Quinazoline analogs as receptor tyrosine kinase inhibitors

[0001] This invention relates to new type I receptor tyrosine kinase inhibitors and related kinases, pharmaceutical compositions containing such inhibitors, and methods for preparing these inhibitors. These inhibitors are useful for treating hyperproliferative diseases such as cancer and inflammation in mammals, and in particular humans.

2. Description of the Related Art [0002] The type I receptor tyrosine kinase family consists of four closely related receptors: EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER) and ErbB4 (HER4) (Discussion in Riese and Stem, Bioessays (1998) 20: 41-48, Olayioye et al., EMBO Journal (2000) 19: 3159-3167 and Schlessinger, Cell (2002) 110: 669-672). They are single-pass transmembrane glycoprotein receptors containing the extracellular ligand binding region and the intracellular signaling domain. In addition, all of these receptors contain an intracellular active tyrosine kinase domain, except for ErbB3, whose kinase domain has no enzymatic activity. Upon activation, these receptors transmit extracellular signals through the cytosol to the nucleus. The activation process begins by binding the ligand to the extracellular domain of the receptor by one of many different hormones. The ligand binding is followed by homo- or heterodimerization, which results in activation of tyrosine kinase domains and tyrosine phosphorylation in intracellular signaling domains. Since no known ErbB2 ligand has been described and ErbB3 does not contain an active kinase domain, these receptors must be homodimerized to elicit a response. The phosphotyrosines then recruit the cofactors necessary to initiate several different signaling cascades, including the ras / raf / MEK / MAPK and PI3K / AKT pathways. The exact signal elicited will depend on what ligands are present because the intracellular signaling domains differ in activated pathways. These signaling pathways lead to both cell proliferation and cell survival by inhibiting apoptosis.

[0003] Several researchers have demonstrated the role of EGFR and ErbB2 in cancer development (Discussion in the publication Salomon, et al., Crit. Rev. Oncol. Hematol. (1995) 19: 183-232, Klapper, et al., Adv. Cancer Res (2000) 77, 25-79 and Hynes and Stem, Biochim. Biophys. Acta (1994) 1198: 165-184). Squamous cell carcinomas of the head, neck and lungs express high levels of EGFR. Constitutively active EGFR has also been found in gliomas, breast cancer and lung cancer. About 30% of all breast cancers have over-expression of ErbB2. It is also involved in other cancers in humans, including colon, ovarian, bladder, stomach, esophagus, lung, uterus and prostate cancers. ErbB2 overexpression is also associated with poor prognosis for human cancer, including metastasis and early relapse.

[0004] The type I tyrosine kinase receptor family has become an active area of ​​cancer research (discussed in Mendelsohn and Baselga, Oncogene (2000) 19: 6550-6565 and

Normanno et al., Endocrine-Related Cancer (2003) 10: 1-21). Clinical efficacy has been demonstrated for several inhibitors1

EP 1 660 090 B1 pathways of the EGFR and ErbB2 signaling pathway in the treatment of cancer. In the United States in 1998, herceptin, a humanized version of the anti-ErbB2 monoclonal antibody, was approved for the treatment of breast cancer. Small molecule EGRF, Iressa and Tarceva inhibitors are expected to be available on the market.

In addition, there are several other antibodies and small molecules in clinical and preclinical studies that are directed at disrupting the type I receptor tyrosine kinase I signaling pathway. For example, IMC-225 has been shown to be effective, which is a humanized antibody against the extracellular domain of EGFR, and which is likely to be approved.

[0005] WO 97/30034 discloses quinazoline derivatives, methods for their preparation, pharmaceutical compositions containing them, and the use of their properties as receptor tyrosine kinase inhibitors for the treatment of a proliferative disease such as cancer.

SUMMARY OF THE INVENTION [0006] The present invention provides compounds, methods for their preparation, and pharmaceutical compositions containing those compounds that inhibit type I receptor tyrosine kinases. These compounds, generally referred to as quinazoline analogues, are useful as therapeutic agents for diseases that can be treated by inhibition Type I receptor tyrosine kinases. They may also act as serine and threonine inhibitors and as dual specificity kinase inhibitors. In general, the invention relates to a compound, including separated enantiomers, diastereomers, solvates and pharmaceutically acceptable salts, which is represented by Formula I:

[0007]

<img file="PL1660090T3_D0001.tif" />

[0008] wherein A is bonded to at least one carbon atom at the 5, 6, 7 or 8 positions of the bicyclic ring, and wherein the bicyclic ring is substituted with zero, one or two independent₃ ne groups R³;

[0009] X is N or C-CN;

[0010] A is Z;

₁ [0011] R¹ is a substituted or unsubstituted, monocyclic or bicyclic, aryl or heteroaryl residue;

[0012] R² is H;

[0013] R³ is hydrogen or -OR⁶;

[0014] Z is

<img file="PL1660090T3_D0002.tif" />

[0015] wherein, when R⁶ = H, then Z also includes [0016]

<img file="PL1660090T3_D0003.tif" />

[0017] and wherein Z comprises one or more R groups⁸ or R⁹where such R groups⁸ and R⁹ may be associated with the same or with different atoms;

[0018] W is O and V is CR⁸R⁹;

[0019] R⁶, R⁸ and R⁹ are independently selected from the group consisting of hydrogen, trifluoromethyl, C1-C10 alkyl, (CH2) 0-4C3-C10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl, wherein such alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl are optionally substituted with one to five groups independently selected from the group consisting of oxo, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, cyano group, nitro group, OR⁶, NO⁶R⁸, SR⁶, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl;

[0020] or R⁶ and R⁸ together with the atoms to which they are attached they may be independently bonded and may form a 3- to 10-membered cycloalkyl ring or heterocycloalkyl ring optionally containing one or more additional heteroatoms selected from the group consisting of O, S, SO, SO2 and NR⁶wherein each ring carbon atom is optionally substituted with one to three groups independently selected from the group consisting of halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, cyano group, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, OR⁸, NO⁶R⁸, SR⁶, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl, provided that such a ring does not contain two adjacent O or two adjacent S atoms;

[0021] or R⁸ and R⁹ together with the atoms to which they are attached they may be independently bonded and may form a 3- to 10-membered cycloalkyl ring or heterocycloalkyl ring optionally containing one or more additional heteroatoms selected from the group consisting of O, S, SO, SO2 and NR⁶wherein each ring carbon atom is optionally substituted with one to three groups independently selected from the group consisting of halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, cyano group, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, OR⁸, NO⁶R⁸, SR⁶, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl, provided that such a ring does not contain two adjacent O or two adjacent S atoms;

[0022] The term "alkyl" as used herein refers to a linear or branched saturated monovalent hydrocarbon radical of one to twelve carbon atoms, wherein the alkyl radical may optionally be independently substituted with one or more substituents described herein, "Alkylene "means a linear or branched saturated divalent hydrocarbon radical of one to twelve carbon atoms,

[0024] "alkenyl" refers to a monovalent hydrocarbon radical with a linear or branched chain and two to twelve carbon atoms containing at least one double bond, such alkenyl radical may be optionally independently substituted with one or more of those described herein substituents, and includes radicals with "cis" and "trans" orientations, or alternatively, with "E" and "Z" orientations, [0025] "alkenylene" refers to a linear or branched divalent hydrocarbon radical of two to twelve carbon atoms containing at least one double bond, wherein said alkenylene radical may optionally be independently substituted with one or more substituents described herein. " alkynyl "refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms, containing at least one triple bond, wherein said alkynyl radical may optionally be independently substituted with one or more substituents described herein, "alkynylene" refers to a linear or branched divalent hydrocarbon radical of two to twelve carbon atoms containing at least one triple bond, wherein said alkynylene radical may be optionally substituted independently with one or more substituents described herein, [0028] "allyl" refers to a radical of formula RC = CHCHR wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or any substituent as defined herein, wherein such allyl may optionally be independently substituted with one or more substituents described herein, "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon radical containing from three to twelve carbon atoms, wherein the cycloalkyl may optionally be independently substituted with one or more substituents described herein, and further includes bicyclic and tricyclic cycloalkyl structures, which may include saturated or partially unsaturated cycloalkyl fused to a saturated or partially unsaturated cycloalkyl or heterocycloalkyl ring or an aryl or heteroaryl ring, [0030] "heteroalkyl" refers to a linear or branched saturated monovalent hydrocarbon radical of one to twelve carbon atoms in which at least one of the carbon atoms is replaced by a heteroatom selected from N, O or S, which radical may be carbon or heteroatom radical, and optionally it may be independently substituted with one or more substituents described herein, and wherein the term "heteroalkyl" includes alkoxy and heteroalkoxy, [0031] "heterocycloalkyl" refers to a saturated or partially unsaturated cyclic radical with up to 8 ring atoms, in which at least one ring atom is a heteroatom selected from nitrogen, oxygen and sulfur , and the other ring atoms are C, wherein one or more ring atoms may optionally be independently substituted with one or more substituents described below, wherein the radical may be a carbon radical or a heteroatom radical, including heterocyclic radicals that are fused to aromatic or heteroaromatic rings, "heteroalkenyl" refers to a monovalent hydrocarbon radical with a linear or branched chain of three to twelve carbon atoms, containing at least one double bond in which at least one of the carbon atoms has been replaced with a heteroatom selected from N,

EP 1 660 090 B1

O or S, which radical may be a carbon radical or a heteroatom radical, and may optionally be independently substituted with one or more substituents described herein and include radicals having "cis" and "trans" orientations, or alternatively, having "E" orientations and "Z", "heteroalkynyl" refers to a linear or branched monovalent hydrocarbon radical of three to twelve carbon atoms containing at least one triple bond, wherein at least one of the carbon atoms has been replaced with a heteroatom selected from N, O or S, which radical may be a carbon radical or a heteroatom radical, and may optionally be independently substituted with one or more substituents described herein, "heteroallyl" refers to radicals of the formula RC = CHCHR in which R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or any substituent as described herein, and wherein at least one of the carbon atoms has been replaced with a heteroatom selected from N, O or S, which radical may be a carbon radical or a heteroatom radical, and may optionally be independently substituted with one or more substituents described herein, "Aryl" is a monovalent aromatic hydrocarbon monocyclic radical with 6 to 10 ring atoms or a polycyclic aromatic hydrocarbon, optionally independently substituted with one or more substituents described herein, "Heteroaryl" means a monovalent monocyclic aromatic radical of 5 to 10 ring atoms or a polycyclic aromatic radical containing one or more ring heteroatoms selected from N, O, or S, and the remaining atoms in the ring are C, optionally independently substituted with one or more substituents described herein, "halo" means fluoro, chloro, bromine or iodine and the term "halogen" refers to a fluoro, chloro, bromo or iodo substituent, and when the group is substituted by a substituent, this substituent is selected from halogen, alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl , heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Gn-cycloalkyl, Gn-heterocycloalkyl, Gn-OR¹, Gn-NO2, Gn-CN, Gn-CO2R^1,, Gn- (C = O) R^1,,

Gn-O (C = O) R^1,, Gn-O-alkyl, Gn-OAr, Gn-SH, Gn-SR^1,, Gn-SOR^1,, Gn-SO2R^1,, Gn-S-Ar, Gn-SOAr, Gn-SO2Ar, aryl, heteroaryl, Gn-Ar, Gn- (C = O) NR^2'R^3', Gn-NR^2'R^3', Gn-NR^1'(C = O) R ', Gn-SO2 NR^2'R^3', PO3H2 and SO3H2, where G is alkylene containing from 1 to 4 carbon atoms, or alkenylene or alkynylene, each of which contains from 2 to 4 carbon atoms, wherein such alkylene, alkenylene or alkynylene may be substituted with 1 '2' 3 '' or unsubstituted; n is zero or 1; R^1', R^2' and R^3' independently are alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Gn-cycloalkyl or Gnheterocycloalkyl; and Ar is aryl or heteroaryl and wherein such alkyl, allyl, alkenyl, alkynyl, heteroalkyl, 1 'heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Gn-cycloalkyl, Gn-heterocycloalkyl, Ar, R^1', 2' 3'

R^2' and R^3' may be further substituted or unsubstituted.

[0039] The invention also relates to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of compounds of general Formula I. Also described are methods for preparing compounds of Formula I.

[0040] In another aspect, the present invention provides compounds that inhibit type I receptor tyrosine kinase activity, such as EGFR, ErbB2, ErbB3, ErbB4, VEGFR2, Flt3 and FGFR, including compounds of Formula I.

[0041] In a further aspect, the present invention provides compounds for use in a method of treatment of diseases or conditions mediated by type I receptor tyrosine kinases, which includes

EP 1 660 090 B1 administers to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or its in vivo cleavable prodrug.

[0042] In a further aspect, the present invention provides compounds for use in a method of inhibiting the production of type I receptor tyrosine kinases, which comprises administering to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or its in vivo cleavable prodrug.

[0043] In another aspect, the present invention provides compounds for use in a method providing a type I receptor kinase inhibitory activity, comprising administering to a warm-blooded animal an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or an in vivo cleavable prodrug thereof.

[0044] In another aspect, the present invention provides compounds for use in a method of treatment or prevention of a condition mediated by type I receptor kinase, comprising administering the compound in an amount effective to treat or prevent the condition mediated by said type I receptor kinase, or a pharmaceutical composition containing such a compound to a human or animal in need thereof, wherein the compound is a compound of Formula I, or a pharmaceutically acceptable salt thereof or its in vivo cleavable prodrug. The condition that can be treated and mediated by type I receptor kinase includes hyperproliferative disorders, including head and neck cancer, lung cancer, breast cancer, colon, ovary, bladder, stomach, kidney, skin, pancreas, leukemia, lymphoma, cancer esophagus, uterus or prostate.

[0045] The compounds of Formula I can be advantageously used in combination with other known therapeutic agents.

[0046] The invention also relates to pharmaceutical compositions comprising an effective amount of an agent selected from compounds of Formula I, or a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite or pharmaceutically acceptable salt thereof.

[0047] Additional advantages and new features of this invention will be set forth in the following descriptive part, and after reading the description or after carrying out this invention, they will become apparent to those skilled in the art. The benefits of the invention can be realized and obtained using the tools, combinations, compositions and methods specifically described in the appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS [0048] The attached drawings, which are incorporated herein and which form part of the description, illustrate non-limiting embodiments of the present invention and, in combination with the description, serve to explain the foundations of the present invention.

In the drawings:

[0049] In Fig [0050] In Fig [0051] In Fig [0052] In Fig [0053] In Fig [0054] The Fig is a reaction scheme for the production of iminoamidines.

another reaction scheme for iminoamidine production is shown.

another reaction scheme for iminoamidine production is shown.

another reaction scheme for iminoamidine production is shown.

is a reaction scheme for the production of oxazolines.

another reaction scheme for oxazoline production is shown.

EP 1 660 090 B1

DETAILED DESCRIPTION OF THE INVENTION [0055] Compounds of Formula I of the invention are useful for inhibiting type I receptor tyrosine kinases such as EGFR (HER1), ErbB2 (HER2), ErbB3 (HER3), ErbB4 (HER4), VEGFR2, Flt3 and FGFR. Compounds of Formula I may also be useful as inhibitors of serine, threonine and dual specificity kinases such as Raf, MEK and p38. Such compounds have utility as therapeutic agents in diseases that can be treated by inhibiting the signaling pathway of receptor type I tyrosine kinases and the pathways of serine, threonine and dual specificity kinases. In general, the invention relates to a compound, including separated enantiomers, diastereomers, solvates and pharmaceutically acceptable salts, which is represented by Formula I:

[0056]

<img file="PL1660090T3_D0004.tif" />

[0057] wherein A is bonded to at least one carbon atom at the 5, 6, 7 or 8 positions of the bicyclic ring, wherein the bicyclic ring is substituted with zero, one or two independent₃ lying groups R³;

[0058] X is N or C-CN;

[0059] A is Z;

₁ [0060] R¹ is a substituted or unsubstituted, monocyclic or bicyclic aryl or heteroaryl residue;

[0061] R² is H;

[0062] R³ is hydrogen or -OR⁶; [0063] Z is

<img file="PL1660090T3_D0005.tif" />

[0064] wherein, when R⁶ = H, then Z also includes [0065]

<img file="PL1660090T3_D0006.tif" />

[0066] and wherein Z include one or more R groups⁸ or R⁹which are R groups⁸ and R⁹ may be associated with the same or with different atoms;

EP 1 660 090 B1 [0067] W is O and V is CR⁸R⁹;

[0068] R⁶, R⁸ and R⁹ are independently selected from the group consisting of hydrogen, trifluoromethyl, C1-C10 alkyl, (CH2) 0-4C3-C10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl, wherein such alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl are optionally substituted with one to five groups independently selected from the group consisting of oxo, halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, cyano group, nitro group, OR⁶, NO⁶R⁸, SR⁶, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl;

[0069] or R⁶ and R⁸ together with the atoms to which they are attached, they can be independently connected to form a 3 to 10-membered cycloalkyl ring or heterocycloalkyl ring optionally containing one or more additional heteroatoms selected from the group consisting of O, S, SO, SO2 and NR⁶wherein each ring carbon atom is optionally substituted with one to three groups independently selected from the group consisting of halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, cyano group, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, OR⁸, NO⁶R⁸, SR⁶, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl, provided that such a ring does not contain two adjacent O or two adjacent S atoms;

[0070] or R⁸ and R⁹ together with the atoms to which they are attached, they can be independently linked to form a 3 to 10-membered cycloalkyl ring or heterocycloalkyl ring containing one or more additional heteroatoms selected from the group consisting of O, S, SO, SO2 and NR⁶wherein each ring carbon atom may optionally be substituted with one to three groups independently selected from the group consisting of halogen, C1-C10 alkyl, C2-C10 alkenyl, C2-C10alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, cyano group, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, OR⁸, NO⁶R⁸, SR⁶, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, partially unsaturated heterocyclyl and heterocyclylalkyl, provided that such a ring does not contain two adjacent O or two adjacent S atoms;

[0071] The term "alkyl" as used herein refers to a saturated monovalent hydrocarbon radical, linear or branched, with one to twelve carbon atoms, wherein the alkyl radical may optionally be independently substituted with one or more substituents, "Alkylene" means a linear or branched saturated divalent hydrocarbon radical of one to twelve carbon atoms, [0073] "alkenyl" refers to a linear or branched monovalent hydrocarbon radical having two to twelve carbon atoms containing at least one double bond, wherein such alkenyl radical may be optionally independently substituted with one or more substituents described herein, and includes radicals with "cis" and "trans" orientations, or alternatively, with "E" and "Z" orientations, [0074] "alkenylene" refers to a linear or branched divalent hydrocarbon radical of two to twelve carbon atoms containing at least one double bond, wherein said alkenylene radical may be optionally substituted independently with one or more substituents described herein,

[0075] "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms containing at least one triple bond, wherein such alkynyl radical may optionally be independently substituted with one or more substituents described herein [0076] "alkynylene" refers to a linear or branched divalent hydrocarbon radical of two to twelve carbon atoms, containing at least one triple bond, wherein said alkynylene radical may be optionally substituted independently with one or more substituents described herein, "allyl" refers to a radical of formula RC = CHCHR, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or any substituent as defined herein, wherein such allyl may optionally be independently substituted with one or more substituents described herein, [0078] "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon radical containing from three to twelve carbon atoms, wherein such cycloalkyl may optionally be independently substituted with one or more substituents described herein, and further includes bicyclic and tricyclic cycloalkyl structures, which may include a saturated or partially unsaturated cycloalkyl condensed with a saturated or partially unsaturated cycloalkyl or heterocycloalkyl ring or an aryl or heteroaryl ring, [0079] "heteroalkyl" refers to a saturated monovalent hydrocarbon radical having a linear or branched chain having one to a twelve carbon atom which at least one of the carbon atoms is replaced by a heteroatom selected from N, O or S, which radical may be a carbon radical or a heteroatom radical, and may optionally be independently substituted with one or more substituents described herein, and wherein the term "heteroalkyl" includes alkoxy and heteroalkoxy radicals, "heterocycloalkyl" refers to saturated or partially unsaturated a cyclic radical with 3 to 8 ring atoms in which at least one ring atom is a heteroatom selected from nitrogen, oxygen and sulfur, and the remaining ring atoms are C atoms, wherein one or more ring atoms may optionally be independently substituted with one or more substituents as described below, which radical may be a carbon radical or a heteroatom radical, including heterocyclic radicals that are fused with aromatic rings or heteroaromatic, [0081] "heteroalkenyl" refers to a linear or branched monovalent hydrocarbon radical of three to twelve carbon atoms containing at least one double bond in which at least one of the carbon atoms has been replaced with a heteroatom selected from N, O or S, with what radical can be a carbon radical or a heteroatom radical, and optionally it may be independently substituted with one or more substituents described herein and include radicals having "cis" and "trans" orientations, or alternatively, having "E" and "Z" orientations, "heteroalkynyl" refers to linear or a branched monovalent hydrocarbon radical of three to twelve carbon atoms containing at least one triple bond in which at least one of the carbon atoms has been replaced with a heteroatom selected from N, O or S, wherein the radical may be a carbon radical or a heteroatom radical, and may optionally be independently substituted with one or more substituents described herein,

[0083] "heteroallyl" refers to radicals of the formula RC = CHCHR in which R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or any substituent as described herein and in which at least one of the carbon atoms has been replaced with a heteroatom selected from N, O or S, which radical may be a carbon radical or a heteroatom radical, and may optionally be independently substituted with one or more substituents described herein, [0084] "Aryl" means a monovalent aromatic hydrocarbon monocyclic radical with 6 to 10 ring atoms or a polycyclic aromatic hydrocarbon, optionally independently substituted with one or more substituents described herein, "Heteroaryl" means a monovalent monocyclic aromatic radical with 5 to 10 ring atoms or a polycyclic aromatic radical containing one or more ring heteroatoms selected from N, O, or S, and the remaining ring atoms are C, optionally independently substituted with one or more substituents described herein, "halo" means fluoro, chloro, bromo or iodo, and the term "halogen" refers to fluoro, chloro, bromo or iodo , And when the group is substituted with a substituent, the substituent is selected from halogen, alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Gn-cycloalkyl, Gn-heterocycloalkyl, Gn-OR^1,, Gn-NO2, Gn-CN, Gn-CO2R^1,,

Gn (C = O) R^1,, Gn-O (C = O) R^1,, Gn-O-alkyl, Gn-OAr, Gn-SH, Gn-SR^1,, Gn-SOR^1,, Gn-SO2R^1,, Gn-S-Ar, Gn-SOAr,

Gn-SO2Ar, aryl, heteroaryl, Gn-Ar, Gn- (C = O) NR^2'R^3', Gn-NR^2'R^3', Gn-NR^1,(C = O) R ', Gn-SO2 NR^2'R^3',

PO3H2, and SO3H2, in which G is alkylene containing from 1 to 4 carbon atoms, or alkenylene or alkynylene, each of which contains from 2 to 4 carbon atoms, wherein such alkylene, alkenylene or alkynylene 1 '2' 3 'can be substituted or unsubstituted; n is zero or 1; R^1', R^2' and R^3' independently are alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Gncycloalkyl or Gn-heterocycloalkyl; and Ar is aryl or heteroaryl, wherein such alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Gn-cycloalkyl, Gn1 '2' 3 'heterocycloalkyl, Ar, R^1', R^2' and R^3' may be further substituted or unsubstituted.

[0088] The term "alkyl" as used herein refers to a linear or branched saturated monovalent hydrocarbon radical of one to twelve carbon atoms, wherein the alkyl radical may optionally be independently substituted with one or more substituents described below. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, etc.

[0089] "Alkylene" means a linear or branched saturated divalent hydrocarbon radical with one to twelve carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, etc. [0090] The term "alkenyl" refers to a monovalent hydrocarbon radical a linear or branched chain of two to twelve carbon atoms containing at least one double bond, such as ethenyl, propenyl, etc., wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having "cis" and "trans" orientations or, alternatively, having "E" and "Z" orientations.

[0091] The term "alkenylene" refers to a linear or branched divalent hydrocarbon radical of two to twelve carbon atoms containing at least one double bond, wherein said alkenylene radical may be optionally substituted independently with one or more substituents described herein. Examples include, but are not limited to, ethenylene, propenylene, etc.

[0092] The term "alkynyl" refers to a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms containing at least one triple bond. Examples include, but are not limited to, ethynyl, propynyl, etc., wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein.

[0093] The term "alkynylene" refers to a linear or branched divalent hydrocarbon radical of two to twelve carbon atoms containing at least one triple bond, wherein such alkynylene radical may optionally be independently substituted with one or more substituents described herein.

[0094] The term "allyl" refers to a radical of formula RC = CHCHR wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or any substituent as defined herein, wherein allyl may optionally be independently substituted with one or more substituents described herein.

[0095] The term "cycloalkyl" refers to a saturated or partially unsaturated cyclic hydrocarbon radical containing from three to twelve carbon atoms, wherein the cycloalkyl may optionally be independently substituted with one or more substituents described herein. The term "cycloalkyl" includes bicyclic and tricyclic cycloalkyl structures, wherein such bicyclic and tricyclic structures may include saturated or partially unsaturated cycloalkyl condensed with a saturated or partially unsaturated cycloalkyl or heterocycloalkyl ring or an aryl or heteroaryl ring. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norboranes, etc.

[0096] The term "heteroalkyl" refers to a saturated monovalent linear or branched chain hydrocarbon radical of one to twelve carbon atoms in which at least one of the carbon atoms is replaced by a heteroatom selected from N, O or S, which radical may be a carbon radical or heteroatom radical (i.e. a heteroatom may be at the center or end of the radical). The heteroalkyl radical may be optionally substituted independently with one or more substituents described herein. The term "heteroalkyl" includes alkoxy and heteroalkoxy radicals.

[0097] The term "heterocycloalkyl" refers to a saturated or partially unsaturated cyclic radical with 3 to 8 ring atoms, in which at least one ring atom is a heteroatom selected from nitrogen, oxygen and sulfur, and the remaining ring atoms are C atoms, wherein one or more ring atoms may optionally be independently substituted with one or more substituents as described below. Such a radical may be a carbon radical or a heteroatom radical. "Heterocycloalkyl" also includes heterocyclic radicals that are fused to aromatic or heteroaromatic rings. Examples of heterocycloalkyl rings include, but are not limited to, pyrrolidine, piperidine, piperazine, tetrahydropyranyl, morpholine, thiomorpholine, homopiperazine, phthalimide and derivatives thereof.

[0098] The term "heteroalkenyl" refers to a monovalent hydrocarbon radical with a linear or branched chain of three to twelve carbon atoms containing at least one double bond, e.g., ethenyl, propenyl, etc., wherein at least one of the carbon atoms replaced with a heteroatom selected from N, O, or S, the radical may be a carbon radical or a heteroatom radical (i.e. a heteroatom may be present at the center or end of the radical). The heteroalkenyl radical may optionally be independently substituted with one or more substituents described herein and include radicals having "cis" and "trans" orientations or, alternatively, having "E" and "Z" orientations.

[0099] The term "heteroalkynyl" refers to a linear or branched monovalent hydrocarbon radical of three to twelve carbon atoms containing at least one triple bond. Examples include, but are not limited to, ethynyl, propynyl, etc., wherein at least one of the carbon atoms has been replaced with a heteroatom selected from N, O, or S, and such radical may be a carbon radical or a heteroatom radical (i.e. the heteroatom may be present in the middle or end of the radical). The heteroalkynyl radical may be optionally substituted independently with one or more substituents described herein.

[0100] The term "heteroallyl" refers to radicals of the formula RC = CHCHR, wherein R is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or any substituent as described herein, and wherein at least one of atoms carbon has been replaced with a heteroatom selected from N, O or S, which radical may be a carbon radical or a heteroatom radical (i.e. a heteroatom may be present at the center or end of the radical). Heteroallyl may optionally be independently substituted with one or more substituents described herein.

[0101] "Aryl" means a monovalent aromatic monocyclic hydrocarbon radical of 6 to 10 ring atoms or a polycyclic aromatic hydrocarbon, optionally substituted independently with one or more substituents described herein. More specifically, the term aryl includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.

[0102] "Heteroaryl" means a monovalent monocyclic aromatic radical of 5 to 10 ring atoms or a polycyclic aromatic radical containing one or more ring heteroatoms selected from N, O, or S, and the remaining ring atoms are C atoms. The aromatic radical is optionally independently substituted with one or more substituents described herein. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl, benzopyranyl, thiazolyl and derivatives thereof.

[0103] The term "halo" means fluoro, chloro, bromo or iodo, and the term "halogen" refers to fluoro, chloro, bromo or iodo substituent.

[0104] In general, different residues or functional groups in the compounds of formula I may optionally be substituted with one or more substituents. Examples of substituents suitable for the purposes of the present invention include, but are not limited to, halogen, alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Gn-cycloalkyl, Gn-heterocycloalkyl, Gn-OR, Gn -NO2, GnCN, Gn-CO2R, Gn- (C = O) R, Gn-O (C = O) R, Gn-O-alkyl, Gn-OAr, Gn-SH, Gn-SR, Gn-SOR, Gn-SO2R, GnS-Ar, Gn-SOAr, Gn-SO2Ar, aryl, heteroaryl, Gn-Ar, Gn- (C = O) NR²R³, Gn-NR²R³, Gn-NR (C = O) R, Gn-SO2 23

NO²R³, PO3H2, and SO3H2 in which G is alkylene having 1 to 4 carbon atoms, or alkenylene or alkynylene, each of which contains 2 to 4 carbon atoms, wherein such alkylene, alkenylene or 1 2 3 alkynylene may be substituted or unsubstituted; n is zero or 1; R¹, R² and R³ independently are alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Gn-cycloalkyl or Gn-heterocycloalkyl; and Ar is aryl or heteroaryl, wherein such alkyl, allyl, alkenyl, alkynyl, heteroalkyl, heteroallyl, heteroalkenyl, heteroalkynyl, alkoxy, heteroalkoxy, Gn-cycloalkyl, 1 2 3

Gn-heterocycloalkyl, Ar, R¹, R² and R³ may be further substituted or unsubstituted.

[0105] The compounds of this invention may contain one or more asymmetric centers; and thus such compounds can be prepared as single (R) or (S) stereoisomers or as mixtures thereof.

Unless otherwise indicated, the description or naming of a particular compound in the description and claims includes both individual enantiomers and their racemic or other mixtures. So, this invention

EP 1 660 090 B1 also includes racemates and separated enantiomers and diastereomers of a compound of Formula I. Methods for determining stereochemistry and separation of stereoisomers are well known in the art (see discussion in Chapter 4 "Advanced Organic Chemistry", 4th Edition, J. March, John Wiley and Sons, New York, 1992).

In addition to compounds of Formula I, the invention also includes solvates, pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds.

[0107] The term "solvate" refers to the association of a compound molecule with one or more solvent molecules.

[0108] "Pharmaceutically acceptable prodrug" means a compound that can undergo physiological or solvolysis conversion to a particular compound or a pharmaceutically acceptable salt thereof.

[0109] "Pharmaceutically active metabolite" means a pharmaceutically active product made by metabolizing a particular compound or a salt thereof in the body. Compound metabolites can be identified by routine methods known in the art, and their activities can be determined using assays such as those described herein.

[0110] Prodrugs and active metabolites of a compound can be identified by routine methods known in the art. Various forms of prodrugs are known in the art. For example, such derived prodrugs are described, for example, in a) Design of Prodrugs, published by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, pp. 309-396, published by K. Widder , et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, published by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard pp. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8: 1-38 (1992); d) H. Bundgaard, et al., Journal of

Pharmaceutical Sciences, 77: 285 (1988); and e) N. Kakeya, et al., Chem. Pharm. Bull., 32: 692 (1984).

[0111] "Pharmaceutically acceptable salt" means a salt that retains the biological effectiveness of the free acids and bases of a particular compound and which is not undesirable from a biological or other point of view. The compound of the invention may contain sufficiently acidic, sufficiently basic, or both functional groups, and thus may react with many inorganic or organic bases and inorganic or organic acids, thereby forming a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds of the present invention with a mineral or organic acid or with an inorganic base and such salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphate, chlorides, bromides iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrate, capronates, heptanates, propiolates, oxalates, malonates, succinates, suberinates, sebacates, fumarate, maleates, butane-1,4-dianes, hexine-1,6-diates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, sulfonates, xylene sulfonates, phenylpropionates, phenylpropionates citrates, lactates, γ-hydroxybutyrate, glycolates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, tosylates, besylates, acetates and mandelates.

[0112] When the compound of the invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method known in the art, for example, by treating

The free base is an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc., or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid , malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid and pyranosidylic acid such as glucuronic acid or galacturonic acid, alphahydroxy acid such as citric acid or tartaric acid, amino acid, such as aspartic acid or glutamic acid, aromatic acid such as benzoic acid or cinnamic acid, sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid, etc.

[0113] When the compound of the invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method known in the art, for example, by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), metal hydroxide alkaline or alkaline earth metal hydroxide, etc. Illustrative examples of suitable salts include, but are not limited to, organic salts formed with amino acids such as glycine and arginine, salts with ammonia, primary, secondary and tertiary amines, and salts with cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts formed with sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0114] Compounds of the invention can be prepared using the reactions and synthesis schemes described below, using methods available in the art of readily available starting materials.

[0115] Therapeutic Aspects of the Invention [0116] Therapeutically effective amounts of compounds of the invention can be used to treat diseases via the modulation or regulation of type I receptor tyrosine kinases and / or serine, threonine and / or dual specificity kinases. The term "effective amount" means the amount of a compound that, when administered to a mammal in need thereof, is sufficient to provide treatment for a disease associated with the activity of one or more of type I receptor tyrosine kinases and / or serine, threonine and / or dual specificity kinases. Thus, for example, a therapeutically effective amount of a compound selected from compounds of Formula I, a salt, active metabolite or prodrug thereof is an amount sufficient to modulate, regulate or inhibit the activity of one or more of type I receptor tyrosine kinases and / or serine, threonine and / or dual specificity kinases at which the disease state associated with such activity is reduced or alleviated.

[0117] The amount of a given agent that corresponds to that amount will vary depending on various factors, such as the particular compound, disease state and severity, type (e.g. weight) of the mammal requiring treatment, but in each case it is routinely determined by a specialist in this field of technology. The term "treatment" as used herein means at least ameliorating in a mammal, such as a human, a disease state that is caused, at least in part, by the activity of one or more of type I receptor tyrosine kinases and / or serine, threonine and / or dual specificity kinases, and includes, but is not limited to, preventing the occurrence of a disease state in a mammal, in particular when such a predisposition has been found in such a mammal, but this condition has not yet been diagnosed; modulating and / or inhibiting the disease state; and / or alleviating the disease condition.

[0118] When a compound of Formula I, or a pharmaceutically acceptable salt thereof, or in vivo cleavable prodrug, is used for the therapeutic treatment (including prophylactic treatment) of mammals, including humans, it is typically formulated in a pharmaceutical form in accordance with standard pharmaceutical practice.

EP 1 660 090 B1 pharmaceutical composition. In accordance with this aspect of the invention, a pharmaceutical composition is provided that comprises a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a in vivo cleavable prodrug, as previously defined, in association with a pharmaceutically acceptable diluent or carrier.

[0119] The compositions of the invention may be in oral form (for example, as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example , as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example in the form of a finely divided powder or liquid aerosol), for administration by insufflation (e.g. in the form of a finely divided powder) or for parenteral administration (e.g. in the form of a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular administration, or as a suppository for rectal administration). For example, compositions intended for oral use may contain one or more coloring, sweetening, flavoring and / or preserving agents.

[0120] For tablet formulations, suitable pharmaceutically acceptable excipients include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch; glidants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants such as ascorbic acid. Tablet formulations may be uncoated or coated to modify their distribution and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and / or appearance, and in each case conventional coating materials and procedures well known in the art are used.

[0121] Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.

[0122] Aqueous suspensions generally contain the active ingredient in finely powdered form with one or more suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia; suspending or wetting agents, such as lecithin or condensation products of alkylene oxide and fatty acids (for example, polyoxyethylene stearate), or condensation products of ethylene oxide and long-chain aliphatic alcohols, for example heptadekaethyleneoxycetanol, or ethylene oxygen condensation products with partial fatty acids derived and hexitol such as polyoxyethylene sorbitan monooleate, or ethylene oxygen condensation products with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate), antioxidants (such as ascorbic acid), coloring agents, flavors and / or sweeteners (such as sucrose, saccharin or aspartame).

[0123] Oily suspensions may be formulated by suspending the active ingredient in vegetable oil (such as peanut oil, olive oil, sesame oil or coconut oil) or in mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening substance, such as beeswax, hard paraffin or cetyl alcohol. To improve the taste of the oral preparation, also sweeteners as mentioned above and flavors can be added. These compositions can be preserved by the addition of an antioxidant such as ascorbic acid.

[0124] Dispersible powders and granules suitable for preparation of aqueous suspensions after the addition of water generally contain the active ingredient in combination with a dispersing or wetting agent, a containing substance and one or more preservatives. As suitable dispersing or wetting agents and suspending agents, mention may be made of the substances mentioned above. Other excipients such as sweeteners, flavors and colors may also be present.

[0125] The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or peanut oil, or a mineral oil, such as liquid paraffin, or a mixture of any of these oils. Suitable emulsifiers may be, for example, naturally occurring resins such as acacia or tragacanth, naturally occurring phosphatides such as soybean, lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides (e.g. sorbitan monooleate) and products condensation of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. These emulsions may also contain sweetening, flavoring and preserving agents. [0126] Syrups and elixirs may be formulated using sweeteners such as glycerol, propylene glycol, sorbitol, aspartame or sucrose and may also contain a soothing substance, preservative, flavoring and / or coloring agent.

[0127] The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known methods using one or more suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenteral, diluent or solvent, for example a solution in 1,3-butanediol.

[0128] Suppository formulations can be prepared by mixing the active ingredient with a suitable non-irritating excipient that is solid at normal temperatures but liquid at the rectal temperature and thus melts in the rectum and releases the drug. Suitable excipients include, for example, cocoa butter and polyethylene glycols.

[0129] Formulations for topical administration, such as creams, ointments, gels and aqueous or oily solutions or suspensions, can generally be prepared by mixing the active ingredient with a conventional topically acceptable vehicle or diluent using conventional techniques known in the art.

[0130] Compositions for administration by insufflation may be in the form of a finely divided powder containing particles of medium diameter, for example, 30 μm or less, which contains the active ingredient alone or diluted in one or more physiologically acceptable carriers such as lactose. The insufflation powder is then preferably kept in the capsule containing 16

For example, 1 to 50 mg of active ingredient for use in a turbo inhaler, as with the known blowing agent, sodium cromoglycate.

[0131] Compositions for administration by inhalation may be in the form of a conventional pressurized atomizer adapted to dispense an active ingredient in the form of an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons can be used and the atomizer is typically adapted to dispense a metered amount of active ingredient.

[0132] For further information on the formulation, see Chapter 25.2 Volume 5 Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990.

[0133] The amount of a compound of this invention that is combined with one or more excipients to form a unit dose varies depending on the subject being treated and the particular route of administration. For example, for a formulation intended for oral administration to humans, such a dose may contain, for example, from 0.5 mg to 2 g of active ingredient in combination with a suitable and convenient amount of excipient, which may range from 5 to about 98% by weight based on the weight of the total composition. Unit doses generally contain about 1 mg to about 500 mg of active ingredient. For further information on routes of administration and dosing schedules, see Chapter 25.3 Volume 5 Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990.

[0134] For therapeutic or prophylactic purposes, the dose of the compound will of course vary depending on the nature and severity of the condition, age and sex of the animal or patient, and route of administration, according to principles well known in medicine.

[0135] Although compounds of Formula I are primarily valuable as therapeutic agents for use in warm-blooded animals (including humans), they are also useful when it is necessary to control type I receptor tyrosine kinases and / or serine, threonine and / or kinases with dual specificity. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the development of new pharmacological agents.

[0136] The activity of the compounds of this invention can be evaluated in studies on the inhibition of type I receptor tyrosine kinases and / or serine, threonine and / or dual specificity kinases in vitro, in vivo or in a cell line. In vitro tests include tests in which inhibition of kinase activity is determined. The in vitro tests then calculate the inhibitor's ability to bind to kinases, which can be measured by radiolabeling the inhibitor before binding, isolating the inhibitor / kinase complex and determining the amount of radiolabeled binding, or by performing a competitive test in which new inhibitors are incubated with known radioligands. . These and other useful in vitro assays and cell culture assays are well known to those skilled in the art.

[0137] Although the invention has been described and illustrated with great accuracy, it should be understood that the present disclosure is exemplary only, and one skilled in the art can make numerous changes to the combination and in individual parts of the invention without departing from the spirit and scope thereof that is claimed herein.

BIOLOGICAL EXAMPLES

EGFR / ErbB2 enzyme tests

[0138] 96-well plates of Thermo LabSystems Immulon 4HBX were coated by overnight incubation at room temperature of 100 μΐ per well of 0.25 mg / ml Poly (Glu, Tyr) 4: 1 (PGT) (Sigma Chemical Co. , St. Louis, MO) in PBS (phosphate buffered saline). Excess PGT was removed by aspiration and the plate was washed three times with washing buffer (0.1% Tween 20 in PBS). The kinase reaction was carried out in 100 μΐ 50 mM HEPES (pH 7.3) containing 125 mM sodium chloride, 24 mM magnesium chloride, 0.1 mM sodium orthovanadate, 15 μΜ ATP (adenosine triphosphate) and 0.3 unit / ml EGFR ( epidermal growth factor receptor) (BIOMOL Research Laboratories, Inc., Plymouth Meeting, PA). Compound in DMSO (dimethyl sulfoxide) was added to give a final DMSO concentration of about 1%. Phosphorylation was started by the addition of ATP and the whole was incubated at room temperature for 30 minutes. The kinase reaction was terminated by withdrawing the reaction mixture, followed by washing with washing buffer (see above). Phosphorylated PGT was detected after 30 incubations with 100 μl per well of HRP conjugated anti-phosphotyrosine PY20 antibody diluted to 0.2 μg / ml 3% BSA and 0.05% Tween 20 in PBS. Antibody was removed by aspiration and the plate was washed with washing buffer. The colorimetric signal was developed by adding 100 μl per well of TMB Microwell Peroxidase Substrate peroxidase substrate (Kirkegaard and Perry, Gaithersburg, MD) and stopped by the addition of 100 μl per well of 1M phosphoric acid. Phosphotyrosine was measured by absorbance at 450 nm.

[0139] ErbB2 kinase was tested as described above using 250 ng / ml of intracellular erbB2 domain instead of EGFR. The intracellular ErbB2 tyrosine kinase domain (amino acids 691-1255) is expressed as his-labeled protein in Baculovirus and is purified by ion exchange size exclusion chromatography with chelating nickel.

[0140] For compounds of the present invention, IC 50 values ​​ranged from 1 nM to 50 mM.

MANUFACTURING EXAMPLES [0141] The preparation of compounds of the present invention is illustrated in Figures 1-6.

[0142] Figure 1 shows the synthesis of iminoamidine compounds of the present invention. Hydrazones (3) can be prepared by standard methods of condensation of aldehyde (1) with hydrazine (2). This can be done in a wide variety of organic solvents. Preferably, the condensation is carried out in a mixed solvent DCM iIPA system. Coupling to form iminoamidines (5) can be carried out by heating the hydrazone (3) in a mixture of THF and IPA solvents at a temperature of about 50 ° C in the presence of imidane (4).

[0143] Figure 2 shows an alternative synthesis of iminoamidine compounds of the present invention. In this method, the amide (6) is treated with POCl3 in a suitable organic solvent, such as benzene or DCM, and an intermediate imidoyl chloride is obtained. Hydrazone (3) is then added to this mixture to obtain the desired iminoamidine (5). Coupling may require slightly elevated temperatures (45 to 90 ° C).

[0144] Figures 3 and 4 illustrate the synthesis of iminoamidine compounds of the present invention, in which iminoamidine (7) is prepared, and then it is condensed with aldehyde (1). In Figure 3, iminoamidine (7) can be prepared by coupling hydrazine (2) with imidane (4) in a suitable organic solvent. The resulting iminoamidine (7) can then be condensed with the aldehyde (1)

In a suitable organic solvent such as THF and IPA or EtOH at room temperature or slightly elevated (45 to 90 ° C) to give the desired iminoamidine (5). In Figure 4, iminoamidine (7) can be prepared by coupling hydrazine (2) with thioimidane (8) in a suitable organic solvent. Similar to Figure 3, the iminoamidine (7) produced can then be condensed with the aldehyde (1) in a suitable organic solvent, such as THF and IPA or EtOH, at room temperature or slightly elevated (45 to 90 ° C) to give the desired iminoamidine (5).

[0145] Oxazoline compounds of formula I can be prepared as shown in Figure 5. Aniline (9) can be condensed with thioCDI in a suitable organic solvent such as a mixture of THF and DCE. The obtained intermediate compound is not isolated, but in situ treated with an amino alcohol (10). The addition reaction can be carried out at room temperature or slightly elevated (45 to 90 ° C). In general, the thiourea (11) produced can be isolated and used without further purification. The desired oxazoline (12) can be prepared from thiourea (11) in one of several ways illustrated in Figure 5. Thiourea (11) can be treated with tosyl chloride and NaOH in a mixture of THF and water at room temperature. Alternatively, thiourea (11) can be treated with various carbodiimides, such as EDCI, DCC, DCI, in suitable organic solvents such as THF, DMF, DCM or DCE, at room temperature or slightly elevated (45 to 90 ° C).

[0146] Figure 6 illustrates an alternative method of preparing the oxazoline compounds of the present invention. Aniline (9) can be coupled with diphenyl N-cyano carboimidate (13), without a base, or in the presence of a base such as NaH or Et3N, in organic solvents such as DMF, MeCN, dioxane, pyridine, IPA or DCM, at room temperature or elevated (45 to 120 ° C) to give cyanoisourea (14). Preferably, cyanoisourea (14) is prepared by coupling aniline (9) and diphenyl N-cyanocarboimidate diphenyl (13) in a THF / DCE / tBuOH mixture at 8090 ° C. Oxazoline (12) can be prepared by coupling the amino alcohol (10) and cyanoisourea (14) in various organic solvents, including THF and IPA. Preferably, coupling of compounds (10) and (14) is carried out in a mixture of THF and IPA at elevated temperature (45 to 120 ° C).

[0147] To illustrate the invention, the following examples are provided. However, it should be understood that these examples do not limit the scope of the invention, but merely suggest how to carry out the invention. It will be apparent to those skilled in the art that the chemical reactions described herein can be readily adapted to produce many other quinazoline analogs of the invention and it is believed that alternative methods for preparing compounds of this invention are also within the scope of the invention. For example, the synthesis of compounds not illustrated in the examples can be successfully carried out using modifications obvious to those skilled in the art of the described methods, e.g., by appropriately changing the protecting groups used, by using other than described, appropriate reagents known in the art, and / or by introducing routine modifications of reaction conditions. Alternatively, it is believed that other reactions disclosed herein or known in the art may be used to prepare other compounds of the invention.

EXAMPLES [0148] Unless otherwise stated, in the examples below all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical

EP 1 660 090 B1

Company, Lancaster, TCI or Maybridge and were used without further purification unless otherwise indicated.

[0149] The reactions described below were generally carried out under positive nitrogen or argon pressure or with a drying tube (unless otherwise indicated) in anhydrous solvents, and the reaction flasks were generally equipped with a rubber septum for introducing substrates and reagents with a syringe. The glassware was dried in an oven and / or in a heat stream.

[0150] Column chromatography was carried out using a Biotage system (Manufacturer: Dyax Corporation) on a silica gel column or on a SepPak silica cartridge (Waters).

[0151] Spectra ¹H NMR was recorded on a Varian apparatus operating at 400 MHz. spectrum¹H-NMR was obtained as CDCl3 solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm). Other NMR solvents were used as needed. The following abbreviations have been used for peak multiplicity determinations: s (singlet), d (doublet), t (triplet), m (multiplet), br (extended), dd (doublet of doublets), dt (doublet of doublets).

Example 1 (Comparative Example) [0152]

<img file="PL1660090T3_D0007.tif" />

Preparation of (E) -2-methoxy-N - ((4- (3-methyl-4-phenoxyphenylamino) quinazolin-6-yl) methyleneamino) acetamidine [0153] Step A: (6-Hydrazonomethylquinazolin-4-yl) - ( 3-methyl-4-phenoxyphenyl) amine was prepared by adding hydrazine (50 mg, 1.00 mmol) to a solution of 4- (3-methyl-4-phenoxyphenylamino) -quinazoline-6-carbaldehyde (250 mg, 0.70 mmol) in the mixture 1: 1 DCM: IPA (6 ml). After stirring at room temperature for 4 hours, excess hydrazine and solvent were removed under reduced pressure to give the desired hydrazone as a brown solid which was used in the next step without purification.

Step B: (E) -2-methoxy-N - ((4- (3-methyl-4-phenoxyphenylamino) quinazolin-6-yl) methyleneamino) acetamidine was prepared by adding (6-hydrazonomethylquinazolin-4-yl) - ( 3-methyl-4-phenoxyphenyl) amine (30 mg, 0.081 mmol) while stirring to a mixture of Et3N (20 mg, 0.19 mmol) and 2-methoxyacetimidic acid methyl ester (20 mg, 0.20 mmol) in a 1: 1 DCM mixture : IPA (4 ml). The reaction mixture was stirred at 50 ° C for 1 hour, then cooled to room temperature and stirred for 16 hours. Concentration and purification by column chromatography (10: 8: 1 EtOAc: hexanes: MeOH) gave the desired product (16 mg, 45%). MS ESI (+) m / z 441 (M + 1) detected;¹H NMR (400 mHz, CD3OD) δ 8.64 (s, 1H), 8.49 (s, 1H), 8.41 (m, 2H), 7.76 (d, 1H), 7.63

EP 1 660 090 B1 (d, 1H), 7.55 (dd, 1H), 7.32 (m, 2H), 7.05 (m, 1H), 6.93 (m, 3H), 4.13 (s, 2H), 3.45 (s, 3H), 3.41 (s, 1H), 2.24 (s, 3H).

[0155] The following compounds (Examples 2-5) were prepared as described in Example 1 using the appropriate quin azoline-6-aldehyde, hydrazine and imidane.

Example2 (Comparative example) [0156]

<img file="PL1660090T3_D0008.tif" />

(E) -2-methoxy-N-methyl-N - ((4-3-methyl-4-phenoxyphenylamino) quinazolin-6-yl) methyleneamino) acetamidine [0157] MS APCI (+) m / z 455 (M + 1 detected) ); ¹H NMR (400 mHz, CD3OD) δ 8.48 (s, 1H), 8.23 ​​(s, 1H), 8.26 (d, 1H), 7.91 (s, 1H), 7.77 (d , 1H), 7.64 (d, 1H), 7.54 (dd, 1H), 7.32 (m, 2H), 7.05 (m, 1H), 6.94 (m, 3H), 4 , 55 (s, 2H), 3.72 (m, 1H), 3.54 (s, 3H), 2.25 (s, 3H), 2.15 (s, 3H).

Example3 (Comparative example) [0158]

<img file="PL1660090T3_D0009.tif" />

(E) -N - ((4- (4- (3-fluorobenzyloxy) -3-chlorophenylamino) quinazolin-6-yl) methyleneamino) -2-methoxyacetamidine [0159] MS APCI (+) m / z 493, 495 detected (M + 1, standard Cl); ¹H NMR (400 mHz, DMSO-D6) δ 8.75 (s, 1H), 8.59 (s, 1H), 8.46 (d, 1H), 8.40 (s, 1H), 8.03 (d, 1H), 7.76 (m, 2H), 7.47 (m, 1H), 7.31 (m, 3H), 7.19 (m, 1H), 5.27 (s, 2H) , 4.02 (s, 2H), 3.34 (m, 4H).

Example4 (Comparative example) [0160]

EP 1 660 090 B1

<img file="PL1660090T3_D0010.tif" />

(E) -N- (4- (3-methyl-4- (6-methylpyridin-3-yloxy) phenylamino) quinazolin-6-yl) methyleneamino-2-methoxyacetamidine. MS ESI (+) m / Detected from 456 (M + 1); ¹H NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 8.5 (s, 1H), 8.41 (m, 2H), 8.12 (s, 1H), 7.79 (d , 1H), 7.7 (s, 1H), 7.61 (d, 1H), 7.26 (m, 2H), 7.01 (d, 1H), 4.12 (s, 2H), 3 , 43 (s, 3H), 2.52 (s, 3H), 2.12 (s, 3H).

Example 5 (Comparative Example) [0162]

<img file="PL1660090T3_D0011.tif" />

(E) -N - ((4- (4- (3-fluoro-benzyloxy) -3-chlorophenylamino) -quinazolin-6-yl) -methyleneamino) -acetamidine [0163] MS ESI (+) m / z 463, 465 detected (M + 1, standard Cl); ¹H NMR (400 MHz, CD3OD) δ 8.64 (s, 1H), 8.52 (s, 1H), 8.42 (m, 2H), 7.92 (s, 1H), 7.78 (d , 1H), 7.6 (d, 1H), 7.4 (m, 1H), 7.31 (d, 1H), 7.25 (d, 1H), 7.19 (d, 1H), 7 , 06 (t, 1H), 5.21 (s, 2H), 2.06 (s, 3H).

Example 6 [0164]

<img file="PL1660090T3_D0012.tif" />

Preparation of N4- [3-chloro-4- (3-fluorobenzyloxy) -phenyl] -N6- (4,5-dihydrooxazol-2-yl) -quinazoline-4,6-diamine [0165] Step A: N-4- [3 -chloro-4- (3-fluorobenzyloxy) -phenyl] -N6- (2-phenyl-N-cyanoisourea) quinazoline-4,6-diamine was prepared by mixing N-4- [3-chloro-4- (3-fluoro -benzyloxy) -phenyl] quinazoline-4,6-diamine (0.63 g, 1.60 mmol) and diphenyl N-cyanocarboimidate (1.0 g, 4.20 mmol) in THF

EP 1 660 090 B1 (20 ml), DCE (10 ml) and t-BuOH (10 ml) at room temperature for 2 hours and then at 80-90 ° C for 3 hours. An additional 0.40 g diphenyl N-cyano carboimidate was added. After stirring at 80-90 ° C for 3 hours, the reaction mixture was cooled to room temperature and concentrated. DCM (100 ml) was added and the solid was isolated by filtration through a sintered glass funnel, dried to give 0.67 g (77.6%) of a brown-yellow substance.

Step B: N4- [3-chloro-4- (3-fluorobenzyloxy) -phenyl] -N6- (4,5-dihydrooxazol-2-yl) -quinazoline-4,6-diamine was prepared by adding 2-aminoethanol (10 mg, 0.164 mmol) to a mixture of N-4- [3-chloro4- (3-fluorobenzyloxy) -phenyl] -N6- (2-phenyl-N-cyanoisourea) -quinazoline-4,6-diamine (30 mg, 0.056 mmol ) in 1: 1 THF: isopropyl alcohol (2 ml) and by heating to 100 ° C for 20 hours. The reaction mixture was concentrated under reduced pressure, purified by column chromatography (5% MeOH in ethyl acetate) to afford the desired product as a white solid (19 mg, 74%). MS ESI (+) m / z 464, 466 (M + 1, standard Cl) detected;¹H NMR (400 mHz, acetone-d6) δ 8.52 (s, 1H), 8.43 (bs, 1H), 8.17 (d, 1H), 7.85 (dd, 1H), 7.74 (d, 1H), 7.70 (d, 1H), 7.48 (m, 1H), 7.38 (d, 1H), 7.35 (d, 1h), 7.21 (d, 1H) , 7.12 (m, 1H), 5.29 (s, 2H), 4.42 (t, 2H), 3.93 (t, 2H).

Example 7 [0167]

<img file="PL1660090T3_D0013.tif" />

Preparation of N4- [3-chloro-4- (3-fluorobenzyloxy) -phenyl] -N6- (3a, 4,6,6a-tetrahydrofuro [3,4-d] oxazol-2-yl) -quinazoline-4,6-diamine [0168] N4- [3-chloro-4- (3-fluorobenzyloxy) -phenyl] -N6- (3a, 4,6,6a-tetrahydrofuro [3,4-d] oxazol-2-yl) quinazoline-4, 6-diamine was prepared by adding thioCDI (27 mg, 0.152 mmol) to a mixed solution of N4- [3-chloro-4- (3-fluoro-benzyloxy) -phenyl] -quinazoline-4,6-diamine (60 mg, 0.152 mmol) in 1: 1 THF: DCM (8 ml). After 3 hours, 2-amino-cyclopentanol (30 mg, 0.30 mmol) was added and the reaction mixture was stirred for 4 hours. The solvent was removed under reduced pressure and the resulting thiourea was triturated with diethyl ether. The sucrose thiourea was suspended in THF (10 mL) and 1M NaOH in water (0.38 mL) was added, followed by the addition of 1M TsClwTHF solution (0.17 mL). After 1 hour, the reaction mixture was diluted with EtOAc and water, and the phases were separated. The aqueous phase was extracted with EtOAc and the combined organic extracts dried (Na2SO4) and concentrated. Purification by column chromatography (10: 5: 1 EtOAc: hexanes: MeOH) gave the desired product (50 mg, 65%). MS APCI (+) m / z 506, 508 (M + 1, standard Cl) detected;¹H NMR (400 mHz, CD3CN) δ 8.49 (s, 1H), 8.23 ​​(bs, 1H), 7.94 (s, 1H), 7.73 (m, 2H), 7.59 (m , 2H), 7.45 (m, 1H), 7.35 (d, 1H), 7.29 (d, 1H), 7.19-7.10 (m, 3H), 5.23 (s, 2H), 5.18 (m, 1H), 4.66 (m, 1H), 4.11 (d, 1H), 3.96 (d, 1H), 3.56 (dd, 2H).

[0169] The following compounds (Examples 8-56) were prepared as described in Example 7 using the appropriate quinazoline-6-aniline and amino alcohol.

Example 8 [0170]

<img file="PL1660090T3_D0014.tif" />

N4- [3-chloro-4- (3-fluorobenzyloxy) -phenyl] -N6- (3,8-dioxa-1-aza-spiro [4.5] dec-1-en-2-yl) -chinazolina4,6- diamine. MS APCI (+) m / z 534, 536 (M + 1, standard Cl) detected; ¹H NMR (400 mHz, CD3CN) δ 8.50 (s, 1H), 8.12 (s, 1H), 7.99 (s, 1H), 7.73 (d, 1H), 7.60 (d , 1H), 7.47 (m, 1H), 7.34 (d, 1H), 7.29 (d, 1H), 7.15 (d, 1H), 7.11 (d, 1H), 5 , 23 (s, 2H), 4.19 (m, 2H), 3.88 (m, 2H), 3.59 (m, 2H), 3.30 (m, 2H), 1.78 (m, 5H).

Example 9 [0172]

<img file="PL1660090T3_D0015.tif" />

N6- (3,8-dioxa-1-aza-spiro [4.5] dec-1-en-2-yl) -N4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenyl] quinazoline -4,6-diamine. MS APCI (+) m / z 497 (M + 1) detected; ¹H NMR (400 mHz, CD3OD) δ 8.44 (s, 1H), 8.19 (bs, 1H), 8.13 (d, 1H), 7.71 (m, 3H), 7.63 (dd , 1H), 7.29 (m, 2H), 7.00 (d, 1H), 4.30 (s, 2H), 3.97 (m, 2H), 3.55 (m, 2H), 2 , 50 (s, 3H), 2.27 (s, 3H), 1.96 (m, 2H), 1.77 (m, 2H).

Example 10 [0174]

EP 1 660 090 B1

<img file="PL1660090T3_D0016.tif" />

2- {4- [3-Methyl-4- (6-methylpyridin-3-yloxy) -phenylamino] -quinazolin-6-ylamino} -3a, 4,6,6a-tetrahydropyrrolo [3,4-d acid tert-butyl ester ] oxazole-5-carboxy [0175] MS APCI (+) m / z 568 (M + 1) detected.

Example 11 [0176]

<img file="PL1660090T3_D0017.tif" />

N4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenyl] -N6- (4,5,6,6a-tetrahydro-3aH-pyrrolo [3,4-d] oxazol-2-yl ) quinazoline-4,6-diamine [0177] N4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenyl] -N6- (4,5,6,6a-tetrahydro-3aH-pyrrolo [ 3,4d] oxazol-2-yl) -quinazoline-4,6-diamine was prepared from 2- {4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenylamino] -quinazolin-6- acid tert-butyl ester. ylamino} -3a, 4,6,6a-tetrahydropyrrolo [3,4-d] oxazole-5-carboxylic acid by standard methods for removal of the BOC protecting group, using TFA in methylene chloride. MS APCI (+) m / z 468 (M + 1) detected;¹H NMR (400 mHz, CD3OD) δ 8.42 (s, 1H), 8.21 (bs,

1H), 8.13 (d, 1H), 7.68 (m, 2H), 7.60 (m, 2H), 7.28 (m, 2H), 6.98 (d, 1H), 5, 18 (m, 1H), 4.74 (m, 1H), 3.34 (d, 1H), 3.16 (d, 1H), 2.86 (m, 2H), 2.50 (s, 3H ), 2.26 (s, 3H).

Example 12 [0178]

<img file="PL1660090T3_D0018.tif" />

1- (2- {4- [3-methyl-4- (6-methylpyridin-3-yloxy) phenylamino] quinazolin-6-ylamino} -3a, 4,6,6-tetrahydro-pyrrolo [3,4-d ] oxazol-5-yl) -ethanone

[0179] 1- (2- {4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenylamino] -quinazolin-6-ylamino} -3a, 4,6,6-tetrahydropyrrole [3,4-d] oxazol-5-yl) -ethanone was prepared from N4- [3-methyl-4- (6-methylpyridin-3-yloxy) phenyl] -N6- (4,5,6,6a-tetrahydro- 3aH-pyrrolo [3,4-d] oxazol-2-yl) -quinazoline-4,6-diaminystandard by acetylation methods using acetic anhydride in a mixture of pyridine and methylene chloride. MS APCI (+) m / z 510 (M + 1) detected;¹H NMR (400 mHz, CD3OD) δ 8.44 (s, 1H), 8.26 (d, 1H), 8.13 (d, 1H), 7.71 (m, 2H), 7.63 (m , 2H), 7.28 (m, 2H), 7.00 (d, 1H), 5.28 (m, 1H), 4.89 (m, 1H), 4.15 (d, 0.5H) , 4.03 (m, 1H), 3.84 (d, 0.5H), 3.75 (m, 1H), 3.47 (m, 1H), 2.50 (s, 3H), 2, 27 (s, 3H), 2.09 (d, 3H).

Example 13 [0180]

<img file="PL1660090T3_D0019.tif" />

N4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenyl] -N6- (3-oxa-1,8-diaza-spiro [4.5] dec-1-en-2-yl) quinazoline -4,6-diamine [0181] N4- [3-Methyl-4- (6-methylpyridin-3-yloxy) -phenyl] -N6- (3-oxa-1,8-diazaspiro [4.5] dec-1- en-2-yl) quinazoline-4,6-diamine was prepared from 2- {4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenylamino] -quinazolin-6-ylamino} tert-butyl ester. 3-oxa-1,8-diaza-spiro [4.5] dec-1-ene-8-carboxylic acid by standard methods to remove the BOC protecting group, using TFA in methylene chloride. MS ESI (+) m / z 496 (M + 1) detected;¹H NMR (400 mHz, CD3OD) δ 8.43 (s, 1H), 8.39 (s, 1H), 8.12 (d, 1H), 7.70 (m, 3H), 7.61 (dd , 1H), 7.28 (m, 2H), 6.98 (d, 1H), 3.45 (m, 2H), 3.32 (m, 2H), 3.25 (m, 2H) 2, 50 (s, 3H), 2.32 (m, 2H), 2.25 (s, 3H), 2.01 (m, 2H).

Example 14 [0182]

<img file="PL1660090T3_D0020.tif" />

1- (2- {4- [3-methyl-4- (6-methylpyridin-3-yloxy) phenylamino] quinazolin-6-ylamino} -3-oxa-1,8-diaza-spiro [4.5] dec-1 -en-8-yl) -ethanone [0183] 1- (2- {4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenylamino] -quinazolin-6-ylamino} -3-oxa -1,8diazaspiro [4.5] dec-1-en-8-yl) -ethanone prepared from N4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenyl] N6- (3-oxa-1 , 8-diaza-spiro [4.5] dec-1-en-2-yl) -quinazoline-4,6-diamine by standard methods of acetylation using acetic anhydride in a pyridine mixture and methylene chloride.

EP 1 660 090 B1

Example 15 [0184]

<img file="PL1660090T3_D0021.tif" />

N6- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl) -N4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenyl] quinazoline-4,6-diamine [0185] MS APCI (+) m / z 455 (M + 1) detected; ¹H NMR (400 mHz, CD3OD) δ 8.42 (s, 1H), 8.12 (d, 1H), 7.70 (m, 4H), 7.60 (m, 3H), 7.28 (m , 2H), 6.99 (d, 1H), 4.13 (s, 2H), 2.50 (s, 3H), 2.26 (s, 3H), 1.40 (s, 6H).

Example 16 [0186]

<img file="PL1660090T3_D0022.tif" />

N4- [3-chloro-4- (pyridin-2-ylmethoxy) -phenyl] -N6- (1-oxa-3,8-diazaspiro [4.5] dec-2-en-2-yl) -chinazolino4,6- diamine [0187] N4- [3-chloro-4- (pyridin-2-ylmethoxy) -phenyl] -N6- (1-oxa-3,8-diaza-spiro [4.5] dec-2-en-2-yl ) quinazoline-4,6-diamine was prepared from 2- {4- [3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino] -quinazolin-6-ylamino} -1-oxa-3.8 tert-butyl ester. -diaza-spiro [4.5] dec-2-ene-8-carboxylic acid by standard methods for removal of the BOC protecting group using TFA in methylene chloride. MS ESI (+) m / z 516.518 (M + 1, reference Cl) detected; ¹H NMR (400 mHz, CDCl3) δ 8.61 (s, 1H), 8.58 (d, 1H), 8.22 (bs, 1H), 7.97 (d, 1H), 7.70 (m , 2H), 7.67 (d, 1H), 7.64 (dd, 1H), 7.35 (d, 1H), 7.26 (m, 1H), 7.02 (d, 1H), 5 , 31 (s, 2H), 3.73 (s, 2H), 3.05 (m, 2H), 2.96 (m, 2H), 1.97 (m, 2H), 1.80 (m, 2H).

Example 17 [0188]

EP 1 660 090 B1

<img file="PL1660090T3_D0023.tif" />

1- (2- {4- [3-methyl-4- (6-methylpyridin-3-yloxy) phenylamino] quinazolin-6-ylamino} -1-oxa-3,8-diazaspiro [4.5] dec-2 -en-8-yl) -ethanone [0189] 1- (2- {4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenylamino] -quinazolin-6-ylamino} -1-oxa -3,8-diaza-spiro [4.5] dec-2-en-8-yl) -ethanone was prepared from 2- {4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenylamino] tert-butyl ester. -quinazolin-6-ylamino} -1-oxa-3,8-diazaspiro [4.5] dec-2-ene-8-carboxyl by standard methods to remove the BOC protecting group, using TFA in methylene chloride followed by standard acetylation using acetic anhydride ₁ in a mixture of pyridine and methylene chloride. MS ESI (+) m / z 538 (M + 1) detected;¹H NMR (400 mHz, CDCl3) δ 8.68 (s, 1H), 8.28 (d, 1H), 7.83 (d, 1H), 7.64 (s, 1H), 7.52 (d , 2H), 7.48 (d, 2H), 7.12 (m, 3H), 6.93 (d, 1H), 3.69 (m, 2H), 2.53 (s, 3H), 2 , 29 (s, 3H), 2.14 (s, 3H), 2.02 (m, 2H), 1.78 (m, 2H), 1.30 (m, 2H), 0.87 (m, 2H).

Example 18 [0190]

<img file="PL1660090T3_D0024.tif" />

(4-methyl-2- {4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenylamino] -quinazolin-6-ylamino} -4,5-dihydrooxazol-4-yl) -methanol [ 0191] MS ESI (+) m / z 471 (M + 1) detected; 1H NMR (400 mHz, CDCl3) δ 8.54 (s, 1H), 8.19 (d, 1H), 8.16 (bs, 1H), 7.72 (m, 2H), 7.58 (dd , 1H), 7.48 (dd, 1H), 7.19 (dd, 1H), 7.13 (d, 1H), 6.95 (d, 1H), 4.39 (d, 1H), 4 , 01 (d, 1H), 3.42 (s, 2H), 2.52 (s, 3H), 2.29 (s, 3H), 1.39 (s, 3H).

Example 19 [0192]

EP 1 660 090 B1

cl

<img file="PL1660090T3_D0025.tif" />

about

N4- [3-chloro-4- (3-fluorobenzyloxy) -phenyl] -N6- (1,8-dioxa-3-aza-spiro [4.5] dec-2-en-2-yl) -chinazolino4,6- diamine MS ESI (+) m / z 534 (M + 1) detected; ¹H NMR (400 mHz, CDCl3) δ 8.64 (s, 1H), 8.25 (bs, 1H), 7.78 (m, 2H), 7.60 (bs, 1H), 7.49 (d , 1H), 7.44 (d, 1H), 7.35 (m, 2H), 7.23 (m, 2H), 7.02 (m, 1H), 6.94 (d, 1H), 5 , 15 (s, 2H), 3.81 (m, 4H), 3.69 (m, 2H), 1.94 (m, 2H), 1.87 (m, 2H).

Example 20 [0194]

N6- (1,8-dioxa-3-aza-spiro [4.5] dec-2-en-2-yl) -N4- [3-methyl-4- (6-methylpyridin-3-yloxy-phenyl] chinazolini-4 6-diamine MS ESI (+) m / z 497 (M + 1) detected; ¹H NMR (400 mHz, CDCl3) δ 8.67 (s, 1H), 8.27 (d, 1H), 7.82 (d, 1H), 7.69 (s, 1H), 7.63 (s , 1H), 7.50 (m, 2H), 7.12 (m, 4H), 6.92 (d, 1H), 3.82 (m, 4H), 3.67 (m, 2H), 2 , 53 (s, 3H), 2.29 (s, 3H), 1.95 (m, 2H), 1.88 (m, 2H).

Example 21 [0196]

N4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (5-methyl-4,5-dihydro-2-yl) quinazoline-4,6-diamine

[0197] MS ESI (+) m / z 467.469 (M + 1, standard Cl) was detected; ¹H NMR (400 mHz, DMSO-D6) δ 9.60 (s, 1H), 8.52 (s, 1H), 8.20 (bs, 1H), 8.13 (s, 1H), 7.93 (d, 1H), 7.87 (d, 1H), 7.82 (d, 1H), 7.71 (d, 2H), 7.38 (d, 1H), 5.60 (s, 2H) , 4.82 (m, 1H), 3.80 (m, 1H), 3.26 (m, 1H), 2.56 (s, 3H).

Example 22 [0198]

<img file="PL1660090T3_D0026.tif" />

N4- [3-chloro-4- (thiazol-2-ylmethoxy-phenyl] -N6- (4,5-dihydro-oxazol-2-yl) -quinazoline-4,6-diamine. MS ESI (+ ) m / z 453, 455 (M + 1, standard Cl); ¹H NMR (400 mHz, DMSO-D6) δ 9.54 (s, 1H), 8.47 (s, 1H), 8.07 (bs, 1H), 7.86 (d, 1H), 7.80 (d, 1H), 7.76 (d, 1H), 7.66 (m, 2H), 7.32 (d, 1H), 5.55 (s, 2H), 4.38 (m, 2H) , 3.62 (m, 1H), 3.18 (m, 1H).

Example 23 [0200]

<img file="PL1660090T3_D0027.tif" />

N6- (5,5-dimethyl-4,5-dihydrooxazol-2-yl) -N4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenyl] -quinazoline-4,6-diamine [0201] MS APCI (+) m / z 455 (M + 1) detected; ¹H NMR (400 mHz, CD3OD) δ 8.42 (s, 1H), 8.17 (bs, 1H), 8.12 (d, 1H), 7.70 (d, 1H), 7.69 (s , 1H), 7.61 (dd, 1H), 7.57 (dd, 1H), 7.28 (m, 2H), 6.98 (d, 1H), 3.64 (s, 2H), 2 , 50 (s, 3H), 2.26 (s, 3H), 1.51 (s, 6H).

Example 24 [0202]

<img file="PL1660090T3_D0028.tif" />

EP 1 660 090 B1

N4- [3-chloro-4- (pyridin-2-ylmethoxy) phenyl] -N6- (4,5-dihydrooxazol-2-yl) quinazoline-4,6-diamine. MS ESI (+) detected m / z 447, 449 (M + 1, standard Cl); ¹H NMR (400 mHz, DMSO-D6) δ 9.53 (bs, 1H), 8.59 (d, 1H), 8.45 (s, 1H), 8.05 (bs, 1H), 7.89 (m, 2H), 7.74 (d, 1H), 7.65 (d, 1H), 7.58 (d, 1H), 7.38 (dd, 1H), 7.25 (d, 1H) , 5.29 (s, 2H), 4.38 (m, 2H), 3.62 (m, 2H).

Example 25 [0204]

<img file="PL1660090T3_D0029.tif" />

N4- [3-chloro-4- (pyridin-2-ylmethoxy) phenyl] -N6- (4-methyl-4,5-dihydrooxazol-2-yl) quinazoline-4,6-diamine. MS ESI ( +) m / z 461, 463 (M + 1, standard Cl); ¹H NMR (400 mHz, DMSO-D6) δ 9.51 (bs, 1H), 8.58 (d, 1H), 8.44 (s, 1H), 8.04 (bs, 1H), 7.86 (m, 1H), 7.72 (d, 1H), 7.58 (m, 3H), 7.34 (m, 1H), 7.22 (d, 1H), 5.27 (s, 2H) , 4.74 (m, 1H), 3.72 (m, 1H), 3.15 (m, 1H), 1.32 (s, 3H).

Example 26 [0206]

<img file="PL1660090T3_D0030.tif" />

N4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (1,8-dioxa-3-aza-spiro [4.5] dec-2-en-2-yl) -chinazolino4. 6-diamine. MS ESI (+) m / z 523, 525 (M + 1, standard Cl) detected; ¹H NMR (400 mHz, CDCl3) δ 8.64 (s, 1H), 7.78 (m, 2H), 7.60 (bs, 1H), 7.50 (d, 1H), 7.43 (d , 1H), 7.35 (m, 1H), 7.23 (m, 2H), 7.02 (m, 1H), 6.95 (d, 1H), 5.15 (s, 2H), 3 , 81 (m, 4H), 3.69 (m, 2H), 1.94 (m, 2H), 1.87 (m, 2H).

Example 27 [0208]

EP 1 660 090 B1

<img file="PL1660090T3_D0031.tif" />

N4- [3-chloro-4- (3-fluorobenzyloxy) -phenyl-N6- (5-methyl-4,5-dihydrooxazol-2-yl) -quinazoline-4,6-diamine [0209] ¹H NMR (400 mHz, CD3OD) δ 8.50 (s, 1H), 8.12 (bs, 1H), 8.02 (d, 1H), 7.97 (d, 1H), 7.60 (dd , 1H), 7.44 (m, 2H), 7.34 (d, 1H), 7.29 (d, 1H), 7.14 (d, 1H), 7.10 (d, 1H), 5 , 22 (s, 2H), 4.79 (m, 1H), 3.87 (m, 1H), 3.36 (m, 1H), 1.40 (d, 3H).

Example 28 [0210]

<img file="PL1660090T3_D0032.tif" />

N4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenyl] -N6- (3a, 4,6,6-tetrahydro-pyrazolo [3,4-d] oxazol-2-yl) quinazolin-4 , 6-diamine. MS APCI (+) m / z 469 (M + 1) detected; ¹H NMR (400 mHz, CD3OD) δ 8.43 (s, 1H), 8.26 (bs, 1H), 8.13 (d, 1H), 7.70 (m, 3H), 7.62 (m , 2H), 7.29 (m, 2H), 7.08 (s, 1H), 7.00 (d, 1H), 5.25 (m, 1H), 4.82 (m, 1H), 4 , 17 (d, 1H), 4.02 (d, 1H), 3.64 (m, 2H), 2.50 (s, 3H), 2.27 (s, 3H).

Example 29 [0212]

<img file="PL1660090T3_D0033.tif" />

(1RS, 5SR) -1- (5-methyl-2- (4- (3-methyl-4- (6-methylpyridin-3-yloxy) phenylamino) quinazolin-6-ylamino) 4,5-dihydro-5- il) ethanol [0213] MS ESI (+) m / z 485 (M + 1) detected; ¹H NMR (400 mHz, CDCl3) δ 8.58 (s, 1H), 8.22 (d, 1H), 8.17 (bs, 1H), 7.74 (d, 1H), 7.71 (d , 1H), 7.60 (dd, 1H), 7.36 (d, 1H), 7.16 (dd, 1H), 7.10 (d, 1H), 6.94 (d, 1H),

4.02 (d, 1H), 3.92 (m, 1H), 3.55 (d, 1H), 2.52 (s, 3H), 2.28 (s, 3H), 1.45 (s , 3H), 1.22 (m, 4H).

EP 1 660 090 B1

Example 30 [0214]

<img file="PL1660090T3_D0034.tif" />

N6- (4,5-dihydrooxazol-2-yl) -N4- [3-methyl-4- (6-methylpyridin-3-yloxy) phenyl] quinazoline-4,6-diamine. MS ESI ( +) m / z 427 (M + 1); ¹H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.45 (s, 1H), 8.18 (d, 1H), 7.80 (s, 1H), 7.72 (d, 1H), 7.65 (d, 1H), 7.21 (m, 3H), 6.96 (d, 1H), 4.38 (m, 2H), 3.64 (m, 2H) , 2.51 (s, 3H), 2.20 (s, 3H).

Example 31 [0216]

<img file="PL1660090T3_D0035.tif" />

(2- {4- [3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino] -quinazolin-6-ylamino} -4-methyl-4,5-dihydrooxazol-4-yl) -methanol [0217] MS ESI (+) m / z 491, 493 (M + 1, standard Cl) detected; ¹H NMR (400 mHz, CDCl3) δ 8.57 (s, 1H), 8.56 (s, 1H), 8.13 (bs, 1H), 7.97 (d, 1H), 7.81 (m , 1H), 7.73 (m, 2H), 7.61 (dd, 1H), 7.44 (dd, 1H), 7.29 (m, 1H), 7.04 (d, 1H), 5 , 30 (s, 2H), 3.64 (d, 1H), 3.52 (d, 1H), 3.43 (s, 2H), 1.26 (s, 3H).

Example 32 [0218]

<img file="PL1660090T3_D0036.tif" />

(1RS, 5SR) -1- (2- (4- (3-chloro-4- (pyridin-2-ylmethoxy) phenylamino) quinazolin-6-ylamino) -5-methyl-4,5-dihydrooxazol-5-yl) ethanol

[0219] MS ESI (+) m / z 505, 507 (M + 1, standard Cl) was detected; ¹H NMR (400 mHz, CDCl3) δ 8.60 (s, 1H), 8.58 (s, 1H), 8.12 (bs, 1H), 7.95 (d, 1H), 7.77 (m , 1H), 7.72 (d, 1H), 7.69 (d, 1H), 7.63 (dd, 1H), 7.25 (m, 2H), 7.02 (d, 1H), 5 , 30 (s, 2H), 4.07 (d, 1H), 3.98 (q, 1H), 3.56 (d, 1H), 1.45 (s, 3H), 1.22 (d, 3H).

Example 33 [0220]

<img file="PL1660090T3_D0037.tif" />

N4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (4,4-dimethyl-4,5-dihydrooxazol-2-yl) -quinazoline-4,6-diamine. MS detected APCI (+) m / z 481, 483 (M + 1, standard Cl); ¹H NMR (400 mHz, DMSO-D6) δ 9.52 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.96 (bs, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.78 (d, 1H), 7.65 (d, 1H), 7.32 (d, 1H), 5.55 (s, 2H) , 3.17 (d, 2H), 1.28 (s, 6H).

Example 34 [0222]

<img file="PL1660090T3_D0038.tif" />

(1 RS, 5SR) -1- (2- (4- (4- (3-fluorobenzyloxy) -3-chlorophenylamino) quinazolin-6-ylamino) -5-methyl-4,5-dihydrooxazol-5-yl) ethanol [0223] MS ESI (+) m / z 522, 524 (M + 1, standard Cl) was detected; ¹H NMR (400 mHz, CDCl3) δ 8.57 (s, 1H), 8.10 (bs, 1H), 7.91 (d, 1H), 7.70 (d, 1H), 7.65 (dd , 1H), 7.36 (m, 1H), 7.30 (m, 1H), 7.24 (m, 2H), 7.00 (m, 1H), 6.98 (d, 1H), 5 , 16 (s, 2H), 4.05 (d, 1H), 3.95 (q, 1H), 3.55 (d, 1H), 1.45 (s, 3H), 1.21 (d, 3H).

Example 35 [0224]

EP 1 660 090 B1

<img file="PL1660090T3_D0039.tif" />

N6- (5-methyl-4,5-dihydrooxazol-2-yl) -N4- [3-methyl-4- (6-methylpyridin-3-yloxy) phenyl] quinazoline-4,6-diamine. MS detected APCI (+) m / z 441 (M + 1); ¹H NMR (400 mHz, DMSO-D6) δ 9.51 (s, 1H), 8.45 (s, 1H), 8.18 (d, 1H), 7.80 (s, 1H), 7.69 (m, 3H), 7.23 (m, 2H), 6.96 (d, 1H), 4.77 (m, 1H), 4.13 (m, 1H), 6.73 (m, 1H) , 2.44 (s, 3H), 2.20 (s, 3H), 1.36 (d, 3H).

Example 36 [0226]

N4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6-4-methyl-4,5-dihydrooxazol-2-yl) -quinazoline-4,6-diamine. MS APCI (+ ) m / z 467, 469 (M + 1, standard Cl); ¹H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.69 (m, 3H), 7.32 (d, 1H), 7.02 (s, 1H), 5.54 (s, 2H) , 4.47 (m, 1H), 3.99 (m, 1H), 3.90 (m, 1H), 1.18 (d, 3H).

Example 37 [0228]

N

NN

<img file="PL1660090T3_D0040.tif" />

about

N4- [3-chloro-4- (pyridin-2-ylmethoxy) -phenyl] -N6- (1,8-dioxa-3-aza-spiro [4.5] dec-2-en-2-yl) -chinazolino4. 6-diamine

[0229] MS APCI (+) m / z 517, 519 (M + 1, standard Cl) detected; ¹H NMR (400 mHz, CDCl3) δ 8.66 (s, 1H), 8.60 (d, 1H), 7.87 (s, 1H), 7.81 (d, 1H), 7.76 (m , 1H), 7.66 (d, 1H), 7.51 (m, 2H), 7.44 (d, 1H), 7.25 (m, 1H), 7.01 (d, 1H), 5 , 30 (s, 2H), 3.82 (m, 4H), 3.75 (m, 1H), 3.69 (m, 1H), 1.95 (m, 2H), 1.87 (m, 2H).

Example 38 [0230]

<img file="PL1660090T3_D0041.tif" />

N6- (4-methyl-4,5-dihydrooxazol-2-yl) -N4- [3-methyl-4- (6-methylpyridin-3-yloxy) -phenyl] -quinazoline-4,6-diamine. MS detected APCI (+) m / z441 (M + 1); ¹H NMR (400 mHz, DMSO-D6) δ 9.51 (s, 1H), 8.44 (s, 1H), 8.15 (d, 1H), 8.05 (bs, 1H), 7.79 (s, 1H), 7.71 (d, 1H), 7.62 (m, 2H), 7.20 (m, 2H), 6.99 (s, 1H), 6.93 (d, 1H) , 4.45 (m, 1H), 4.02 (m, 1H), 3.87 (m, 1H), 2.41 (s, 3H), 2.18 (s, 3H), 1.17 ( d, 3H).

Example 39 [0232]

<img file="PL1660090T3_D0042.tif" />

N4- [3-chloro-4- (pyridin-2-ylmethoxy) phenyl] -N6- (4,5-dihydrooxazol-2-yl) quinazoline-4,6-diamine. MS ESI (+) detected m / z 447, 449 (M + 1, standard Cl); ¹H NMR (400 mHz, DMSO-D6) δ 9.53 (bs, 1H), 8.59 (d, 1H), 8.45 (s, 1H), 8.05 (bs, 1H), 7.89 (m, 2H), 7.74 (d, 1H), 7.65 (d, 1H), 7.58 (d, 1H), 7.38 (dd, 1H), 7.25 (d, 1H) , 5.29 (s, 2H), 4.38 (m, 2H), 3.62 (m, 2H).

Example 40

<img file="PL1660090T3_D0043.tif" />

[0234]

EP 1 660 090 B1

N4- [3-chloro-4- (pyridin-2-ylmethoxy) phenyl] -N6- (4-methyl-4,5-dihydrooxazol-2-yl) quinazoline-4,6-diamine [0235] MS ESI ( +) m / z 461, 463 (M + 1, standard Cl); ¹H NMR (400 mHz, DMSO-D6) δ 9.51 (bs, 1H), 8.58 (d, 1H), 8.44 (s, 1H), 8.04 (bs, 1H), 7.86 (m, 1H), 7.72 (d, 1H), 7.58 (m, 3H), 7.34 (m, 1H), 7.22 (d, 1H), 5.27 (s, 2H) , 4.74 (m, 1H), 3.72 (m, 1H), 3.15 (m, 1H), 1.32 (s, 3H).

Example 41 [0236]

<img file="PL1660090T3_D0044.tif" />

N4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (3a, 4,6,6-tetrahydro-pyrazolo [3,4-d] oxazol-2-yl) -chinazolino4,6- diamine. MS APCI (+) m / z 495, 497 (M + 1, standard Cl) detected; ¹H NMR (400 mHz, CD3OD) δ 8.47 (s, 1H), 8.23 ​​(br, s, 1H), 7.95 (d, 1H), 7.83 (d, 1H), 7.71 (d, 1H), 7.66 (dd, 1H), 7.63 (d, 1H), 7.59 (dd, 1H), 7.2 (d, 1H), 5.50 (s, 2H) , 4.19 (d, 1H), 4.05 (d, 1H), 3.65 (m, 2H), 3.19 (m, 2H).

Example 42 [0238]

<img file="PL1660090T3_D0045.tif" />

N4- [3-Methyl-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (3a, 4,6,6-tetrahydro-pyrazolo [3,4-d] oxazol-2-yl) -chinazolino4,6- diamine. MS ESI (+) m / z475 (M + 1) detected; ¹H NMR (400 mHz, CD3OD) δ 8.37 (s, 1H), 8.25 (br s, 1H), 7.83 (d, 1H), 7.69 (d, 1H), 7.65 ( d, 1H), 7.59 (m, 1H), 7.52 (m, 2H), 7.07 (d, 1H), 5.46 (s, 2H), 4.17 (d, 1H), 4.02 (d, 1H), 3.64 (m, 2H), 2.34 (m, 5H).

Example 43 [0240]

EP 1 660 090 B1

<img file="PL1660090T3_D0046.tif" />

N4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (1,8-dioxa-3-aza-spiro [4.5] dec-2-en-2-yl) -chinazolino4. 6-diamine. MS ESI (+) m / z 523, 525 (M + 1, standard Cl) detected; ¹H NMR (400 mHz, CDCl3) δ 8.64 (s, 1H), 7.78 (m, 2H), 7.60 (bs, 1H), 7.50 (d, 1H), 7.43 (d , 1H), 7.35 (m, 1H), 7.23 (m, 2H), 7.02 (m, 1H), 6.95 (d, 1H), 5.15 (s, 2H), 3 , 81 (m, 4H), 3.69 (m, 2H), 1.94 (m, 2H), 1.87 (m, 2H).

Example 44 [0242]

<img file="PL1660090T3_D0047.tif" />

N4- [3-chloro-4- (pyridin-2-ylmethoxy) phenyl] -N6- (5-methyl-4,5-dihydrooxazol-2-yl) quinazoline-4,6-diamine. MS ESI detected ( +) m / z 461, 463 (M + 1, standard Cl); ¹H NMR (400 mHz, DMSO-D6) δ 9.51 (s, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 8.04 (m, 2H), 7.86 (m, 1H), 7.63 (m, 4H), 7.34 (m, 1H), 7.22 (d, 1H), 5.27 (s, 2H), 4.74 (m, 1H) , 3.72 (m, 1H), 3.15 (m, 1H), 1.34 (d, 3H).

Example 45 [0244]

<img file="PL1660090T3_D0048.tif" />

N4- [3-chloro-4- (3-fluorobenzyloxy) -phenyl] -N6- (4-methyl-4,5-dihydro-2-yl) quinazoline-4,6-diamine

[0245] MS ESI (+) m / z 478 (M + 1) detected; ¹H NMR (400 mHz, DMSO-D6) δ 9.51 (s, 1H), 8.46 (s, 1H), 8.06 (m, 2H), 7.76 (d, 1H), 7.64 (d, 1H), 7.47 (m, 2H), 7.32 (m, 2H), 7.24 (d, 1H), 7.18 (m, 1H), 5.25 (s, 2H) , 4.47 (m, 1H), 3.95 (m, 1H), 3.17 (m, 1H), 1.19 (d, 3H).

Example 46 [0246]

<img file="PL1660090T3_D0049.tif" />

N4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (4,5,6,6a-tetrahydro-3aH-pyrrolo [3,4-d] oxazol-2-yl) quinazoline -4,6-diamine [0247] N4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (4,5,6,6a-tetrahydro-3aH-pyrrolo [3,4- d] oxazol-2-yl) -quinazoline-4,6-diamine was prepared from 2- {4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenylamino] -quinazolin-6-ylamino} -3a tert-butyl ester. , 4,6,6a-tetrahydro-pyrrolo [3,4-d] oxazole-5-carboxylic acid by standard methods for removal of the BOC protecting group, using TFA in methylene chloride. MS APCI (+) m / z 494, 496 (M + 1, standard Cl) detected;¹H NMR (400 mHz, CD3OD) δ 8.44 (s, 1H), 8.19 (br, s, 1H), 7.96 (d, 1H), 7.83 (d, 1H), 7.67 (m, 3H), 7.58 (dd, 1H), 7.22 (d, 1H), 5.50 (s, 2H), 5.17 (m, 1H), 4.76 (m, 1H) , 3.32 (d, 1H), 3.16 (d, 1H), 2.85 (m, 2H).

Example 47 [0248]

<img file="PL1660090T3_D0050.tif" />

N4- [3-chloro-4- (pyridin-2-ylmethoxy) -phenyl] -N6- (4,5,6,6a-tetrahydro-3aH-pyrrolo [3,4-d] oxazol-2-yl) quinazoline -4,6-diamine [0249] N4- [3-chloro-4- (pyridin-2-ylmethoxy) -phenyl] -N6- (4,5,6,6a-tetrahydro-3aH-pyrrolo [3,4- d] oxazol2-yl) -quinazoline-4,6-diamine was prepared from 2- {4- [3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino] -quinazolin-6-ylamino} tert-butyl ester. -3a, 4,6,6a-tetrahydro-pyrrolo [3,4-d] oxazole-5-carboxylic acid by standard methods for removal of the BOC protecting group, using TFA in methylene chloride. MS APCI (+) m / z 488.490 (M + 1, reference Cl) detected;¹H NMR (400 mHz, CD3OD) δ 8.56 (d, 1H), 8.44 (s, 1H), 8.21 (br, s, 1H), 7.91 (m, 2H), 7.70 (m, 2H), 7.63 (d, 1H), 7.57 (d, 1H), 7.39 (m, 1H), 7.16 (d, 1H), 5.28 (s, 2H) , 5.17 (m, 1H), 4.78 (m, 1H), 3.34 (d, 1H), 3.16 (d, 1H), 2.84 (m, 2H).

EP 1 660 090 B1

Example 48 [0250]

<img file="PL1660090T3_D0051.tif" />

(2- {4- (3-chloro-4- (3-fluoro-benzyloxy) -phenylamino] -quinazolin-6-ylamino} -4-methyl-4,5-dihydro-oxazol4-yl) -methanol. MS detected ESI (+) m / z 508, 510 (M + 1, standard Cl); ¹H NMR (400mHz, CDCl3) δ 8.57 (s, 1H), 8.14 (s, 1H), 7.93 (d, 1H), 7.74 (d, 1H), 7.63 (dd, 1H), 7.37 (m, 2H), 7.25 (m, 2H), 7.01 (m, 2H), 5.17 (s, 2H), 4.38 (d, 1H), 4, 00 (d, 1H), 3.65 (d, 1H), 3.48 (d, 1H), 1.38 (s, 3H).

Example 49 [0252]

<img file="PL1660090T3_D0052.tif" />

N4- [3-chloro-4- (pyridin-2-ylmethoxy) -phenyl] -N6- (6-oxa-4-aza-spiro [2.4] hept-4-en-5-yl) -chinazolino4,6- diamine. MS APCI (+) m / z 473.475 (M + 1, standard Cl) detected; ¹H NMR (400 mHz, CD3OD) δ 8.56 (d, 1H), 8.45 (s, 1H), 8.21 (s, 1H), 7.98 (d, 1H), 7.92 (m , 1H), 7.72 (m, 2H), 7.63 (m, 2H), 7.40 (m, 1H), 7.18 (d, 1H), 5.28 (s, 2H), 4 , 36 (s, 2H), 1.12 (m, 2H), 0.81 (m, 2H).

Example 50 [0254]

<img file="PL1660090T3_D0053.tif" />

EP 1 660 090 B1 (2- {4- [3-chloro-4- (pyridin-2-ylmethoxy) -phenylamino] -quinazolin-6-ylamino} -4-hydroxymethyl-4,5-dihydro-oxazol-4-yl) -methanol [0255] MS ESI (+) m / z 507, 509 (M + 1, standard Cl) detected; ¹H NMR (400 mHz, DMSO-D6) δ 9.47 (s, 1H), 8.60 (d, 1H), 8.46 (s, 1H), 8.08 (s, 1H), 7.89 (m, 1H), 7.71 (m, 2H), 7.58 (d, 1H), 7.37 (m, 1H), 7.25 (d, 1H), 5.29 (s, 2H) , 4.34 (m, 2H), 3.29 (s, 4H).

Example 51 [0256]

<img file="PL1660090T3_D0054.tif" />

(R) -1 - ((S) -2- (4- (3-chloro-4- (thiazol-2-ylmethoxy) phenylamino) -quinazolin-6-ylamino) -4,5-dihydrooxazol-4-yl) ethanol [ 0257] (R) -1 - ((S) -2- (4- (3-chloro-4- (thiazol-2-ylmethoxy) phenylamino) quinazolin-6-ylamino) -4,5 dihydrooxazol-4-yl) ethanol made from (1R, 4S) -N6- [4- (1-tert-butoxyethyl) -4,5-dihydrooxazol-2-yl] N4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenyl] -quinazoline-4,6-diamines by standard reflective methods₁ by using TFA in methylene chloride. MS ESI (+) m / z 497.499 (M + 1, reference Cl) detected;¹H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s, 1H), 8.08 (d, 1H), 7.87 (d, 1H), 7.80 (d, 1H), 7.76 (dd, 1H), 7.66 (m, 2H), 7.33 (d, 1H), 5.55 (s, 2H), 4.81 (m, 1H) , 4.37 (m, 1H), 4.20 (m, 1H), 3.83 (m, 1H), 3.63 (m, 1H), 1.06 (d, 3H).

Example 52 [0258]

<img file="PL1660090T3_D0055.tif" />

(R) -N4- [3-chloro-4- (thiazol-2-ylmethoxy) phenyl] -N6- (4-methyl-4,5-dihydro-oxazol-2-yl) -quinazoline-4,6-diamine [ 0259] Made using (R) -2-aminopropan-1-ol. MS APCI (+) m / z 467, 469 (M + 1, standard Cl) detected;¹H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.86 (d, 1H),

7.81 (d, 1H), 7.77 (d, 1H), 7.69 (m, 3H), 7.32 (d, 1H), 7.02 (s, 1H), 5.54 (s , 2H), 4.47 (m, 1H), 3.99 (m,

1H), 3.90 (m, 1H), 1.18 (d, 3H).

EP 1 660 090 B1

Example 53 [0260]

<img file="PL1660090T3_D0056.tif" />

(S) -N4- [3-chloro-4- (thiazol-2-ylmethoxy) -phenyl] -N6- (4-methyl-4,5-dihydro-oxazol-2-yl) -quinazoline-4,6-diamine [ 0261] Made using (S) -2-amino-propan-1-ol. MS APCI (+) m / z 467, 469 (M + 1, standard Cl) detected;¹H NMR (400 mHz, DMSO-D6) δ 9.53 (s, 1H), 8.47 (s, 1H), 8.09 (s, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.77 (d, 1H), 7.69 (m, 3H), 7.32 (d, 1H), 7.02 (s, 1H), 5.54 (s, 2H) , 4.47 (m, 1H), 3.99 (m, 1H), 3.90 (m, 1H), 1.18 (d, 3H).

Example 54 [0262]

<img file="PL1660090T3_D0057.tif" />

(S) -N4- [3-chloro-4- (pyridin-2-ylmethoxy) -phenyl] -N6- (5-methyl-4,5-dihydro-oxazol-2-yl) -quinazoline-4,6-diamine [ 0263] Made using (S) -1-amino-propan-2-ol. MS ESI (+) m / z 461, 463 (M + 1, standard Cl) detected;¹H NMR (400 mHz, DMSO-D6) δ 9.51 (s, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 8.04 (m, 2H), 7.86 (m, 1H), 7.63 (m, 4H), 7.34 (m, 1H), 7.22 (d, 1H), 5.27 (s, 2H), 4.74 (m, 1H) , 3.72 (m, 1H), 3.15 (m, 1H), 1.34 (d, 3H).

Example 55 [0264]

EP 1 660 090 B1

<img file="PL1660090T3_D0058.tif" />

(ff) -N4- [3-chloro-4- (pyridin-2-ylmethoxy) -phenyl] -N6- (5-methyl-4,5-dihydro-oxazol-2-yl) -quinazoline-4,6-diamine [ 0265] Made using (R) -1-amino-propan-2-ol. MS ESI (+) m / z 461, 463 (M + 1, standard Cl) detected;¹H NMR (400 mHz, DMSO-D6) δ 9.51 (s, 1H), 8.58 (s, 1H), 8.44 (s, 1H), 8.04 (m, 2H), 7.86 (m, 1H), 7.63 (m, 4H), 7.34 (m, 1H), 7.22 (d, 1H), 5.27 (s, 2H), 4.74 (m, 1H) , 3.72 (m, 1H), 3.15 (m, 1H), 1.34 (d, 3H).

Example 56 [0266] .ci

N4- [4- (5-chloropyridin-3-yloxy) -3-methyl-phenyl] -N6- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl) -quinazoline-4,6-diamine [ 0267] MS ESI (+) m / z 475 477 (m + 1, standard Cl) detected; ¹H NMR (400 mHz, DMSO d6) 9.62 (bs, 1H), 8.49 (s, 1H), 8.37 (d, 1H), 8.29 (d, 1H), 8.05 (bs , 1H), 7.87 (s, 1H), 7.80 (d, 1H), 7.68 (d, 1H), 7.41 (m, 1H), 7.10 (d, 1H), 4 , 11 (s, 2H), 2.19 (s, 3H), 1.29 (s, 6H).

Example 57 [0268] .0

<img file="PL1660090T3_D0059.tif" />

N6- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl) -N4- [3-methyl-4- (pyridin-3-yloxy) -phenyl] -quinazoline-4,6-diamine

[0269] MS ESI (+) m / z 441 (m + 1) detected; ¹H NMR (400 mHz, DMSO d6) 9.54 (bs, 1H), 8.46 (s, 1H), 8.33 (d, 1H), 8.29 (d, 1H), 8.00 (bs , 1H), 7.84 (s, 1H), 7.77 (d, 1H), 7.65 (d, 1H), 7.37 (m, 1H), 7.26 (m, 1H), 7 , 03 (d, 1H), 4.07 (s, 2H), 2.19 (s, 3H), 1.28 (s, 6H).

Example 58 [0270]

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N6- (4,4-dimethyl-4,5-dihydro-oxazol-2-yl) -N4- [4- (5-fluoro-pyridin-3-yloxy) -3-methylphenyl] quinazoline4,6-diamine [ 0271] MS ESI (+) m / z 459 (m + 1) detected; ¹H NMR (400 mHz, DMSO d6) 9.70 (bs, 1H), 8.51 (s, 1H), 8.43 (d, 1H), 8.20 (d, 1H), 8.11 (bs , 1H), 7.86 (s, 1H), 7.80 (d, 1H), 7.69 (m 2H), 7.29 (d, 1H), 7.11 (d, 1H), 4, 61 (s, 2H), 2.20 (s, 3H), 1.30 (s, 6H).

[0272] The amino alcohols used in the Examples above are known or have been prepared as described below.

Example 59 [0273]

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OH

Preparation of (4-aminotetrahydropyran-4-yl) -methanol [0274] (4-amino-tetrahydropyran-4-yl) -methanol was prepared by adding in portions LLA (99%, 1.2 g) to a mixed mixture of 4-aminotetrahydropyran hydrochloride -4-carboxyl (2.0 g, 11.0 mmol) in THF (30 mL) at 0 ° C. After the addition was complete, the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was cooled to 0 ° C and carefully quenched by adding Na2SO4.10H2O (4 g) in portions. The reaction mixture was diluted with ethyl acetate, warmed to room temperature, filtered through Celite to give the desired product.

Example 60 [0275]

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Preparation of 4-aminomethyl-4-hydroxypiperidine-1-carboxylic acid tert-butyl ester [0276] 4-Aminomethyl-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester was prepared from 1-oxa-6 -aza-spiro [2.5] octane-6-carboxyl (Bourrain et al. Bioorg. Med. Chem. Lett. 9 (23): 3369-3374 (1999)). To a solution of 1-oxa-6-azaspiro [2.5] octane-6-carboxylic acid tert-butyl ester (0.50 g, 2.3 mmol) in MeOH (4 mL) at 0 ° C was added concentrated aqueous NH 4 OH (6 mL ). The cooling bath was removed from the reaction mixture and allowed to warm to room temperature. After 7 hours, the reaction mixture was concentrated under reduced pressure to give the desired product as a white solid.

Example 61 [0277]

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Preparation of 4-aminomethyltetrahydro-pyran-4-ol [0278] 4-Aminomethyl-tetrahydro-pyran-4-ol was prepared from 1,6-dioxa-spiro [2.5] octane. A solution of 1,6-dioxa-spiro [2.5] octane (0.19 g, 1.7 mmol) in MeOH (3.5 mL) was added to concentrated aqueous NH4OH (4.3 mL) at 0 ° C. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and purified by column chromatography (10% MeOH, 2% Et3N in DCM) to obtain 90 mg (41%) of the desired product as a white solid.

Example 62 [0279]

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Preparation of (2RS, 3SR) -1-amino-2-methylbutane-2,3-diol [0280] (2RS, 3SR) -1-amino-2-methylbutane-2,3-diol was prepared from 1,2-dimethylallyl ester acetic acid. To a stirred solution of acetic acid 1,2-dimethylallyl ester (6.80 g, 53.1 mmol) in methylene chloride (500 mL) was slowly added mCPBA (17 g, 69 mmol). After 4 hours, the reaction mixture 45

The mixture was washed with saturated NaHCO3 solution, water and brine. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (20% solution of diethyl ether in pentane; twice) gave 1 - (- 2-methylxiranyl) -ethyl (1-RS, 2-SR) -acetic acid ester (3.45 g, 45%). A small portion of (1RS, 2-SR) -acetic acid 1 - (- 2-methylxiranyl) -ethyl ester was performed in (2RS, 3SR) -3,4-epoxy-3-methyl-2-butanol (JACS (1990) 112 (13): 5285) by the action of K2CO3 in MeOH and the relative stereochemistry of the racemic substance obtained is confirmed. To a mixed solution of acetic acid (R *) - 1 - ((S *) - 2-methyl-oxiranyl) ethyl ester (1.70 g, 11.8 mmol) in MeOH (12 mL) was added K2CO3 (1.54 g, 11.1 mmol). After 1 hour, the reaction mixture was filtered through Celite. The resulting filtered slowly through a dropping funnel was added to 20 mL concentrated aqueous NH4OH solution. After stirring for 16 hours, the reaction mixture was concentrated under reduced pressure, and purified by column chromatography (20% MeOH, 2% Et3N in DCM) to obtain 0.97 g (69%) of the desired product as a light yellow oil.

Example 63

Manufacture N.⁴- [3-chloro-4- (3-fluoro-benzyloxy) -phenyl] -N⁶- (4,5-dihydro-oxazol-2-yl) -N⁶-methylquinazoline-4,6-diamine. StepA: Solution N⁴- [3-chloro-4- (3-fluorobenzyloxy) phenyl] quinazoline-4,6-diamine (1.09 g, 2.76 mmol) and di-t-butyl dicarbonate (2.0 g, 3, 3 equivalents) was heated in t-BuOH: DCE (1: 1) in a closed flask at 90-95 ° C for 20 minutes, then cooled to room temperature. The volatiles were removed under reduced pressure, and the product was purified by silica gel chromatography (60% EtOAc / hexanes) to give a yellow solid (670 mg, 49%).

[0282] Step B: The purified material from Step A at 0 ° C was taken up in THF (5-10 mL) and LAH (1.0 M solution in THF, 1 equivalent) was added. The solution was heated to reflux for 1 hour and then cooled to room temperature. The reaction mixture was diluted with THF and quenched by the addition of sodium sulfate cascartrate hydrate in portions. The reaction mixture was filtered and the product purified by silica gel chromatography (100% EtOAc) to give a yellow solid.

[0283] Step C: The purified substance from EtapuB (63 mg, 0.15 mmol) was taken up in THF (3 mL) and 2-chloroethyl isocyanate (32 μ, 2.4 equivalents) was added. The reaction mixture was heated at 50 ° C until a solid precipitate formed. Filtration in vacuo afforded the product as a light yellow solid (26 mg, 33%).

[0284] StepD: The substance from StepC was absorbed in MeCN (2 m |) and 40% KF was added per g of aluminum (130 mg, 18 equivalents). The mixture was refluxed for 12 hours, diluted with MeCN and filtered through Ce. After chromatography on silica, N was obtained⁴- [3-ch | chloro-4- (3-| uorobenzy | oxy) -phenyl | o] -N⁶- (4,5-dihydro-oxazole | -2-i | o) -N⁶-meth | o-quinazo | ino-4,6-diamine (6 mg, 25%). [0285] Other compounds of the present invention include:

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[0286] The terms "includes," "including," "contain," "comprising" and "comprises" as used in this specification and claims are intended to determine the presence of certain features, integers, components or steps, but do not exclude the presence or adding one or more other characteristics, integers, components, steps or groups.