is the same as defined in 9 ');
    14 ') C 2-5 alkenyl X 7 R 37 wherein X 7 is -O-, -S-, -SO-, -SO 2 -, -NR 47 CO-, -CONR 48 -, -SO 2 NR 49 -, -NR 50 SO 2 - or -NR 51 -, wherein R 47 , R 48 , R 49 , R 50 and R 51 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl), and R 37 is the same as defined in 9 ');
    15 ') C 2-5 alkynyl X 8 R 37 wherein X 8 is -O-, -S-, -SO-, -SO 2 -, -NR 52 CO-, -CONR 53 -, -SO 2 NR 54 -, -NR 55 SO 2 - or -NR 56 - (wherein, R 52, R 53, R 54, R 55 and R 56 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C Gt ; and R &lt; 37 &gt; are as defined above;
    16 ') C 1-3 alkyl X 9 C 1-3 alkyl R 37 wherein X 9 is -O-, -S-, -SO-, -SO 2 -, -NR 57 CO-, -CONR 58 - , -SO 2 NR 59 -, -NR 60 SO 2 - or -NR 61 - (wherein, R 57, R 58, R 59, R 60 and R 61 are independently hydrogen, C 1-3 alkyl, or C 1 each -3 alkoxyC 2-3 alkyl, and R 37 is as defined above; And
    17 ') C 1-3 alkyl X 9 C 1-3 alkyl R 36 wherein X 9 and R 36 are as defined in 5' above.
    [7" claim-type="Currently amended] 7. Use according to any one of claims 1 to 6, wherein in the compounds of formula (I), R 1 is hydrogen and R 4 is hydrogen, halo, C 1-4 alkyl or C 1-4 alkoxy.
    [8" claim-type="Currently amended] 8. Use according to any one of claims 1 to 7, wherein at least one of R &lt; 2 &gt; and R &lt; 3 &gt; comprises 3 or more optionally substituted carbon atoms or a chain of heteroatoms selected from oxygen, nitrogen or sulfur.
    [9" claim-type="Currently amended] 9. The use according to claim 8, wherein said chain is substituted by a polar group which serves solubility.
    [10" claim-type="Currently amended] 10. Compounds according to any one of claims 1 to 9, wherein in the compounds of formula (I) R 3 is an X 1 R 15 group, wherein X 1 is oxygen and R 15 is immediately adjacent to X 1 Lt; / RTI &gt; group.
    [11" claim-type="Currently amended] Claim 10 wherein, R 1, R 2, R 3 or R at least one of the four cross linking (bridging) an alkylene, alkenylene or alkynylene group R a, R b, R b ', R c, R c' in , R d, R g, R j, R n, R n ', R p, R t', R u ', R v, R v', R e, R h, R k, R t, R f, the use as R i, and X 1 R 15 group containing R m and R u, at least one of the groups is to include a hydroxy substituent.
    [12" claim-type="Currently amended] The method according to any one of claims 1 to 11, wherein, in the compound of Formula (I), R 5 is NHC (O) R 9, or NHS (O) 2 R 9, wherein, R 9 is claim 1, wherein Lt; / RTI &gt; is as defined in claim &lt; RTI ID =
    [13" claim-type="Currently amended] The method according to any one of claims 1 to 11, wherein, in the compound of Formula (I), R 5 is C (O) R 9, C (O) OR 9, S (O) R 9, S (O ) oR 9, S (O) 2 oR 9, C (O) NR 10 R 11, and S (O) NR 10 R 11 or S (O) ONR 10 R 11 , wherein, R 9, R 10 and R 11 Lt; / RTI &gt; is as defined in claim 1.
    [14" claim-type="Currently amended] 13. The method of claim 12 or 13, wherein the R 9, R 10 or R 11,
    Aryl optionally substituted with one or more functional groups,
    C 3-6 cycloalkyl optionally substituted with one or more functional groups,
    Aralkyl optionally substituted with at least one functional group, wherein the aryl moiety may further comprise at least one alkyl substituent,
    A heterocyclyl optionally substituted with at least one functional alkyl, alkenyl or alkynyl group,
    Alkyl optionally substituted by one functional group or cycloalkyl or heterocyclyl group wherein said cycloalkyl or heterocyclyl group itself may be optionally substituted with one or more functional groups or alkyl groups,
    An alkenyl optionally substituted by one functional group or an aryl or heterocyclyl group, wherein the aryl or heterocyclyl group may be substituted with at least one functional group or an alkyl group, and
    An alkynyl optionally substituted by one functional group or an aryl or heterocyclyl group, wherein the aryl or heterocyclyl group may be optionally substituted with at least one functional group or an alkyl group,
    &Lt; / RTI &gt;
    [15" claim-type="Currently amended] The use according to claim 1, wherein the compound of formula (I) is a compound of formula (II) or a salt, ester, amide or prodrug thereof:
    &Lt;

    Wherein X, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as defined in claim 1,
    Z is C (O) or S (O) 2 ,
    R 64 is optionally substituted hydrocarbyl or optionally substituted heterocyclyl.
    [16" claim-type="Currently amended] The use according to claim 15 in the manufacture of a medicament for use in inhibiting aurora 2 kinase, wherein the compound of formula (II) is a compound of formula (IIC), or a salt, ester or amide thereof:
    (IIC)

    Wherein X is O or S, S (O) or S (O) 2 , or NR 8 , wherein R 8 is hydrogen or C 1-6 alkyl;
    Z is C (O) or S (O) 2 ;
    R 65 is optionally substituted hydrocarbyl or optionally substituted heterocyclyl;
    R 7 and R 8 are independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxymethyl, di (C 1-4 alkoxy) methyl, C 1-4 alkanoyl, trifluoromethyl A 5 to 6 membered heteroaromatic ring having 1 to 3 heteroatoms (independently selected from O, S and N), optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, C 2-5 alkenyl, C 2-5 alkynyl, phenyl, Cyclic group wherein said heterocyclic group may be aromatic or non-aromatic and may be saturated (linked through a ring carbon or nitrogen atom) or unsaturated (linked via a ring carbon atom), said phenyl, benzyl or hetero cyclic group is hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro, C 2-4 alkanoylamino, C 1 -4 alkanoylamino, C 1-4 alkoxycarbonyl, C 1-4 alkyl sulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, carbamoyl, NC 1-4 alkyl carbamoyl , N, N-di (C 1 ( C1-4 alkyl) carbamoyl, aminosulfonyl, NC 1-4 alkylaminosulfonyl, N, N-di (C 1-4 alkyl) aminosulfonyl, C 1-4 alkylsulfonylamino, and morpholino , A saturated heterocyclic group selected from oxo, hydroxy, halogeno, C 1-3 alkyl, C 1 -alkyl, C 1 -C 6 alkoxy, Up to 5 substituents selected from halogen, halogen, cyano, nitro, and C 1-4 alkoxycarbonyl, each of which may be optionally substituted with one or two substituents selected from halogen, C 1 -C 3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, Lt; / RTI &gt; may be on one or more ring carbon atoms);
    R 1, R 2, R 3 , R 4 is halo, cyano, nitro, trifluoromethyl, C 1-3 alkyl, -NR 13 R 14 (wherein, R 13 and R 14 may be the same or different , Each independently represent hydrogen or C 1-3 alkyl), or -X 1 R 15 , wherein X 1 is a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, - S-, -SO-, -SO 2 -, -NR 16 CO-, -CONR 16 -, -SO 2 NR 16 -, -NR 17 SO 2 - or -NR 18 - (wherein, R 16, R 17, and R &lt; 18 &gt; each independently represent hydrogen, C1-3 alkyl or C1-3 alkoxyC2-3 alkyl, and R &lt; 15 &gt; is selected from one of the following groups:
    1 &apos;) C 1-5 alkyl which is unsubstituted or may be substituted with one or more groups selected from hydroxy, fluoro or amino, or hydrogen;
    2 ') C 1-5 alkyl X 2 COR 19 wherein X 2 is -O- or -NR 20 - wherein R 20 is hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl , R 19 represents C 1-3 alkyl, -NR 21 R 22 or -OR 23 wherein R 21 , R 22 and R 23 may be the same or different and each represents hydrogen, C 1 -3 alkyl or C 1-3 alkoxyC 2-3 alkyl;
    3 ') C 1-5 alkyl X 3 R 24 wherein X 3 is -O-, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 25 CO-, -C (O) NR 26 -, -SO 2 NR 27 -, -NR 28 SO 2 - or -NR 29 - wherein R 25 , R 26 , R 27 , R 28 and R 29 are each independently hydrogen, C 1 3 alkyl or C 1-3 alkoxy C 2-3 alkyl, and R 24 represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl, or one or two independently selected from O, S and N Wherein the C 1-3 alkyl group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy, and wherein the C 1-3 alkyl group may be substituted with one or two substituents selected from the group consisting of The cyclic group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy;
    4 ') C 1-5 alkyl X 4 C 1-5 alkyl X 5 R 30 wherein X 4 and X 5 may be the same or different and are each -O-, -S-, -SO-, -SO 2 -, -NR 31 CO-, -CONR 32 -, -SO 2 NR 33 -, -NR 34 SO 2 - or -NR 35 - represents a (wherein, R 31, R 32, R 33, R 34 and R 35 each independently represent hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl), and R 30 represents hydrogen or C 1-3 alkyl;
    5 ') R 36 wherein R 36 is a 5 or 6 membered saturated heterocyclic ring (linked via carbon or nitrogen) having 1 or 2 heteroatoms independently selected from O, S and N, The heterocyclic group may be optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl and C 1-4 alkylsulfonyl Lt; / RTI &gt; alkyl optionally substituted with one or two substituents selected from C1-4 alkyl;
    6 ') C 1-5 alkyl R 36 wherein R 36 is as defined in 5'above;
    7 ') C 2-5 alkenyl R 36 wherein R 36 is as defined in 5'above;
    8 ') C 2-5 alkynyl R 36 wherein R 36 is as defined in 5'above;
    9 ') R 37 wherein R 37 is a pyridone group, a phenyl group, or a 5 or 6 membered aromatic heterocyclic group (linked via carbon or nitrogen) having 1 to 3 heteroatoms selected from O, N and S Wherein said pyridone, phenyl or aromatic heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogeno, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, C 1-4 hydroxy alkoxy, carboxy, trifluoromethyl, cyano, -C (O) NR 38 R 39, and -NR 40 C (O) R 41 ( wherein, R 38 , R 39 , R 40 and R 41 , which may be the same or different, each represent hydrogen, C 1-4 alkyl or C 1-3 alkoxy C 2-3 alkyl) May be on};
    10 ') C 1-5 alkyl R 37 wherein R 37 is as defined in 9'above;
    11 ') C 2-5 alkenyl R 37 wherein R 37 is as defined in 9'above;
    12 ') C 2-5 alkynyl R 37 wherein R 37 is as defined in 9'above;
    13 ') C 1-5 alkyl X 6 R 37 wherein X 6 is -O-, -S-, -SO-, -SO 2 -, -NR 42 CO-, -CONR 43 -, -SO 2 NR 44 -, -NR 45 SO 2 - or -NR 46 - (wherein, R 42, R 43, R 44, R 45 and R 46 are independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2 each -3 alkyl, and R 37 is the same as defined in 9 ');
    14 ') C 2-5 alkenyl X 7 R 37 wherein X 7 is -O-, -S-, -SO-, -SO 2 -, -NR 47 CO-, -CONR 48 -, -SO 2 NR 49 -, -NR 50 SO 2 - or -NR 51 -, wherein R 47 , R 48 , R 49 , R 50 and R 51 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl), and R 37 is the same as defined in 9 ');
    15 ') C 2-5 alkynyl X 8 R 37 wherein X 8 is -O-, -S-, -SO-, -SO 2 -, -NR 52 CO-, -CONR 53 -, -SO 2 NR 54 -, -NR 55 SO 2 - or -NR 56 - (wherein, R 52, R 53, R 54, R 55 and R 56 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C Gt ; and R &lt; 37 &gt; are as defined above;
    16 ') C 1-3 alkyl X 9 C 1-3 alkyl R 37 wherein X 9 is -O-, -S-, -SO-, -SO 2 -, -NR 57 CO-, -CONR 58 - , -SO 2 NR 59 -, -NR 60 SO 2 - or -NR 61 - (wherein, R 57, R 58, R 59, R 60 and R 61 are independently hydrogen, C 1-3 alkyl, or C 1 each -3 alkoxyC 2-3 alkyl, and R 37 is as defined above; And
    17 ') C 1-3 alkyl X 9 C 1-3 alkyl R 36 wherein X 9 and R 36 are as defined in 5' above.
    [17" claim-type="Currently amended] The use according to claim 1, wherein the compound of formula (I) is a compound of formula (VI), or a salt, ester, amide or prodrug thereof:
    &Lt; Formula (VI)

    Wherein X, R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are as defined in claim 1;
    Y is C, S or S (O);
    R 65 is R 9 , OR 9 or NR 10 R 11 , wherein R 9 , R 10 and R 11 are as defined in claim 1.
    [18" claim-type="Currently amended] 18. Use according to claim 17, wherein the compound of formula (VI) is a compound of formula (VIC), or a salt, ester or amide thereof:
    <Formula VIC>

    Wherein X is O or S, S (O) or S (O) 2 , or NR 8 wherein R 8 is hydrogen or C 1-6 alkyl;
    Y is C, S or S (O);
    R 65 is selected from R 9 , OR 9 or NR 10 R 11 wherein R 9 , R 10 and R 11 are selected from hydrogen, optionally substituted hydrocarbyl and optionally substituted heterocyclyl, R 10 and R 11 are Together with the nitrogen atom to which they are attached, form an optionally substituted heterocyclic ring optionally further comprising a further heteroatom;
    R 7 and R 8 are independently selected from the group consisting of hydrogen, halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkoxymethyl, di (C 1-4 alkoxy) methyl, C 1-4 alkanoyl, trifluoromethyl A 5 to 6 membered heteroaromatic ring having 1 to 3 heteroatoms (independently selected from O, S and N), optionally substituted with one or more substituents selected from the group consisting of halogen, cyano, amino, C 2-5 alkenyl, C 2-5 alkynyl, phenyl, Cyclic group wherein said heterocyclic group may be aromatic or non-aromatic and may be saturated (linked through a ring carbon or nitrogen atom) or unsaturated (linked via a ring carbon atom), said phenyl, benzyl or hetero cyclic group is hydroxy, halogeno, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro, C 2-4 alkanoylamino, C 1 -4 alkanoylamino, C 1-4 alkoxycarbonyl, C 1-4 alkyl sulfanyl, C 1-4 alkylsulfinyl, C 1-4 alkylsulfonyl, carbamoyl, NC 1-4 alkyl carbamoyl , N, N-di (C ( C1-4 alkyl) carbamoyl, aminosulfonyl, NC 1-4 alkylaminosulfonyl, N, N-di (C 1-4 alkyl) aminosulfonyl, C 1-4 alkylsulfonylamino, Halogen, C 1-3 alkyl, C &lt; RTI ID = 0.0 &gt; (Ci- 3 alkyl) &lt; / RTI &gt; selected from pyrrolidinyl, pyrrolidinyl, piperazinyl, piperidinyl, imidazolidinyl and pyrazolidinyl 1-3 alkoxycarbonyl, C 1-3 alkanoyloxy, trifluoromethyl, cyano, amino, nitro and C 1-4 alkoxycarbonyl of 5 or less is selected from that can have a selected one or two substituents) from Wherein the substituents may be on one or more ring carbon atoms;
    R 1, R 2, R 3 , R 4 is halo, cyano, nitro, trifluoromethyl, C 1-3 alkyl, -NR 13 R 14 (wherein, R 13 and R 14 may be the same or different , Each independently represent hydrogen or C 1-3 alkyl), or -X 1 R 15 , wherein X 1 is a direct bond, -O-, -CH 2 -, -OCO-, carbonyl, - S-, -SO-, -SO 2 -, -NR 16 CO-, -CONR 16 -, -SO 2 NR 16 -, -NR 17 SO 2 - or -NR 18 - (wherein, R 16, R 17, and R &lt; 18 &gt; each independently represent hydrogen, C1-3 alkyl or C1-3 alkoxyC2-3 alkyl, and R &lt; 15 &gt; is selected from one of the following groups:
    1 &apos;) C 1-5 alkyl which is unsubstituted or may be substituted with one or more groups selected from hydroxy, fluoro or amino, or hydrogen;
    2 ') C 1-5 alkyl X 2 COR 19 wherein X 2 is -O- or -NR 20 - wherein R 20 is hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl , R 19 represents C 1-3 alkyl, -NR 21 R 22 or -OR 23 wherein R 21 , R 22 and R 23 may be the same or different and each represents hydrogen, C 1 -3 alkyl or C 1-3 alkoxyC 2-3 alkyl;
    3 ') C 1-5 alkyl X 3 R 24 wherein X 3 is -O-, -S-, -SO-, -SO 2 -, -OC (O) -, -NR 25 CO-, -C (O) NR 26 -, -SO 2 NR 27 -, -NR 28 SO 2 - or -NR 29 - wherein R 25 , R 26 , R 27 , R 28 and R 29 are each independently hydrogen, C 1 3 alkyl or C 1-3 alkoxy C 2-3 alkyl, and R 24 represents hydrogen, C 1-3 alkyl, cyclopentyl, cyclohexyl, or one or two independently selected from O, S and N Wherein the C 1-3 alkyl group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno and C 1-4 alkoxy, and wherein the C 1-3 alkyl group may be substituted with one or two substituents selected from the group consisting of The cyclic group may have 1 or 2 substituents selected from oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl and C 1-4 alkoxy;
    4 ') C 1-5 alkyl X 4 C 1-5 alkyl X 5 R 30 wherein X 4 and X 5 may be the same or different and are each -O-, -S-, -SO-, -SO 2 -, -NR 31 CO-, -CONR 32 -, -SO 2 NR 33 -, -NR 34 SO 2 - or -NR 35 - represents a (wherein, R 31, R 32, R 33, R 34 and R 35 each independently represent hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl), and R 30 represents hydrogen or C 1-3 alkyl;
    5 ') R 36 wherein R 36 is a 5 or 6 membered saturated heterocyclic ring (linked via carbon or nitrogen) having 1 or 2 heteroatoms independently selected from O, S and N, The heterocyclic group may be optionally substituted with one or more substituents selected from the group consisting of oxo, hydroxy, halogeno, C 1-4 alkyl, C 1-4 hydroxyalkyl, C 1-4 alkoxy, C 1-4 alkoxyC 1-4 alkyl and C 1-4 alkylsulfonyl Lt; / RTI &gt; alkyl optionally substituted with one or two substituents selected from C1-4 alkyl;
    6 ') C 1-5 alkyl R 36 wherein R 36 is as defined in 5'above;
    7 ') C 2-5 alkenyl R 36 wherein R 36 is as defined in 5'above;
    8 ') C 2-5 alkynyl R 36 wherein R 36 is as defined in 5'above;
    9 ') R 37 wherein R 37 is a pyridone group, a phenyl group, or a 5 or 6 membered aromatic heterocyclic group (linked via carbon or nitrogen) having 1 to 3 heteroatoms selected from O, N and S Wherein said pyridone, phenyl or aromatic heterocyclic group is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogeno, amino, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxyalkyl, C 1-4 aminoalkyl, C 1-4 alkylamino, C 1-4 hydroxy alkoxy, carboxy, trifluoromethyl, cyano, -C (O) NR 38 R 39, and -NR 40 C (O) R 41 ( wherein, R 38 , R 39 , R 40 and R 41 , which may be the same or different, each represent hydrogen, C 1-4 alkyl or C 1-3 alkoxy C 2-3 alkyl) May be on};
    10 ') C 1-5 alkyl R 37 wherein R 37 is as defined in 9'above;
    11 ') C 2-5 alkenyl R 37 wherein R 37 is as defined in 9'above;
    12 ') C 2-5 alkynyl R 37 wherein R 37 is as defined in 9'above;
    13 ') C 1-5 alkyl X 6 R 37 wherein X 6 is -O-, -S-, -SO-, -SO 2 -, -NR 42 CO-, -CONR 43 -, -SO 2 NR 44 -, -NR 45 SO 2 - or -NR 46 - (wherein, R 42, R 43, R 44, R 45 and R 46 are independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2 each -3 alkyl, and R 37 is the same as defined in 9 ');
    14 ') C 2-5 alkenyl X 7 R 37 wherein X 7 is -O-, -S-, -SO-, -SO 2 -, -NR 47 CO-, -CONR 48 -, -SO 2 NR 49 -, -NR 50 SO 2 - or -NR 51 -, wherein R 47 , R 48 , R 49 , R 50 and R 51 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C 2-3 alkyl), and R 37 is the same as defined in 9 ');
    15 ') C 2-5 alkynyl X 8 R 37 wherein X 8 is -O-, -S-, -SO-, -SO 2 -, -NR 52 CO-, -CONR 53 -, -SO 2 NR 54 -, -NR 55 SO 2 - or -NR 56 - (wherein, R 52, R 53, R 54, R 55 and R 56 are each independently hydrogen, C 1-3 alkyl or C 1-3 alkoxy C Gt ; and R &lt; 37 &gt; are as defined above;
    16 ') C 1-3 alkyl X 9 C 1-3 alkyl R 37 wherein X 9 is -O-, -S-, -SO-, -SO 2 -, -NR 57 CO-, -CONR 58 - , -SO 2 NR 59 -, -NR 60 SO 2 - or -NR 61 - (wherein, R 57, R 58, R 59, R 60 and R 61 are independently hydrogen, C 1-3 alkyl, or C 1 each -3 alkoxyC 2-3 alkyl, and R 37 is as defined above; And
    17 ') C 1-3 alkyl X 9 C 1-3 alkyl R 36 wherein X 9 and R 36 are as defined in 5' above.
    [19" claim-type="Currently amended] Comprising a compound of formula (II) as defined in claim 15,
    (i) when R 1 , R 4 , R 6 , R 7 and R 8 are both hydrogen and R 2 and R 3 are both hydrogen or both are methoxy, then R 64 is not phenyl;
    (ii) when R 1 , R 4 , R 6 , R 7 and R 8 are both hydrogen, R 2 and R 3 are methoxy and Z is C (O), R 64 is not methyl;
    (iii) when all of R 1 , R 2 , R 3 , R 4 , R 6 , R 7 and R 8 are hydrogen, X is oxygen, R 6 is 4-methyl-1-piperazinyl, (O), R &lt; 64 &gt; is not methyl
    A compound of formula (IIA), or a salt, ester, amide or prodrug thereof.
    [20" claim-type="Currently amended] Is as defined in claim 16, provided that in the formula,
    (i) when R 1 , R 4 , R 7 and R 8 are both hydrogen and R 2 and R 3 are both hydrogen or both are methoxy, then R 64 is not phenyl;
    (ii) when R 1 , R 4 , R 6 , R 7 and R 8 are both hydrogen, R 2 and R 3 are methoxy and Z is C (O), R 64 is not methyl
    A compound of formula (IIC), or a salt, ester or amide thereof.
    [21" claim-type="Currently amended] A compound of formula (IIB), or a salt, ester, amide or prodrug thereof:
    <Formula IIB>

    Wherein R 1 , R 4 , R 6 , R 7 , R 8 , R 64 , Z and X are as defined in claim 15, R 2 ' and R 3' are each R 2 and R 3 , , One or more of said groups, preferably R 3 ', is a group of the formula X 1 -R 15' , wherein X 1 is as defined above and R 15 ' is as defined in claim 1, to be.
    [22" claim-type="Currently amended] A compound of formula (IID), or a salt, ester or amide thereof:
    <Formula IID>

    Wherein R 1 , R 4 , R 7 , R 8 , X, Z and R 64 are as defined in claim 16, R 2 ' and R 3' are as defined in claim 16, and R 2 and R 3 , with the proviso that at least one of said groups, preferably R 3 ', is of the formula X 1 -R 15' , wherein X 1 is as defined in claim 16 and R 15 ' is as defined in claim 16, R &lt; 15 &gt;, but not methyl).
    [23" claim-type="Currently amended] Compounds of formula (VIA), or salts, esters, amides or prodrugs thereof:
    (VIA)

    Wherein, X, Y, R 1, R 4, R 6, R 7, R 8 are as defined in claim 1, R 65 are as defined in claim 17 wherein, R 68 and R 69 is at least of which R 2 and R 3 as defined in claim 1, except that one is of the formula X 1 R 15 , wherein R 15 is as defined in any of claims 1 to 6, , When either R 68 or R 69 is morpholinofoxy, the remainder is not a group of formula (18) as defined in any of claims 1 to 6, and wherein R 68 or R 69 Is methoxyethoxy, the remainder is not methoxy.
    [24" claim-type="Currently amended] 24. A compound according to claim 23, or a salt, ester or amide thereof, of formula VIB.
    <Formula VIB>

    Wherein, X, Y, R 1, R 4, R 6, R 7, R 8 are as defined in claim 18, R 65 are as defined in claim 18 wherein, R 68 and R 69 is at least of which one has the general formula X 1 R 15 but to correspond to the R 2 and R 3 as defined in claim 18 except that (wherein, R 15 is as defined in claim 18), provided that the R 68 or R 69 Is morpholinophoxy, the remainder is not a group of formula (18) as defined in claim 18, and when either R 68 or R 69 is methoxyethoxy, the remainder is methyl It is not.
    [25" claim-type="Currently amended] 25. Compounds according to any one of claims 19 to 24, wherein X is NH.
    [26" claim-type="Currently amended] 25. The compound according to any one of claims 19 to 24, wherein X &lt; 1 &gt; is oxygen.
    [27" claim-type="Currently amended] To if the step of the compounds as the reaction of (Formula IX) to a compound of formula (VIII) ', and if necessary, groups R 1', R 2 ", R 3" or R 4 'groups to respectively R 1, R 2 Or R 2 ' or R 68 , R 3 or R 3' or R 69 , and R 4 , or to other groups. : &Lt;
    &Lt; Formula (VIII) &gt;

    <Formula IX '

    Wherein R 1 ' corresponds to the group R 1 or a precursor thereof as defined for the compound of any of claims 19 to 26;
    R 2 &quot; corresponds to a group of R 2 or R 2 ' or R 68 as defined for the compound of any of claims 19 to 26 or a precursor thereof;
    R 3 " corresponds to a group R 3 or R 3 ' or R 69 or a precursor thereof as defined for the compound of any of paragraphs 19 to 26;
    R 4 ' corresponds to a group R 4 or a precursor thereof as defined for compounds of claims 19 to 26;
    R 6 'is 18 and R 6, when present on any one of the compounds of wherein to 26, wherein in the case where there is no R 6 hydrogen;
    R 85 is a leaving group;
    X, R &lt; 7 &gt; and R &lt; 8 &gt; are as defined for a compound according to any one of claims 19 to 26;
    R 86 is a group of the formula NHZR 64 or Y (O) R 65 , wherein Z, R 64 , Y and R 65 are as defined for a compound of any of claims 19 to 26.
    [28" claim-type="Currently amended] Comprising administering to a warm-blooded animal, such as a human, an effective amount of a compound of formula (I) as defined in claim 1, or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof, or a prodrug thereof, A method for inhibiting aurora 2 kinase in an animal in need of such treatment.
    [29" claim-type="Currently amended] A compound of formula (IIA), (IIB) or (VIA), or a pharmaceutically acceptable salt or a biologically active form thereof, as defined in any of claims 19, 20 or 23, (IIC), (IID) or (VIB) as defined in claim 21, 22 or 24, respectively, or a pharmaceutically acceptable salt or solvate thereof, In vivo hydrolysable esters or amides.
    [30" claim-type="Currently amended] (IIA), (IIB) or (VIA) or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide or prodrug thereof as defined in claim 19 or 20 or 23, respectively, (IIC), (IID) or (VIB), or a pharmaceutically acceptable salt or in vivo hydrolysable ester or amide thereof, as defined in any of claims 21, 22 or 24, Together with an acceptable carrier.
    [31" claim-type="Currently amended] 18. Use according to any one of claims 1 to 15 or 17, wherein the compound of formula (I) is a prodrug.
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    同族专利:
    公开号 | 公开日
    IL148576D0|2002-09-12|
    JP2003509499A|2003-03-11|
    RU2002110461A|2004-03-10|
    EE200200119A|2003-04-15|
    HK1046686A1|2003-01-24|
    AT449083T|2009-12-15|
    US7709479B1|2010-05-04|
    AU7301000A|2001-04-24|
    IS6305A|2002-03-18|
    BR0014116A|2002-05-21|
    CZ20021009A3|2002-06-12|
    DE60043349D1|2009-12-31|
    ES2334879T3|2010-03-17|
    EP1218354A1|2002-07-03|
    JP4870304B2|2012-02-08|
    HU0300059A2|2003-07-28|
    EP1218354B1|2009-11-18|
    SK3822002A3|2002-10-08|
    CA2384291A1|2001-03-29|
    NO20021399L|2002-04-30|
    CO5200785A1|2002-09-27|
    HU0300059A3|2003-08-28|
    WO2001021596A1|2001-03-29|
    BG106492A|2003-01-31|
    NO20021399D0|2002-03-20|
    CN1391562A|2003-01-15|
    PL354323A1|2004-01-12|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1999-09-21|Priority to GBGB9922170.7A
    1999-09-21|Priority to GBGB9922154.1A
    1999-09-21|Priority to GB9922154.1
    1999-09-21|Priority to GB9922170.7
    2000-09-18|Application filed by 다비드 에 질레스, 아스트라제네카 아베
    2000-09-18|Priority to PCT/GB2000/003580
    2002-05-03|Publication of KR20020032612A
    优先权:
    申请号 | 申请日 | 专利标题
    GBGB9922170.7A|GB9922170D0|1999-09-21|1999-09-21|Chemical compounds|
    GBGB9922154.1A|GB9922154D0|1999-09-21|1999-09-21|Chemical compounds|
    GB9922154.1|1999-09-21|
    GB9922170.7|1999-09-21|
    PCT/GB2000/003580|WO2001021596A1|1999-09-21|2000-09-18|Quinazoline derivatives and their use as pharmaceuticals|
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