Pyrrolo[2,3-D]Pyrimidines and Their Use as Tyrosine Kinase Inhibitors

专利摘要:
The present invention relates to compounds of formula (I) and pharmaceutically acceptable salts thereof which are useful for the treatment of proliferative diseases and immune system diseases in mammals. <Formula I> Wherein R 1 is hydrogen, 2-phenyl-1,3-dioxan-5-yl, C 1-6 alkyl group, C 3-8 cycloalkyl group, C 5-7 cycloalkenyl group or (optionally substituted phenyl) C 1-6 alkyl group, wherein the alkyl, cycloalkyl, and cycloalkenyl groups represent one or more groups of formula OR A wherein R A represents H or a C 1-6 alkyl group, provided that the group of formula OR A Is not located at the carbon atom bonded to; R 2 represents hydrogen, a C 1-6 alkyl group, a C 3-8 cycloalkyl group, halo, hydroxy, a (optionally substituted phenyl) C 1-6 alkyl group, optionally substituted phenyl or R 4 ; R 3 represents a group of formula (a); <Formula (a)> Wherein the phenyl ring is further optionally substituted, A is NH, O, NHSO 2 , SO 2 NH, C 1-4 alkylene chain, NHCO, NHCO 2 , CONH, NHCONH, CO 2 or S (O) p Wherein p is 0, 1 or 2, or A is absent so that R 5 is directly bonded to the phenyl ring, R 5 represents optionally substituted phenyl, and further when A is absent, 5 represents a) a phthalimido group optionally substituted with halo or b) a pyrazolylamino group optionally substituted with at least one of hydroxy or optionally substituted phenyl with pyrazole ring) R 4 represents a heterocyclic group. The invention also relates to a process for the preparation of the compound and to pharmaceutical compositions containing the compound.
公开号:KR20000076426A
申请号:KR1019997008530
申请日:1998-03-09
公开日:2000-12-26
发明作者:데이빗 존 캘더우드；데이빗 노만 존스톤；폴 래퍼티；헬렌 루이스 트위거；라이너 문샤우어；리 아놀드
申请人:스타르크, 카르크；바스프 악티엔게젤샤프트；
IPC主号:

专利说明:

Pyrrolo [2,3-D] Pyrimidines and Their Use as Tyrosine Kinase Inhibitors} as pyrrolo [2,3-D] pyrimidine and tyrosine kinase inhibitors
[2] Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of specific tyrosine residues in proteins. Often, post-translational modifications of these substrate proteins, the enzymes themselves, act as molecular switches that regulate cell proliferation and activation. Abnormal PTK activity has been observed in a number of disease states, including benign and malignant proliferative diseases as well as diseases resulting from inappropriate activation of the immune system (autoimmunity, allograft rejection and graft-versus-host disease). Compounds that selectively inhibit causative PTKs would be useful therapeutics.
[3] Compounds of formula A are described in International Patent Application Publication No. 96/10028 as inhibitors of the protein tyrosine kinase pp60 ^c-src .
[4]
[5] Wherein R ₁ is aryl, R ₂ is hydrogen, lower alkyl or halo, and R ₃ is aryl.
[6] R ₁ is substituted or unsubstituted cyclo-lower alkyl or cyclo-lower alkenyl, and R ₂ and R ₃ are described in International Patent Application Publication No. 97/28161, which is co-pending with the same compound of Formula A as defined above. It is described. R ₁ is lower alkyl or substituted lower alkyl and R ₂ and R ₃ are described in International Patent Application Publication No. 97/32879 in which co-pending compounds of the formula A as defined above are co-pending.
[7] Compounds of formula (B) are described in International Patent Application Publication No. 96/40686 as adenosine kinase inhibitors.
[8]
[9] Wherein X is -N or CR ₇ where R ₇ is hydrogen, halogen, lower alkyl, lower alkoxy or S-lower alkyl; Y is -N or -CH; R ₁ and R ₂ are each independently hydrogen, hydroxy, alkoxy or acyloxy, or R ₁ and R ₂ are both hydroxy protected with each hydroxy protecting group or one dihydroxy protecting group, or R ₁ And R ₂ is absent and there is a double bond between the carbon atoms bonded to R ₁ and R ₂ ; R ₃ is hydrogen, hydroxy, lower alkyl or alkoxy; R ₄ is especially (a) hydrogen, (b) amino, (c) halogen, (d) hydroxy, or R ₃ and R ₄ together are = 0 or spirocyclic together with the carbon atom to which they are attached To form a ring; R ₅ is especially hydrogen, lower alkyl or amino; R ₆ is especially lower alkyl, aryl, heteroaryl or heteroarylalkyl.
[10] <Summary of invention>
[11] The present invention relates to compounds of formula (I), including pharmaceutically acceptable salts.
[12]
[13] Wherein R ₁ is hydrogen, 2-phenyl-1,3-dioxan-5-yl, C _1-6 alkyl group, C _3-8 cycloalkyl group, C _5-7 cycloalkenyl group or (optionally substituted phenyl) C _1-6 alkyl group, wherein the alkyl, cycloalkyl, and cycloalkenyl groups represent one or more groups of formula OR _A wherein R _A represents H or a C _1-6 alkyl group, provided that the group of formula OR _A Is not located at the carbon atom bonded to;
[14] R ₂ represents hydrogen, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, halo, hydroxy, a (optionally substituted phenyl) C _1-6 alkyl group, optionally substituted phenyl or R ₄ ;
[15] R ₃ represents a group of the formula (a);
[16]
[17] Wherein the phenyl ring is further optionally substituted, A is NH, O, NHSO ₂ , SO ₂ NH, C _1-4 alkylene chain, NHCO, NHCO ₂ , CONH, NHCONH, CO ₂ or S (O) _p Wherein p is 0, 1 or 2, or A is absent so that R ₅ is directly bonded to the phenyl ring, R ₅ represents optionally substituted phenyl, and further when A is absent, ₅ represents a) a phthalimido group optionally substituted with halo or b) a pyrazolylamino group optionally substituted with at least one of hydroxy or optionally substituted phenyl with pyrazole ring)
[18] R ₄ is thienyl, benzo (b) thienyl, pyridyl, pyrazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, indazolyl (each of which is a C _1-6 alkyl group, C _3-6 cycloalkyl group, C _1-6 alkoxy, C _1-6 alkylthio, hydroxy, optionally substituted phenyl, (optionally substituted phenyl) C _1-6 alkyl, (optionally substituted phenyl) C _1-6 alkylthio group; or (Optionally substituted with one or more of optionally substituted phenyl) C _1-6 alkoxy groups).
[19] Wherein optionally substituted phenyl is a) a C _1-6 alkyl group, b) a C _1-6 alkoxy group, c) phenoxy, d) hydroxy, e) phenyl C _1-6 alkyl, f) halo, g) Groups of NR ₁₀ R ₁₁ , wherein R ₁₀ and R ₁₁ are independently hydrogen, C _1-6 alkyl group, phenyl, C _1-6 alkanoyl group, (C _1-6 alkoxy) carbonyl group, 5-hydroxy-1 -Phenyl-3-pyrazolyl or represent benzoyl optionally substituted with C _1-6 alkyl, C _1-6 alkoxy or halo, h) a group of formula -COR ₉ wherein R ₉ is hydroxy, C _1-6 alkoxy group, phenoxy or a group of formula NR ₁₀ R ₁₁ , wherein R ₁₀ and R ₁₁ are the same as defined above, i) a phthalimido group optionally substituted with halo, j) phenyl Phenyl optionally substituted with one or more of rings (form naphthyl by benz fusion) or k) nitro.
[20] The following compounds are preferred compounds of formula I:
[21] R ₁ is a C _1-6 alkyl group, C _3-8 cycloalkyl group or (optionally substituted phenyl) C _1-6 alkyl group, wherein the alkyl and cycloalkyl group is one or more groups of OR _A , wherein R _A is H or C _{A 1-6} alkyl group, provided that the formula OR _A group is optionally substituted), which is not located in the carbon bonded to nitrogen;
[22] R ₂ represents hydrogen, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, halo, hydroxy, a (optionally substituted phenyl) C _1-6 alkyl group, optionally substituted phenyl or R ₄ ;
[23] R ₃ represents a group of the formula (a);
[24] <Formula (a)>
[25]
[26] [Wherein, the phenyl ring is further optionally substituted, and A is NH, O, NHSO ₂ , SO ₂ NH, C _1-4 alkylene chain, NHCO, NHCO ₂ , CONH, NHCONH, CO ₂ or S (O) _p Wherein p is 0, 1 or 2, or A is absent so that R ₅ is directly bonded to the phenyl ring, R ₅ represents optionally substituted phenyl, and further when A is absent, ₅ represents a) a phthalimido group optionally substituted with halo or b) a pyrazolylamino group, wherein the pyrazole ring is optionally substituted with one or more of hydroxy or optionally substituted phenyl]
[27] R ₄ is thienyl, benzo (b) thienyl, pyridyl, pyrazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, indazolyl (each of which is a C _1-6 alkyl group, C _3-6 cycloalkyl group, C _1-6 alkoxy, C _1-6 alkylthio, hydroxy, optionally substituted phenyl, (optionally substituted phenyl) C _1-6 alkyl, (optionally substituted phenyl) C _1-6 alkylthio group; or (Optionally substituted with one or more of optionally substituted phenyl) C _1-6 alkoxy groups).
[28] Wherein optionally substituted phenyl is a) a C _1-6 alkyl group, b) a C _1-6 alkoxy group, c) phenoxy, d) hydroxy, e) phenyl C _1-6 alkyl, f) halo, g) Groups of NR ₁₀ R ₁₁ , wherein R ₁₀ and R ₁₁ are independently hydrogen, C _1-6 alkyl group, phenyl, C _1-6 alkanoyl group, (C _1-6 alkoxy) carbonyl group, 5-hydroxy-1 -Phenyl-3-pyrazolyl or represent benzoyl optionally substituted with C _1-6 alkyl, C _1-6 alkoxy or halo, h) a group of formula -COR ₉ wherein R ₉ is hydroxy, C _1-6 alkoxy group, phenoxy or a group of formula NR ₁₀ R ₁₁ , wherein R ₁₀ and R ₁₁ are as defined above, i) a phthalimido group optionally substituted with halo, or j) By phenyl optionally substituted with one or more of the phenyl rings (formed by naphthyl by benz fusion).
[1] The present invention relates to novel, substituted 4-amino-7H-pyrrolo [2,3-d] pyrimidines with therapeutic activity as protein tyrosine kinase inhibitors, pharmaceutical compositions containing these compounds and methods for their preparation .
[29] Preferably R ₁ is a C _3-6 alkyl group (eg propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl or hexyl), C _3-8 cycloalkyl groups (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl), or C _5-7 cycloalkenyl groups (e.g. cyclopentenyl, cyclohexenyl or Cycloheptenyl), wherein the alkyl, cycloalkyl and cycloalkenyl groups are optionally substituted by one or more hydroxy groups, provided that the hydroxy group is not located in the carbon bonded to nitrogen. More preferably R ₁ is isopropyl, tert-butyl, 2-hydroxyethyl, cyclopentyl, neopentyl, 2-hydroxycyclopentyl, 4-hydroxycyclopent-2-ethyl, 3-hydroxycyclopentyl, 2,3,4-trihydroxycyclopentyl, 1,3-dihydroxyprop-2-yl or 2,3-dihydroxypropyl.
[30] Preferably R ₂ represents hydrogen or halo (eg chloro, bromo or iodo). More preferably R ₂ is hydrogen or chloro.
[31] Preferably, R ₃ represents a group of the formula (a).
[32] <Formula (a)>
[33]
[34] Wherein the phenyl ring is further optionally substituted,
[35] A represents O, NHSO ₂ , NHCO or S (O) _p , where p is 0, 1 or 2 and R ₅ represents optionally substituted phenyl. More preferably, A represents O or S. Most preferably A represents O.
[36] More preferably R ₃ is 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4- (phenylthio) phenyl, 4- (4-methoxyphenoxy) phenyl, 4- (phenylsulfinyl ) Phenyl, 4- (phenylsulfonyl) phenyl, 4- (4-hydroxyphenoxy) phenyl, 4- (benzenesulfonamido) phenyl, 4- (benzamido) phenyl, 4- (4-acetami Dophenoxy) phenyl, 4- (2-nitrophenoxy) phenyl, 4- (4-aminophenoxy) phenyl, 4- (3-aminophenoxy) phenyl, 4- (2-aminophenoxy) phenyl, 4- (3-acetamidophenoxy) phenyl, 4- [4- (N-methylacetamido) phenoxy] phenyl, 4- (2-acetamidophenoxy) phenyl, 4- (2-acet Amido-4-nitro-phenoxy) phenyl, 4- (3-carboxy-4-nitrophenoxy) phenyl, 4- (2-carboxy-4-nitrophenoxy) phenyl, 4- (4-trifluoro Methyl-2-nitrophenoxy) phenyl, 4-benzamido-3-methoxyphenyl, 4-benzamido-3-hydroxyphenyl, 4-benzenesulfonamido-3-methoxyphenyl, 4-benzene Sulfonamido-3-hydroxyphenyl, 3-hydroxy-4- (4-tert-butyl Benzenesulfonamido) phenyl, 4- (2-hydroxyphenoxy) phenyl, 4- (4-chlorobenzamido) -3-hydroxyphenyl, 4- (3-methoxy-4-nitrophenoxy) Phenyl, 4- (4-methoxycarbonyl-2-nitrophenoxy) phenyl, 4- (4-carboxy-2-nitrophenoxy) phenyl, 4- (5-chloro-2-nitrophenoxy) phenyl or 4- [4-nitro-2- (2,2-dimethylpropionamido) phenoxy] phenyl is shown.
[37] In one preferred group of compounds of formula (I),
[38] R ₁ represents methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, benzyl or 2-hydroxyethyl;
[39] R ₂ represents hydrogen, methyl, halo, hydroxy or phenyl,
[40] R ₃ is 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4- (4-chloro-N-phthalimido) -3-tolyl, 3-chloro-4- (3-chlorophenoxy C), 4- (4-methylaminophenylamino) phenyl, 4- (4-methylaminophenylamino) -2-methoxyphenyl, 4- (4-methylaminobenzyl) phenyl, 4-anilino-2 -Methoxyphenyl, 3-hydroxy-4- (4-methylbenzamido) phenyl, 3-hydroxy-4- (2-methoxybenzamido) phenyl, 4- (4-chlorobenzamido) 3-hydroxyphenyl, 3-hydroxy-4- (2-naphthalenesulfonamido) phenyl, 3-hydroxy-4- [4- (tert-butyl) -benzenesulfonamido] phenyl, 4- [ N- (5-hydroxy-1-phenylpyrazol-3-yl) amino] phenyl or 4-phenoxycarbonylamino-3-hydroxyphenyl.
[41] A second preferred group of compounds of formula (I) are the compounds represented by formula (Ib) below and pharmaceutically acceptable salts thereof.
[42]
[43] Wherein R ₁ is hydrogen, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _5-7 cycloalkenyl group or (optionally substituted phenyl) C _1-6 alkyl group, wherein alkyl, cycloalkyl and cycloal The kenyl group represents one or more groups of formula OR _A wherein R _A represents H or a C _1-6 alkyl group, provided that the group of formula OR _A is optionally substituted with carbon attached to nitrogen;
[44] R ₂ represents hydrogen or halo;
[45] R _x represents a C _1-6 alkyl group, C _1-4 alkoxy group, halo or hydroxy;
[46] R _y is a C _1-6 alkyl group, C _1-4 alkoxy group, halo, hydroxy, nitro or a group of formula NR ₁₀ R ₁₁ , wherein R ₁₀ and R ₁₁ are independently hydrogen, C _1-6 alkyl group, phenyl , A C _1-6 alkanoyl group, a (C _1-6 alkoxy) carbonyl group), or R _y is a group of the formula -COR ₉ , wherein R ₉ is a hydroxy, a C _1-6 alkoxy group, Phenoxy or a group of formula NR ₁₀ R ₁₁ , wherein R ₁₀ and R ₁₁ are the same as defined above;
[47] m and n are independently 0, 1 or 2.
[48] Preferred substituents of compounds of formula Ib are as follows.
[49] Preferably R ₁ represents a C _1-6 alkyl group, C _3-8 cycloalkyl group, C _5-7 cycloalkenyl group, wherein the alkyl, cycloalkyl and cycloalkenyl groups are at least one group of the formula OR _A , wherein R _A represents H or a C _1-6 alkyl group, provided that the group of formula OR _A is not located in a carbon bonded to nitrogen. More preferably R ₁ is isopropyl, tert-butyl, 2-hydroxyethyl, cyclopentyl, neopentyl, 2-hydroxycyclopentyl, 4-hydroxycyclopent-2-enyl, 3-hydroxycyclopentyl , 2,3,4-trihydroxycyclopentyl, 1,3-dihydroxyprop-2-yl or 2,3-dihydroxypropyl.
[50] Preferably R ₂ represents hydrogen or chloro.
[51] Preferably R _x represents a hydroxy or C _1-4 alkoxy group. More preferably R _x represents hydroxy or methoxy.
[52] Preferably R _y represents a C _1-4 alkyl group, C _1-4 alkoxy group, nitro, acetamido, amino, N-methylacetamido, carboxy, hydroxy or halo.
[53] Preferably m represents 0 or 1. More preferably m represents 0.
[54] Preferably n represents 0 or 1. More preferably n represents 0 or 1 and R _y represents hydroxy, amino or acetamido.
[55] Of course, any group containing a chain of 3 or more atoms, as mentioned herein, may be straight or branched. For example, the alkyl group may include propyl, including n-propyl and isopropyl, and butyl, including n-butyl, sec-butyl, isobutyl, and tert-butyl. As used herein, "halo" refers to fluoro, chloro, bromo and iodo.
[56] Compounds of formula (I) may exist as salts with pharmaceutically acceptable acids. Such salts are included in the present invention. Examples of such salts are hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate [eg, (+)-tartrate, (-)-tartrate or Mixtures thereof, including racemic mixtures], and salts with amino acids such as succinate, benzoate and glutamic acid. Such salts may be prepared by methods known to those skilled in the art.
[57] Certain compounds of formula (I) with acidic substituents may exist as salts with pharmaceutically acceptable bases. Such salts are included in the present invention. Examples of such salts include sodium salts, potassium salts, lysine salts and arginine salts. Such salts may be prepared by methods known to those skilled in the art.
[58] Certain compounds of formula (I) may exist in one or more physical forms (eg, different crystalline forms), and the present invention includes compounds of formula (I) and mixtures thereof in each physical form (eg, each crystalline form). do.
[59] Certain compounds of formula (I) and salts thereof may exist in one or more crystalline forms, and the present invention includes each crystalline form and mixtures thereof. Certain compounds of formula (I) and salts thereof may also exist in solvate forms, for example in the form of hydrates, and the present invention includes each solvate and mixtures thereof.
[60] Certain compounds of formula (I) may have one or more chiral centers and exist in different optically active forms. When the compound of formula (I) has one chiral center, the compound exists in two enantiomeric forms, and the present invention includes a mixture of two enantiomers and enantiomers. Enantiomers are prepared by methods known to those skilled in the art, for example by salt formation of diastereoisomers separable by crystallization; By formation of diastereomeric derivatives or complexes separable by crystallization, gas-liquid or liquid chromatography; By selective reaction of the enantiomer-specific sample with one enantiomer, for example enzymatic esterification; Or by gas-liquid or liquid chromatography in a chiral environment, such as a chiral support (eg, silica with a bound chiral ligand) or in the presence of a chiral solvent. When the desired enantiomer is converted to another chemical property by one of the separation methods described above, it is natural that additional steps are required to liberate the desired enantiomeric form. Alternatively, certain enantiomers can be synthesized by asymmetric synthesis using an optically active sample, substrate, catalyst or solvent, or by converting one enantiomer to another enantiomer by asymmetric modification.
[61] When the compound of formula (I) has one or more chiral centers, it may exist in diastereoisomeric forms. Diastereomeric pairs can be separated by methods known to those skilled in the art, for example by chromatography or crystallization, and the individual enantiomers in each pair can be separated as mentioned above. The present invention includes each diastereoisomer of a compound of formula (I) and mixtures thereof.
[62] Certain compounds of formula I include
[63] 4-amino-5- (2-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[64] 4-amino-5- (3-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[65] 4-amino-7-methyl-5- (4-phenoxyphenyl) pyrrolo [2,3-d] pyrimidine
[66] 4-amino-5- (4-phenoxyphenyl) -6-phenyl-7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[67] 4-amino-6-methyl-5- (4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[68] 4-amino-6-hydroxy-5- (4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[69] 4-amino-7-butyl-5- (4-phenoxyphenyl) pyrrolo [2,3-d] pyrimidine
[70] 4-amino-5- [3-chloro-4- (3-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[71] 4-amino-5- [4- (4-methylaminophenylamino) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[72] 4-amino-5- [4- (4-methylaminophenylamino) -2-methoxyphenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[73] 4-amino-5- [4- (4-methylaminobenzyl) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[74] 4-amino-5- [3-hydroxy-4- (4-methylbenzamido) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[75] 4-amino-5- [3-hydroxy-4- (2-methoxybenzamido) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[76] 4-amino-5- [4- (4-chlorobenzamido-3-hydroxyphenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[77] 4-amino-5- [3-hydroxy-4- (2-naphthalenesulfonamido) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[78] 4-amino-5- {3-hydroxy-4- [4- (tert-butyl) benzenesulfonamido] phenyl} -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[79] 4-amino-5- {4- [N- (5-hydroxy-1-phenylpyrazol-3-yl) amino] phenyl} -7- (tert-butyl) pyrrolo [2,3-d] pyrid Midine
[80] 4-amino-5- (4-phenoxycarbonylamino-3-hydroxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[81] 4-amino-5- [4- (4-chloro-N-phthalimido) -3-methylphenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[82] 4-amino-5- [4- (2-methylphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[83] 4-amino-5- [4- (3-methylphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[84] 4-amino-5- [4- (2-methoxyphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[85] 4-amino-5- [4- (3-methoxyphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[86] 4-amino-5- [4- (2-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[87] 4-amino-5- [4- (3-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[88] 4-amino-5- [4- (2-ethoxycarbonylphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[89] 4-amino-5- [4- (3-ethoxycarbonylphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[90] 4-amino-5- [4- (2-carbamoylphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[91] 4-amino-5- [4- (3-carbamoylphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[92] 4-amino-5- [4- (2-hydroxyphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[93] 4-amino-5- [4- (3-hydroxyphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[94] 4-amino-5- (2-methyl-4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[95] 4-amino-5- (3-methyl-4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[96] 4-amino-5- (2-methoxy-4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[97] 4-amino-5- (3-methoxy-4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[98] 4-amino-5- (2-chloro-4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[99] 4-amino-5- (3-chloro-4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[100] 4-amino-5- (2-ethoxycarbonyl-4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[101] 4-amino-5- (3-ethoxycarbonyl-4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[102] 4-amino-5- (2-carbamoyl-4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[103] 4-amino-5- (3-carbamoyl-4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[104] 4-amino-5- (2-hydroxy-4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[105] 4-amino-5- (3-hydroxy-4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[106] 4-amino-5- [2-chloro-4- (3-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[107] 4-amino-5- [2-methyl-4- (3-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[108] 4-amino-5- [3-methyl-4- (3-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[109] 4-amino-5- [2-methoxy-4- (3-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[110] 4-amino-5- [3-methoxy-4- (3-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[111] 4-amino-5- [2-ethoxycarbonyl-4- (3-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[112] 4-amino-5- [3-ethoxycarbonyl-4- (3-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[113] 4-amino-5- [2-carbamoyl-4- (3-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[114] 4-amino-5- [3-carbamoyl-4- (3-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[115] 4-amino-5- [2-hydroxy-4- (3-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[116] 4-amino-5- [3-hydroxy-4- (3-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[117] 4-amino-5- [2-chloro-4- (2-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[118] 4-amino-5- [2-chloro-4- (4-chlorophenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[119] 4-amino-5- [3-chloro-4- (3-methylphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[120] 4-amino-5- [4- (3-carbethoxyphenoxy) -3-chlorophenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[121] 4-amino-5- [4- (3-carbamoylphenoxy) -3-chlorophenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[122] 4-amino-5- [3-chloro-4- (3-hydroxyphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[123] 4-amino-5- [3-methyl-4- (3-methylphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[124] 4-amino-5- [3-methoxy-4- (3-methoxyphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[125] 4-amino-5- [3-hydroxy-4- (3-hydroxyphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[126] 4-amino-5- [3-methyl-4- (3-methoxyphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[127] 4-amino-5- [3-methoxy-4- (3-methylphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[128] 4-amino-5- [2-methoxy-4- (3-methylphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[129] 4-amino-5- [2-methyl-4- (3-methoxyphenoxy) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine
[130] 7-tert-butyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[131] 7-tert-butyl-6-chloro-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[132] 7-isopropyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[133] 7-cyclopentyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[134] 5- (4-biphenylyl) -7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[135] 7-neopentyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[136] 7-tert-butyl-5- [4- (phenylthio) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[137] 7-tert-butyl-5- [4- (4-methoxyphenoxy) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[138] 7-tert-butyl-5- [4- (phenylsulfinyl) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[139] 7-tert-butyl-5- [4- (phenylsulfonyl) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[140] 4- [4- (4-amino-7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenol
[141] N- [4- (4-amino-7-isopropyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) phenyl] benzenesulfonamide
[142] N- [4- (4-amino-7-isopropyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) phenyl] benzeneamide
[143] N- {4- [4- (4-amino-7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenyl} acetamide
[144] 7-isopropyl-5- [4- (2-nitrophenoxy) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[145] 5- [4- (4-aminophenoxy) phenyl] -7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[146] 5- [4- (3-aminophenoxy) phenyl] -7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[147] 5- [4- (2-aminophenoxy) phenyl] -7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[148] N- {3- [4- (4-amino-7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenyl} acetamide
[149] N- {4- [4- (4-amino-7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenyl} -N-methylacetamide
[150] N- {2- [4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenyl} acetamide
[151] N- {2- [4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -5-nitrophenyl} acetamide
[152] 5- [4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -2-nitrobenzoic acid
[153] 2- [4- (4-Amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -5-nitrobenzoic acid
[154] 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] ethanol
[155] 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentanol
[156] 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopent-2-enol
[157] 6-chloro-7-cyclopentyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[158] 5- (4-phenoxyphenyl) -7- (2-phenyl-1,3-dioxan-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[159] 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentanol
[160] 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentane-1,2,3-triol
[161] 7-cyclopentyl-5- (2-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[162] 7-cyclopentyl-5- (3-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[163] 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] propane-1,3-diol
[164] 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] propane-1,2-diol
[165] N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] benzamide
[166] N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-hydroxyphenyl] benzamide
[167] N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] benzenesulfonamide
[168] N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-hydroxyphenyl] benzenesulfonamide
[169] N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-hydroxyphenyl] -4-tert-butylbenzenesulfonamide
[170] 7-cyclopentyl-5- [4- (2-methoxy) phenoxyphenyl] pyrrolo [2,3-d] pyrimidin-4-ylamine
[171] 2- [4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenol
[172] 7-isopropyl-5- [4- (3-methoxy-4-nitrophenoxy) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[173] Methyl 4- [4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -3-nitrobenzoate
[174] 4- [4- (4-amino-7H-pyrrolo [2,3-d] -pyrimidin-5-yl) phenoxy] phenol
[175] N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -4-tert-butylbenzenesulfonamide
[176] 7-cyclopentyl-5- [4- (2-methoxy) phenoxyphenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[177] N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-hydroxyphenyl] -4-chlorobenzeneamide
[178] 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
[179] 5- [4- (5-chloro-2-nitrophenoxy) phenyl] -7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine and
[180] N- {2- [4- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -5-nitrophenyl} -2,2-dimethylpropionamide and
[181] In the form of its pharmaceutically acceptable salts, where appropriate, each enantiomer, racemate or mixture of other enantiomers.
[182] Certain compounds of formula (I) may exist in different tautomeric forms or in different geometric isomers, and the present invention includes each of the tautomers and / or geometric isomers of formula (I) and mixtures thereof.
[183] Certain compounds of formula (I) may exist in different stable form isomers that are separable. Rotation around the asymmetric single bond is limited, allowing for the torsional asymmetry, for example due to steric hindrance or ring strain, to separate different conformational isomers. The present invention includes each form isomer of a compound of formula (I) and mixtures thereof.
[184] Certain compounds of formula (I) may exist in the form of zwitter ions, and the present invention includes each zwitter ion form of a compound of formula (I) and mixtures thereof.
[185] The present invention also includes pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I) or a salt thereof together with a pharmaceutically acceptable diluent or carrier.
[186] The term "active compound" used hereinafter refers to a compound of formula (I) or a salt thereof. For therapeutic use, the active compound can be administered orally, rectally, parenterally or topically, with oral administration being preferred. Thus, the therapeutic compositions of the invention may be in any form of pharmaceutical compositions known for oral, rectal, parenteral or topical administration. Pharmaceutically acceptable carriers suitable for use in such compositions are known in the pharmaceutical art. The composition of the present invention may contain 0.1 to 99% by weight of the active compound. Compositions of the present invention are generally prepared in unit dosage form. The unit dose of the active ingredient is preferably 1 to 500 mg. Excipients used in the preparation of such compositions are excipients known in the pharmaceutical art.
[187] Compositions for oral administration are preferred compositions of the invention, which are present in known pharmaceutical dosage forms such as, for example, tablets, capsules, syrups and aqueous or oily suspensions. Excipients used in the preparation of such compositions are excipients known in the pharmaceutical art. Tablets are prepared by mixing the active compound with an inert diluent such as calcium phosphate in the presence of a disintegrant (eg corn starch) and a lubricant (eg magnesium stearate) and tableting the mixture in a known manner. . Tablets may be formulated in a manner known to those skilled in the art to ensure that the compounds of the present invention are delayed release. If desired, such tablets may be provided with an enteric coating by known methods, for example using cellulose acetate phthalate. Similarly, capsules containing the active compound in the presence or absence of additional excipients, such as hard or soft gelatin capsules, can be prepared by conventional methods, if desired, by providing an enteric coating in a known manner. Tablets and capsules may typically contain 1 to 500 mg of the active compound, respectively. Other compositions for oral administration include, for example, aqueous suspensions containing the active compound in an aqueous medium in the presence of non-toxic antisettling agents such as sodium carboxymethylcellulose, and suitable vegetable oils, for example arachis oil. Oily suspending agents containing the compounds of the present invention are included.
[188] The active compound may be formulated in granules with or without additional excipients. The granules may be taken directly by the patient or may be added to a suitable liquid carrier (eg water) prior to ingestion. The granules may contain disintegrants (eg, pharmaceutically acceptable saturated couples formed from acids and carbonic or bicarbonate salts) to facilitate dispersion in the liquid medium.
[189] Compounds of the invention suitable for rectal administration take the form of known pharmaceutical dosage forms, for example suppositories containing cocoa butter or polyethylene glycol bases.
[190] Pharmaceutical compositions are also known pharmaceutical dosage forms for parenteral administration (eg, sterile suspending agents in aqueous and / or oily media, preferably isotonic with the blood of the patient, and / or sterile solutions in a suitable solvent). May be administered parenterally (eg, by injection and / or infusion) subcutaneously, intramuscularly, intradermal and / or intravenously). Parenteral dosage forms can be sterilized (eg, by microfiltration and / or using a suitable sterilizing agent (such as ethylene oxide)). Optionally, one or more pharmaceutically acceptable adjuvants suitable for parenteral pharmaceutical administration, such as local anesthetics, preservatives, buffers, and / or mixtures thereof, may be added to the parenteral dosage form. Parenteral dosage forms may be stored in suitable sterile sealed containers (eg, ampoules and / or vials) until used. To improve stability during storage, parenteral dosage forms can be frozen after filling in a container and fluid (eg, water) can be removed under reduced pressure.
[191] Pharmaceutical compositions may be administered in known pharmaceutical forms (eg, sprays, aerosols, spray solutions and / or powders) for nasal administration. Weighed dosing systems (eg, aerosols and / or inhalers) known to those skilled in the art can be used.
[192] Pharmaceutical compositions are known pharmaceutical forms for oral administration (e.g., dissolution delaying tablets, chewing gums, troches, lozenges, pastilles, gels, pastes, mouthwashes, rinses and / or powders). ) Can be administered orally (eg sublingually).
[193] Compositions for topical administration may comprise a matrix which disperses the physiologically active compound of the invention to bring the compound into contact with the skin such that they are administered subcutaneously. Suitable subcutaneous compositions include pharmaceutical active compounds in combination with topical vehicles such as mineral oil, petroleum and / or waxes (e.g., paraffin wax or beeswax) and potential subcutaneous accelerators such as dimethyl sulfoxide or propylene glycol. It can be prepared by mixing. Alternatively, the active compound may be dispersed in a pharmaceutically acceptable cream or ointment base. The amount of active compound contained in the topical formulation should be such that a therapeutically effective amount of the compound is delivered while the topical formulation is applied to the skin.
[194] The compounds of the invention may also be administered in a continuous infusion from an external source (eg, by intravenous infusion) or from a source of a compound located in the body. Internal sources include, for example, implanted reservoirs containing the compound to be injected, which are continuously released by, for example, osmotic pressure, and (a) liquid preparations such as suspensions or solutions of the compound to be injected in a pharmaceutically acceptable oil. , Very slightly water-soluble derivatives such as dodecanoate salts), or (b) a solid in the form of a support (eg, synthetic resin or beeswax material) in which the compound to be injected is implanted. The support may be a monolith containing all compounds or a series of multimers each containing a portion of the compound to be delivered. The amount of active compound present in the internal source should be such that a therapeutically effective amount of the compound can be delivered over a long period of time.
[195] In some formulations it may be advantageous to use the compounds of the invention in the form of very small particles, for example obtained by fluid energy mixing.
[196] In the compositions of the present invention, the active compound can be mixed with other compatible pharmaceutically active ingredients if necessary.
[197] The invention also includes the use of a compound of formula (I) as a medicament.
[198] Both the Src and Syk families of kinases play an important role in regulating immune function. Src systems currently include Fyn, Lck, Fgr, Fes, Lyn, Src, Yes, Hck and Blk. The Syk system is currently known to include only Zap and Syk. The Janus family of kinases is involved in the conversion of growth factors and inflammatory cytokine signals through many receptors. Compounds of formula (I) may function as immunomodulators useful in the maintenance of allografts and in the treatment of autoimmune diseases due to their ability to inhibit one or more kinases. Due to their ability to modulate T cell activation or potentiating inflammatory processes, these compounds can be used to treat autoimmune diseases. Transplantation, ie transplantation of host-to-graft to solid organs or graft-to-host to bone marrow, is limited by the toxicity of currently available immunosuppressive agents due to rejection, and potent drugs with improved therapeutic indices will help. will be. Genetic targeting experiments demonstrated the important role of Src in the biology of osteoclasts involved in bone resorption. The ability of the compounds of formula (I) to modulate Src may also be useful for the treatment of osteoporosis, Paget's disease, tumor-induced hypercalcemia and for bone modification.
[199] Many tyrosine kinases have been demonstrated to be cancer genes. Chromosomal cleavage (at the Itk kinase cleavage site on the fifth chromosome), translocations as in the case of the BCR (Philadelphia chromosome) and Abl genes, or cleavage of other genes such as cKit, are misregulated proteins that convert the cancer gene into a cancer product. Results in the production of. In other tumors, carcinogenesis is caused by the interaction of self-secreting or exocrine ligand / growth factor receptors. Inhibiting the tyrosine kinase activity of these proteins can prevent disease progression. Restenosis of blood vessels is one of the proliferation of PDGF-dependent endothelial cells. Prophylactic inhibition of PDGFr kinase activity is an effective way to prevent this phenomenon. Thus, compounds of formula (I) that inhibit kinase activity of c-kit, c-fms, EGFr, BCR, Abl, PDGFr, KDR / Flk-1, Flt-1, tie-1, tie-2 and other receptors are positive And in the treatment of neoplastic proliferative diseases.
[200] Pharmaceutical compositions containing a compound of formula (I) or a salt thereof, or a therapeutically effective amount thereof, can be used for the treatment of benign and neoplastic proliferative diseases and immune system diseases. These diseases include: autoimmune diseases such as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple infarction, sarcoidosis, inflammatory bowel disease, myasthenia gravis and systemic lupus erythematosus, psoriasis, tissue transplant rejection (eg kidney rejection), graft versus Host diseases, human carcinomas and leukemias of malignant and neoplastic proliferative diseases such as lung, breast, stomach, bladder, colon, pancreas, uterus, prostate and rectal cancers, and diseases including inadequate angiogenesis, for example diabetic Retinopathy, choroidal neovascularization due to age related macular degeneration, and human infantile hemangioma. Such inhibitors may also be useful for the treatment of diseases associated with VEGF mediated edema, ascites and exudate, including male edema and adult respiratory distress syndrome (ADRS).
[201] The compounds of the present invention may also be useful in preventing such diseases.
[202] Another aspect of the invention provides the use of a compound of formula (I) and salts thereof in the manufacture of a medicament for the treatment of proliferative diseases and / or diseases of the immune system of mammals, in particular humans.
[203] The present invention also provides a method of treating proliferative disease and / or immune system disease comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I).
[204] Now, a process for preparing the compound of formula (I) is described. These methods form another aspect of the present invention. These methods are preferably carried out at atmospheric pressure.
[205] The compounds of formula (I) may be prepared by condensing the compounds of formula (II) with formamide, optionally at a temperature ranging from 50 to 250 ° C., for example in the presence of a 4-dimethylaminopyridine catalyst.
[206]
[207] Wherein R ₁ , R ₂ and R ₃ are as defined above.
[208] Compounds of formula (I) include compounds of formula (I) in which R ₁ and R ₂ are as defined above and R ₃ represents bromo or iodo, for example palladium (O) compounds (eg, Pd (PPh ₃ ) ₄ ) It can be prepared by reacting with a compound of formula III in the presence of a catalyst.
[209] R ₃ B (OH) ₂
[210] In formula, R <_3> is the same as what was defined initially.
[211] A compound of formula (I) wherein R ₁ represents an alkyl group or (optionally substituted phenyl) C _1-6 alkyl group represents a compound of formula (IV) wherein R ₁ represents an alkyl group or (optionally substituted phenyl) C _1-6 alkyl group, and X is It may be prepared by alkylation with a compound of formula R ₁ X, which represents a leaving group, for example halo or tosyloxy.
[212]
[213] In the formula, R ₂ and R ₃ are the same as mentioned above.
[214] The compounds of formula (I) can be prepared by reacting compounds of formula (V) with ammonia or ammonium salts, for example ammonium acetate, in a temperature range of 15 to 250 ° C., preferably in a pressurized bath.
[215]
[216] Wherein R ₁ , R ₂ and R ₃ are the same as defined above and Y represents a leaving group such as halo or phenoxy.
[217] Compounds of formula (I), in which R ₂ represents chloro, bromo or iodo, may be selected from the group consisting of halogenating agents such as iodinating agents (eg N-iodosuccinimide) or brominating agents (eg N- Bromosuccinimide) or a chlorinating agent (e.g., N-chlorosuccinimide).
[218]
[219] Wherein R ₁ and R ₃ are the same as defined above.
[220] A compound of formula (I) wherein R ₃ represents AR ₅ , where A represents NHCO, reacts a compound of formula (VII) with a compound of formula R ₅ COX, wherein X represents a leaving group, for example chloro It can manufacture by making it.
[221]
[222] Wherein R ₁ and R ₂ are the same as defined above, Y represents amino.
[223] In addition, compounds of formula (VII), wherein Y represents halo, for example chloro, can be reacted with compounds of formula R ₅ COX and the product is reacted with ammonia to give compounds of formula (I). When A represents NHSO ₂ , a similar method can be used.
[224] Compounds of formula I, wherein R ₃ represents AR ₅ , wherein A represents O, can be prepared by reacting a compound of formula VIII with a compound of formula R ₅ OH.
[225]
[226] Wherein R ₁ and R ₂ are as defined above and X is halo.
[227] A compound of formula (I) wherein R ₃ represents AR ₅ , wherein A represents O, represents a compound of formula (IX) wherein X is halo, preferably halo activated in the presence of another substituent (e.g., nitro) It can be prepared by reacting with a compound of formula R ₅ X.
[228]
[229] Wherein R ₁ and R ₂ are the same as defined above.
[230] Compounds of formula (II) can be prepared as shown in Scheme 1 where IPA represents propan-2-ol.
[231]
[232] Those skilled in the art will appreciate that compounds of formula I can be converted to other compounds of formula I by known chemical reactions. For example, an alkoxy group may be cleaved to give hydroxy, the nitro group is reduced to an amine, the amine is acylated or sulfonylated and the N-acyl compound may be hydrolyzed to the amine. Compounds of formula (I) in which R ₃ represents AR ₅ , wherein A represents S, can be oxidized to compounds of formula (I) in which A represents SO and SO ₂ by methods known to those skilled in the art.
[233] Compounds of formula III are commercially available or may be prepared by methods known to those skilled in the art.
[234] Compounds of formula IV wherein R ₂ represents hydrogen can be prepared as shown in Scheme 2. The amino groups can be protected before the final step of Scheme 2 by methods known to those skilled in the art and then deprotected after the last step of Scheme 2. Compounds of formula IV wherein R ₂ is not hydrogen can be prepared by similar methods.
[235]
[236] In addition, in Scheme 2, R ₃ may be coupled first before amination. In addition, the substituent R _{1 as} defined above may be present before carrying out both methods.
[237] Compounds of formula V can be prepared as shown in Scheme 3 below.
[238]
[239] Compounds of formula VI wherein R ₃ represents hydrogen can be prepared as shown in Scheme 4 below. Starting materials are described in J. Med. Chem., 1988, 31, 390, and references cited therein. Compounds in which R ₃ is not hydrogen can be prepared by a similar method.
[240]
[241] Compounds of formula (VII) can be prepared by coupling the 5-iodo compound in the same manner as described for the preparation of compounds of formula (IV).
[242] Those skilled in the art will appreciate that if the substituents are the same or similar to the functional groups modified in one of the above methods, they must be protected before this process and then deprotection is performed after this process. Otherwise, competitive side reactions will occur. Alternatively, another method as mentioned above can be used, in which the substituents do not interfere. Suitable protecting groups and their addition and removal methods can be found in the textbook "Protective Groups in Organic Synthesis", T.W. Green, John Wiley and Sons, 1981. For example, suitable protecting groups for amines are formyl or acetyl.
[243] The ex vivo ability of a compound that inhibits this tyrosine kinase can be determined by the following detailed method.
[244] The ability of the compound is such that it inhibits the phosphorylation of external substrates (eg, synthetic peptides [Z. Songyang et al., Nature. 373: 536-539]) in tyrosine by Ick or ZAP70 kinase by the test compound against the control compound. Can be determined.
[245] Expression of ZAP 70
[246] The baculovirus expression vector used was pVL 1393 (Pharmingen, Los Angeles, CA). The nucleotide sequence encoding amino acid M (H) 6 LVPRGS was placed 5 'to the region encoding the entire ZAP70 (amino acids 1-619). Histidine residues allowed for affinity purification of the protein (see below). The LVPRGS bridge is a proteolytic recognition sequence by thrombin, thereby allowing removal of the affinity tag from the enzyme. SF-9 insect cells were infected with a multiplicity of infection of 0.5 and collected 24 hours after infection.
[247] Extraction and Purification of ZAP 70
[248] SF-9 cells were treated with 20 mM Tris (pH 8.0), 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 1 μg / ml Rupeptin, 10 μg / ml aprotinin and 1 mM sodium ortho It was dissolved in a buffer solution consisting of vanadate. This soluble solution was added to a chelating Sepharose HiTrap column in equilibrium in 50 mM HEPES, 0.3 M NaCl, pH 7.5 (Pharmacia). Fusion protein was eluted with 250 mM imidazole. This enzyme was stored in a buffer solution containing 50 mM HEPES, 50 mM NaCl and 5 mM DTT at pH 7.5.
[249] Lck won
[250] Lck or cut Lck can be purchased (e.g. Upstate Biotechnology Inc., Saranac Lake, NY) and Santa Cruz Biotechnology Inc. (Santa Cruz Biotechnology Inc., Santa Cruz, CA) ), Or can be purified from known natural or recombinant sources using conventional methods.
[251] analysis
[252] The method used to measure tyrosine kinase activity has been described previously (Current Protocols in Immunol, John Wiley and Sons, 11.4.1-11.5.6., 1995). Briefly, all reactions were carried out with 50 mM MOPSO, 2 mM MnCl ₂ , 5 mM DTT, 0.1% BSA, 2-200 μM ATP, 30-200 μM peptide, 5% DMSO and 33P ATP (8 Ci / mM) at pH 6.5. It was performed in the configured kinase buffer. The compound and enzyme were mixed in the reaction vessel and the reaction was initiated by the addition of ATP and substrate mixture. The reaction was terminated by adding twice (20 mM) EDTA stop buffer and then spotted on a phosphocellulose filter as part of the mixture. The spot form sample was washed three times with 75 mM phosphoric acid for 5-15 minutes at room temperature. The degree of incorporation of the radiolabelled substance was evaluated by liquid scintillation counting.
[253] Compounds exemplified in the present invention have an IC ₅₀ of less than 5 μm for Lck. Preferred compounds of the invention are selective inhibitors of Lck.
[254] Compounds of formula (I) will have therapeutic utility in treating diseases associated with both PTKs identified as inhibited by compounds of formula (I) and PTKs not yet identified, including those not mentioned herein.
[255] In vitro model for T-cell activation:
[256] Upon activation by mitogen or antigen, T-cells are induced to secrete IL-2, a growth factor that maintains a later proliferative state. Thus, production of IL-2 from a first T-cell or a suitable T-cell line or cell proliferation of the first T-cell or a suitable T-cell line can be measured as a surrogate for T-cell activation. Both of these analyzes are well described in the literature and their parameters are described in the literature (Current Protocols in Immunology, Vol 2, 7.10.1-7.11.2).
[257] Briefly, T-cells can be activated by co-culture with allogeneic stimulating cells, a method called unidirectional response of mixed lymphocytes. Mononuclear cells, which are reactants and stimulators of peripheral blood, are purified by a Ficoll-Hipaque gradient (from Pharmacia) according to the preparation method. Stimulator cells are inactivated by mitosis by treatment with mitomycin c (Sigma) or gamma irradiation. Responsive and stimulatory cells were co-cultured at a ratio of 2: 1 with or without test compounds. Typically 10 ⁵ reaction cells were mixed with 5 × 10 ⁴ stimulation cells and applied (in 200 μl volume) to a U-bottomed microtiter plate (Costar Scientific). These cells were RPMI 1640, 5 × 10 ⁻⁵ M 2-mercaptoethanol and 0.5 supplemented with heat-inactivated fetal bovine serum (manufactured by Hyclone Laboratories) or human AB serum from female suppliers. Cultured in% DMSO. Cultures were pulsed with 0.5 μCi of ³ H thymidine (Amersham) one day before collection (typically three days). Cultures were collected (Betaplate harvester, Wallac), and isotope uptake was assessed by liquid scintillation (betaplate, Wallac).
[258] The same culture can be used to assess T-cell activation by measuring IL-2 production. The supernatant was removed within 18-24 hours after initiation of the culture and IL-2 concentration was measured by ELISA (R and D systems) as instructed by the manufacturer.
[259] In vivo efficiency of the compounds can be directly measured in T-cell activation or tested in known animal models in which T-cells have been demonstrated to be agents. T-cells can be activated in vivo by ligating a portion of the T-cell receptor with monoclonal anti-CD3 antibodies (Ab). In this model, BALB / c mice were intraperitoneally administered 10 μg of anti-CD3 Ab 2 hours before anemia. Animals to be administered the test drug were pretreated with a single dose of a compound of the invention 1 hour prior to anti-CD-3 Ab administration. Serum levels of inflammatory cytokine interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), which are indicative of T-cell activation, were measured by ELISA. A similar model uses in vivo T-cells primed with specific antigens, such as keyhole limpet hemocyanin (KLH), followed by a second ex vivo antigen administration of draining lymph node cells with the same antigen. do. As before, cytokine production measurements are used to assess the activation state of cultured cells. Briefly, C57BL / 6 mice were immunized on day 0 by subcutaneous injection of 100 μg KLH suspended in Freund's complete adjuvant (CFA). Animals were pretreated with a compound of the invention one day prior to immunization and then immunized 1, 2 and 3 days later. Draining lymph nodes were collected on day 4 and their cells were harvested for 24 and 48 hours in tissue culture medium (heat inactivated fetal bovine serum (manufactured by Hyclone Laboratories), 5 × 10 ⁻⁵ M 2 ⁻ ). Incubated at 6 × 10 ⁶ concentrations per ml of RPMI 1640 supplemented with mercaptoethanol and 0.5% DMSO. The self-secreting T-cell growth factor interleukin-2 (IL-2) and / or IFN- [gamma] levels of the culture supernatants were then determined by ELISA.
[260] In addition, leading compounds can be tested in animal models of human disease. Examples of such diseases are experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). EAE models similar to those of human infarction have been described in both rats and mice [FASEB J. 5: 2560-2566, 1991: Rat model: Lab. Invest. 4 (3): 278, 1981; Animal Model: J. Immunol 146 (4): 1163-8, 1991]. Briefly, mice or rats were immunized with emulsions of myelin basic protein (MBP) or neuropeptide derivatives thereof and CFA. Acute diseases can be induced by the addition of bacterial toxins such as asbordetella pertussis. Relapse / relief of the disease is induced by the helpful introduction of T-cells from animals immunized with MBP / peptide.
[261] CIA can be induced in DBA / 1 mice by immunization with type II collagen [J. Immunol: 142 (7): 2237-2243. Mice will show signs of arthritis as early as 10 days after antigen administration and will appear for 90 days after immunization. In both EAE and CIA models the compounds can be administered prophylactically or at the onset of the disease. Efficacy drugs are those that reduce the severity and / or frequency of the disease.
[262] The compound is also used in skin [Ann. Rev. Immunol., 10: 333-58, 1992; Transplantation: 57 (12): 1701-1706, 1994] or cardiac [Am. J. Anat .: 113: 273, 1963. Briefly, full thickness skin grafts were transplanted from C57BL / 6 mice to BALB / c mice. Starting at day 6, the graft was rejected daily. In the mouse neonatal transplant model, neonatal hearts were transplanted into the auricle of adult CBA / J mice in C57BL / 6 mice. The heart began to beat for 4-7 days after transplantation, and the rejection response could be assessed visually using an anatomical microscope to observe the stop of the beat.
[263] The invention is illustrated by the following examples, which are given by way of example only. The final products of each of these examples were characterized by one or more of the methods of high performance liquid chromatography, elemental analysis, nuclear magnetic resonance spectroscopy, infrared spectroscopy and high performance mass spectroscopy.
[264] <Example 1>
[265] a) tert-butylamine (15 ml) was converted to 2-bromo-4'-phenoxyacetophenone (12.7 g, 4'-phenoxy according to Tetrahedron Letters, 1993, 34, 3177) in propan-2-ol. To a solution of cyacetophenone), which is heated with stirring at 80 ° C. for 3 hours. The mixture was cooled to 0 ° C and concentrated hydrochloric acid (10 ml) was added. The suspension was stirred at ambient temperature for 18 hours and the solids were collected by filtration to give 4'-phenoxy-2- (tert-butylamino) acetophenone hydrochloride (3.75 g), melting point 210-212 ° C.
[266] b) (1) 4'-phenoxy-2- (tert-butylamino) acetophenone hydrochloride (3.75 g) in sodium ethoxide (prepared by dissolving sodium (93 mg) in ethanol (50 ml)) At one time, the mixture was stirred at 40 ° C. under nitrogen for 30 minutes.
[267] (2) To another flask sodium (331 mg) was dissolved in ethanol (50 ml) and malononitrile (858 mg) was added. The solution was stirred for 5 minutes at ambient temperature, and then a solution of 4'-phenoxy-2- (tert-butylamino) acenophenone obtained in (1) was added at once except for sodium chloride precipitated in this solution. . The resulting mixture was heated at 50 ° C. for 3 hours and then at 80 ° C. for 2 hours. The solvent was removed under reduced pressure and the resulting oil was partitioned between water and ethyl acetate. The organic layer was separated, dried and evaporated to yield a black solid. This solid was dissolved in hot ethanol, treated with water, filtered and dried to give 2-amino-3-cyano-4- (4-phenoxyphenyl) -1- (tert-butyl) pyrrole.
[268] c) 2-amino-3-cyano-4- (4-phenoxyphenyl) -1- (tert-butyl) pyrrole (1.9 g), formamide (30 ml) and 4-dimethylaminopyridine (10 mg) The mixture was heated at 180 ° C for 6 h. The mixture was cooled to ambient temperature and water was added to precipitate a dark solid. The solid was collected by filtration, washed with water and then boiled in ethanol, and insoluble material was collected by hot filtration and dried. The solid was purified by purified HPLC on silica column using dichloromethane / propan-2-ol / ethanol (98: 1: 1) as mobile phase to afford 7-tert-butyl-5- (4-phenoxyphenyl) -7H- Pyrrolo [2,3-d] pyrimidin-4-ylamine (4-amino-5- (4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine) Was obtained, melting point 157-158 ° C. ¹ H NMR (d ⁶ DMSO) δ 8.15 (1H, s), 7.50-7.35 (4H, m), 7.30 (1H, s), 7.15 (1H, t), 7.10 (4H, m), 6.05 (2H, brs), 1.75 (9H, s).
[269] <Example 2>
[270] a) A solution of 2-bromo-4'-phenoxyacetophenone (20.0 g) in toluene (150 ml) isopropylamine (8.1 g) in toluene (100 ml) while maintaining the temperature of the reaction mixture below 15 ° C. Was added while stirring. The mixture was stirred at this temperature for 30 minutes and then at ambient temperature for 20 minutes. The mixture was filtered and the residue washed with ether. Oxalic acid (10.0 g) in ether (200 ml) was added to the combined filtrate and washings and the mixture was filtered to afford 2-isopropylamino-4'-phenoxyacetophenone oxalate. The oxalate salt was converted to the hydrochloride salt by treatment with concentrated hydrochloric acid. The solid salt was collected by filtration and used directly in the next step.
[271] b) The crude product (3.07 g) from a) above was suspended in methanol (60 ml) and malononitrile (1.0 g) was added with stirring. Nitrogen was bubbled through the cooled suspension in an ice-water bath and then potassium hydroxide (1.75 g) in water (2 ml) was added. After stirring for 15 minutes at this temperature, the mixture was heated to boiling reflux and then boiled for 1 hour while bubbling nitrogen through the mixture. The mixture was cooled and water (200 ml) was added while bubbling nitrogen. The gum obtained was dissolved in ether and separated. The aqueous layer was extracted twice with ether and the combined ether layers were dried, filtered and evaporated to afford a gum which was left under nitrogen overnight to solidify to 2-amino-3-cyano-1-isopropyl-4- (4-phenoxy Cy-phenyl) pyrrole was obtained.
[272] c) The product from b) (2.75 g) was dissolved in formamide (120 ml) and ammonia was bubbled with stirring the mixture and heated in an oil bath at 200-205 ° C. for 2.5 h. The mixture was cooled and added to ice water and then filtered to give a beige solid which was washed with water. It was found that this solid was a mixture of the preferred product and 4-amino-5- [4- (4-bromophenoxy) phenyl] -7-isopropylpyrrolo [2,3-d] pyrimidine. The mixture was hydrogenated in propan-1-ol, ammonium formate and 10% palladium on carbon with stirring in a similar manner as described in Example 5 to give a solid. This solid was purified by flash column chromatography on silica using ethyl acetate / triethylamine (19: 1) as mobile phase to give 7-isopropyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2, 3-d] -pyrimidin-4-ylamine was obtained, melting point 155-156 ° C.
[273] <Example 3>
[274] a) 4-phenoxyacetophenone (150.0 g) was dissolved in acetic acid (2 L) and stirred at 50 ° C. with dividing of pyridinium tribromide (251.6 g). The brown solution was added to water (3 L) and the mixture was extracted with toluene (once with 800 ml, then twice with 400 ml). The combined toluene extracts were washed with water and then aqueous sodium bicarbonate solution until foaming stopped. The combined toluene extracts were separated, dried and filtered and used directly in b) below.
[275] b) A solution of 2-bromo-4'-phenoxyacetophenone in toluene obtained in a) was added to a solution of cyclopentylamine (154 ml) in toluene (1 L) under nitrogen while maintaining the temperature below 5 ° C. It was added with stirring over 1.5 hours. The mixture was then stirred for 2.5 hours while maintaining the temperature below 10 ° C. and then the mixture was filtered. The filtrate was treated by dropwise addition of concentrated hydrochloric acid (120 ml) while maintaining the temperature below 10 ° C. The precipitate was collected by filtration and treated with propan-2-ol / ether (1: 1) to give a solid, which was dried in vacuo at 40 ° C. for 6.5 hours to give 2-cyclopentylamino-4′-phenoxyacetophenone hydro Chloride was obtained.
[276] c) The product from b) (35.1 g) was added to a solution of malononitrile (9.5 g) in methanol (500 ml) under nitrogen, and then an aqueous solution of potassium hydroxide (17.0 g) in water (75 ml) was heated to It was added dropwise over 30 minutes while maintaining at 0 to 5 ° C. This mixture was then heated to reflux for 2.5 hours. Further malononitrile (1.0 g) in methanol (10 ml) was added and the mixture was boiled at reflux for an additional 3 hours. The mixture was left at ambient temperature for 18 hours, methanol was removed under reduced pressure and the residue was placed under nitrogen. The residue is dissolved in dichloromethane (600 ml), washed with water and then brine, then dried, filtered and evaporated to give a brown solid which is treated with diethyl ether to give 2-amino-3-cyano-1 -Cyclopentyl-4- (4-phenoxyphenyl) pyrrole was obtained and used directly in the next step of this example.
[277] d) The product from c) (25.9 g) is dissolved in a mixture of formamide (155 ml), N, N-dimethylformamide (52 ml) and formic acid (20.2 ml) and the mixture at an internal temperature of 166 ° C. Heated under nitrogen for 4 hours. The mixture was cooled and poured into water (3.5 L) and then extracted with ethyl acetate (3 times 1500 ml). The combined ethyl acetate extracts were washed with water, dried, filtered and evaporated to give a solid which was treated with ether and filtered to give a solid which was recrystallized from industrial methylated ethyl alcohol to give 7-cyclopentyl-5- (4- Phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine was obtained, melting point 178-179 ° C.
[278] <Example 4>
[279] This example was carried out in a similar manner to Example 2. 2-bromo-4'-phenylacetophenone (25.0 g) in acetonitrile (150 ml) was reacted with tert-butylamine (28.4 ml) to 4'-phenyl-2- (tert-butylamino) acetophenone hydro Bromide (5.31 g) was obtained, melting point 234-237 ° C. (decomposition). The compound is reacted with malononitrile (1.7 g) and potassium hydroxide (3.0 g) in water (4 ml) in methanol (100 ml) under nitrogen to afford 2-amino-4- (4-biphenylyl) -3- Cyano-1- (tert-butyl) pyrrole (3.75 g) is obtained, which is suspended in formamide (200 ml) saturated with ammonia, and then the mixture is mixed at 200-205 ° C. for 2 hours while passing ammonia through the mixture. Heated. After cooling the mixture was added to ice water (600 g) under nitrogen and the solids were collected by filtration and purified by flash column chromatography on silica using ethyl acetate / triethylamine (19: 1) as mobile phase to give 5- (4- Biphenylyl) -7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine was obtained, melting point 212-214 ° C.
[280] <Example 5>
[281] This example was carried out in a similar manner to Example 2. Neopentylamine (18.4 g) in toluene (100 ml) is reacted with 2-bromo-4'-phenoxyacetophenone (33.0 g) in toluene (150 ml) to 2-neopentyl-4'-phenoxyaceto Obtain phenone hydrochloride (13.6 g), which is reacted with nitrogen hydroxide (7.3 g) in water (10 ml) and malononitrile (3.2 g) in methanol (200 ml) under nitrogen to give 2-amino-3-sia. No-1-neopentyl-4- (4-phenoxyphenyl) pyrrole (6.9 g) is obtained, which is dissolved in formamide (250 ml) saturated with ammonia and reacted to give crude product, which is ethyl acetate / Triethylamine (19: 1) as mobile phase was purified by flash column chromatography on silica to afford the desired product and 4-amino-5- [4- (4-bromophenoxy) phenyl] -7-neopentyl A mixture of pyrrolo [2,3-d] pyrimidine was obtained. The mixture was purified by hydrogenation of the crude product (1.15 g) in propan-1-ol (40 ml), ammonium formate (1.1 g) and 10% palladium on carbon (0.3 g) under nitrogen. The mixture was filtered. The filtrate was concentrated under reduced pressure to give a residue, which was dissolved in warm methanol, then cooled and crystallized by addition of water. The mixture was cooled and the solid collected by filtration and dried to give 7-neopentyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine, melting point 158-158.5 ° C.
[282] <Example 6>
[283] This example was carried out in a similar manner to Example 2. 2-bromo-4'-phenylthioacetophenone (159.0 g), propan-2-ol (400 ml) and tert-butylamine (100 ml) were boiled and refluxed under nitrogen for 18 hours to give 4'-phenylthio- Obtain 2- (tert-butylamino) acetophenone hydrochloride (74.0 g), which is reacted with malononitrile (21.63 g) and potassium hydroxide (0.668 mole) in methanol (2000 ml) to give 2-amino-3- Cyano-4- (4-phenylthiophenyl) -1- (tert-butyl) pyrrole (33.44 g) is obtained, which is dissolved in formamide (1100 ml) and bubbled ammonia gas through the reaction mixture 170 Heating at −180 ° C. for 2 hours gave 7-tert-butyl-5- (4-phenylthiophenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine, melting point 151.5 -152.5 ° C.
[284] <Example 7>
[285] This example was carried out in a similar manner to Example 3. 4- (4-methoxyphenoxy) acetophenone (50.8 g) was reacted with pyridinium tribromide (67.0 g) in acetic acid (650 ml) to give 2-bromo-4 '-(4-methoxyphenoxy) Acetophenone (80.0 g) is obtained which is reacted with tert-butylamine (70 ml) in propan-2-ol (250 ml) to give 2- (tert-butyl) 4 '-(4-methoxyphenoxy) Acetophenone hydrochloride (33.3 g) is obtained, which is dissolved in methanol (475 ml) and reacted with malononitrile (9.5 g) and potassium hydroxide (16.6 g) to give 2-amino-3-cyano-4- ( 4-methoxyphenoxyphenyl) -1- (tert-butyl) pyrrole was obtained. This material (20.0 g) was dissolved in formamide (650 ml) and the mixture was heated at 190 ° C. for 2 hours while bubbling ammonia, terminating the reaction, and ethyl acetate / triethylamine (19: 1) was transferred to the mobile phase. Purification by flash column chromatography on silica using a solution of 7-tert-butyl-5- [4- (4-methoxyphenoxy) phenyl] -7H-pyrrolo [2,3-d] pyrimidine-4- Ilamine was obtained, melting point 171-172 ° C.
[286] <Example 8>
[287] a) In a similar manner as in Example 10 b), 4-chloro-5-iodo-7-isopropylpyrrolo- [2,3-d] pyrimidine (0.57 g) is converted to bis (triphenylphosphine) Reaction with 4-nitrophenylboronic acid (0.30 g) using palladium (II) (0.126 g) to 4-chloro-7-isopropyl-5- (4-nitrophenyl) pyrrolo [2,3-d] Obtain pyrimidine, which is reduced using a mixture of ammonium chloride (22 mg), iron powder (0.45 g) and industrial methylated ethyl alcohol (10 ml) in water (2 ml) to 4-chloro-5- (4 -Aminophenyl) -7-isopropylpyrrolo [2,3-d] pyrimidine, which is reacted with ammonia in 1,4-dioxane in a closed container to give 4-amino-5- (4-aminophenyl ) -7-isopropyl-pyrrolo [2,3-d] pyrimidine was obtained.
[288] b) benzoyl chloride (101 mg) in dichloromethane (1.0 ml) was added 4-amino-5- (4-aminophenyl) -7-isopropylpyrrolo [2, in dichloromethane (7 ml) at 0 ° C. under nitrogen. 3-d] was added to the mixture of pyrimidine (175 mg) and triethylamine (73 mg) with stirring. The mixture was stirred at 0 ° C. for 4 h and then warmed to ambient temperature for 1 h. The reaction mixture was stirred at ambient temperature for 18 hours and then quenched by addition of ice-cold saturated sodium bicarbonate solution (10 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3 times 20 ml). The combined organic layers were washed with water, dried and evaporated to give a pale yellow solid which was purified by purified HPLC to give N- (4- {4-amino-7-isopropyl-7H-pyrrolo [2,3-d] pyridine. Midin-5-yl} phenyl) -benzamide was obtained, melting point 192-195 ° C.
[289] <Example 9>
[290] a) A solution of tert-butylamine (154 ml) in acetonitrile (100 ml) was 2-chloro-4'-iodoacetophenone (158.0 g in acetonitrile (700 ml) over 20 minutes at 20 ° C. under nitrogen. , Prepared as described in Organic Magnetic Resonance 12 (12), 1979 pages 691-695) with stirring. The mixture was warmed to 30 ° C. when the solution was formed, followed by slight exotherm and tert-butylamine hydrochloride precipitated out. The mixture was often cooled to maintain below 37 ° C. The mixture was stirred at ambient temperature for 18 hours and then filtered and the residue was washed with acetonitrile. The combined filtrates and washes were reduced in volume and then dissolved in a mixture in ether (700 ml) and water (500 ml). The mixture was stirred with dilute hydrochloric acid adjusting the pH to 9. The mixture was filtered to remove tert-butylamine hydrochloride. The filtrate was acidified with dilute hydrochloric acid to afford 4'-iodo-2- (tert-butylamino) acetophenone hydrochloride (102.0 g). This product was reacted with malononitrile (29.9 g) and potassium hydroxide (52.3 g) in methanol (1.5 L) and water (100 ml) similarly to Example 2 to give 2-amino-3-cyano-4- ( 4-iodophenyl) -1- (tert-butyl) pyrrole (63.2 g) was obtained, melting point 166.5-167 ° C.
[291] b) The product from a) was reacted with formamide (2 L) while passing ammonia through the solution in a similar manner to Example 2 to give a crude solid, which was recrystallized from toluene to give 4-amino-5- (4- Iodophenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine was obtained, melting point 188-189 ° C.
[292] c) product from b) (600 mg), 4-acetamidophenol (828 mg), potassium carbonate (702 mg), copper chloride (I) (60 mg), 8-hydroxyquinoline (96 mg) and Dimethylacetamide (15 ml) was stirred and boiled under reflux for 4 hours under nitrogen. The mixture was diluted with water (100 ml) and ethyl acetate (50 ml), basified with 5M sodium hydroxide solution (1 ml) and filtered. The filtrate was separated and the organic layer was washed with water, dried and evaporated to give a residue, which was purified by flash column chromatography on silica using ethyl acetate as mobile phase to give N- {4- [4- (4-amino- 7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenyl} -acetamide was obtained. The structure of this compound was confirmed by ¹ H nmr.
[293] <Example 10>
[294] a) 4-chloro-5-iodopyrrolo [2,3-d] pyrimidine (10.0 g, see Example 17) of sodium hydride in N, N-dimethylformamide (250 ml) at 0 ° C. under nitrogen. To the suspension (1.6 g of 60% dispersion in mineral oil) was added portionwise with stirring. When the addition was complete, the mixture was warmed to ambient temperature and when no gas was generated, a solution of isopropyl bromide (34.0 ml) in N, N-dimethylformamide (20 ml) was added dropwise. The mixture was stirred at ambient temperature overnight and then quenched by dropwise addition of water (300 ml) with ice cooling. The mixture was then washed with ethyl acetate (three times 300 ml) and the combined organic layers were washed with water, dried, filtered and evaporated to 4-chloro-5-iodo-7-isopropylpyrrolo- [as a yellow solid. 2,3-d] pyrimidine was obtained, melting point 116-118 ° C. The structure was confirmed by ¹ H nmr.
[295] b) 4-chloro-5-iodo-7-isopropylpyrrolo [2,3-d] pyrimidine (2.8 g), 4-methoxybenzeneboronic acid (1.32 g), bis chloride (triphenylphosphine) A mixture of palladium (II) (625 mg), toluene (85 ml), ethanol (11 ml), water (22 ml) and sodium bicarbonate (2.2 g) was heated at 105 ° C. for 18 hours under nitrogen. The mixture was cooled to ambient temperature and then partitioned between ethyl acetate (100 ml) and brine (100 ml). The organic layer was separated and the aqueous layer was washed with ethyl acetate (twice with 50 ml). The combined organic layers were washed with water, dried, filtered and evaporated under reduced pressure to yield a black oil which was cooled to solidify. This material was purified by flash column chromatography on silica using cyclohexane / ethyl acetate (7: 3) as the mobile phase. The appropriate fractions are combined and concentrated under reduced pressure to give a yellow oil which is left to solidify to yield 4-chloro-7-isopropyl-5- (4-methoxyphenyl) pyrrolo [2,3-d] pyrimidine. It was. The structure was confirmed by ¹ H nmr.
[296] c) 4-chloro-7-isopropyl-5- (4-methoxyphenyl) pyrrolo- [2,3-d] pyrimidine (1.6 g), concentrated ammonia (80 ml, SG .880) and 1, The mixture of 4-dioxane (80 ml) was heated in a pressure vessel at 120 ° C. for 18 hours. The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure to give a solid residue, which was partitioned between ethyl acetate (100 ml) and water (100 ml). The aqueous phase was extracted with ethyl acetate and the combined organic layers were washed with water, dried, filtered and evaporated to 4-amino-7-isopropyl-5- (4-methoxyphenyl) pyrrolo [2,3-d] -pyri Midines were obtained. The structure was confirmed by ¹ H nmr.
[297] d) a solution of boron tribromide (14.4 ml of a 1M solution in dichloromethane) to 4-amino-7-isopropyl-5- (4-methoxyphenyl) pyrrole in dichloromethane (100 ml) at −10 ° C. under nitrogen. To the stirred solution of [2,3-d] pyrimidine (1.35 g) was added dropwise. The reaction mixture was warmed to 0 ° C and stirred at this temperature for 1 hour. Further boron tribromide (9.6 ml of a 1M solution in dichloromethane) at -10 ° C was added and the mixture was warmed to 0 ° C and stirred for 1 h more. The reaction mixture was quenched by dropwise addition of saturated sodium bicarbonate solution (50 ml). The mixture was left overnight and the dichloromethane layer was separated. Insoluble matter at the interface was removed by filtration and dried to afford 4-amino-5- (4-hydroxyphenyl) -7-isopropylpyrrolo- [2,3-d] pyrimidine. The structure was confirmed by ¹ H nmr.
[298] e) 4-amino-5- (4-hydroxyphenyl) -7-isopropylpyrrolo [2,3-d] -pyrimidine (0.29 g), 2-fluoronitrobenzene (0.15 g), potassium carbonate (0.149 g) and a mixture of N, N-dimethylformamide (4.0 ml) were shaken and heated at 120 ° C. for 5 hours. The mixture was evaporated to dryness under reduced pressure and the residue partitioned between ethyl acetate (30 ml) and water (20 ml). The organic layer was separated and washed with water followed by dilute sodium hydroxide solution and brine, then dried, filtered and evaporated to give a solid which was treated with ether to treat 7-isopropyl-5- [4- (2-nitrophenoxy ) Phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine was obtained. The structure was confirmed by ¹ H nmr.
[299] <Example 11>
[300] 7-isopropyl-5- [4- (2-nitrophenoxy) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (0.15 g), ammonium formate (3 equiv) , A mixture of 10% palladium on carbon (15 mg) and ethanol (5 ml) was boiled under reflux for 2 hours under nitrogen. After 1 hour additional ammonium formate (100 mg) was added. The mixture was cooled and filtered through silica. The filter layer was washed with industrial methylated ethyl alcohol (twice with 10 ml). The filtrate was evaporated and the residue was extracted with ethyl acetate. Ethyl acetate was removed under reduced pressure to give a residue, which was purified by flash column chromatography on silica using ethyl acetate as mobile phase to give 5- [4- (2-aminophenoxy) phenyl] -7-isopropyl- 7H-pyrrolo [2,3-d] -pyrimidin-4-ylamine was obtained. The structure was confirmed by ¹ H nmr.
[301] <Example 12>
[302] Triethylamine (56 mg) is 4-amino-5- [4- (2-aminophenoxy) phenyl] -7-isopropylpyrrolo [2,3-d] pyrimidine in anhydrous acetonitrile (5.0 ml). (67 mg) was added followed by acetyl chloride (14.6 mg). The mixture was stirred for 1 h at ambient temperature and further acetyl chloride (7.3 mg) in acetonitrile (0.25 ml) was added and the mixture was stirred at ambient temperature for 0.5 h. The mixture was evaporated to dryness under reduced pressure and the residue partitioned between water (2 ml) and dichloromethane (2 ml). The mixture was filtered through an Empor® cartridge and washed with dichloromethane (2 ml). The dichloromethane layer was separated and evaporated to yield N- {2- [4- (4-amino- (7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenyl } Acetamide was obtained The structure was confirmed by ¹ H nmr.
[303] <Example 13>
[304] N- {4- [4- (4-amino-7-tert-butylpyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -phenyl} acetamide (1.8 g) (Example 9 Prepared as described above), a mixture of industrial methylated ethylalcohol (5 ml) and hydrazine hydrate (30 ml) was boiled reflux for 36 h. The reaction mixture is cooled to ambient temperature and diluted with water (100 ml) and the mixture is extracted with ethyl acetate (3 times 50 ml) to give 5- [4- (4-amino-phenoxy) phenyl] -7-tert -Butyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine was obtained. The structure was confirmed by ¹ H nmr.
[305] <Example 14>
[306] In a manner similar to Example 9, 4-amino-5- (4-iodophenyl) -7-tert-butyl-pyrrolo [2,3-d] pyrimidine (1.8 g), 3-acetamidophenol (2.48 g), potassium carbonate (2.1 g), copper (I) (0.09 g), 8-hydroxyquinoline (0.15 g) and dimethylacetamide (40 ml) are stirred and at 180 ° C. under nitrogen for 4 hours. Heated to form N- {3- [4- (4-amino- (7-tert-butyl-7H-pyrrolo [2,3-d] -pyrimidin-5-yl) phenoxy] phenyl} -acetamide The structure was confirmed by ¹ H nmr.
[307] <Example 15>
[308] N- {3- [4- (4-amino- (7-tert-butyl-7H-pyrrolo [2,3-d] -pyrimidin-5-yl) phenoxy] -phenyl} acetamide (0.6 g ), A mixture of hydrazine hydrate (5 ml) and industrial methylated ethyl alcohol (2 ml) was heated in a steam bath for 2 days and then treated as described in Example 14 to obtain a residue, which was then ethyl acetate as mobile phase. Purification by flash column chromatography on silica gel using 4-amino-5- [4- (3-aminophenoxy) phenyl] -7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidine 4-ylamine was obtained The structure was confirmed by ¹ H nmr.
[309] <Example 16>
[310] Using a method similar to Example 9, 4-amino-5- (4-iodophenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine (100 mg), potassium carbonate ( 104 mg), a mixture of N-methyl- (4-acetamido) phenol (120 mg), 8-hydroxyquinoline (8 mg), copper chloride (I) (5 mg) and dimethylacetamide (8 ml) N- {4- [4- (4-amino-7-tert-butylpyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenyl} -N-methylacetamide was obtained. . The structure was confirmed by ¹ H nmr.
[311] <Example 17>
[312] a) Iodine (52.9 g) was added 4-chloro-pyrrolo [2,3-d] pyrimidine in N, N-dimethylformamide (400 ml) (29.1 g, J. Chem. Soc. 1960, 131)). Potassium hydroxide pellets (31.9 g) were added to the cooled mixture in portions to maintain the temperature of the reaction mixture at about 20 ° C. and the mixture was stirred at ambient temperature for 2 hours. A solution of sodium thiosulfate (900 ml of 10% aqueous solution) was added to the rectified vapor while maintaining the temperature at 30 ° C by external cooling. The mixture was extracted with ethyl acetate and the combined extracts were dried, filtered and evaporated under reduced pressure to give a residue, which was added to water (1 L) and extracted with ethyl acetate (twice with 150 ml). The combined ethyl acetate extracts were dried and evaporated to give a solid, which was recrystallized from ethyl acetate. The obtained solid was stirred with methanol (800 ml) and filtered to remove insoluble matter. The filtrate was evaporated to dryness to afford a pale yellow solid, which was identified as 4-chloro-5-iodo-pyrrolo [2,3-d] pyrimidine, melting point 219-221 ° C.
[313] b) 4-chloro-5-iodo-pyrrolo [2,3-d] -pyrimidine (5.0 g) in sodium hydride (mineral oil) in N, N-dimethylformamide (100 ml) at 0 ° C. under nitrogen. 0.8 g of a 60% dispersion in water) was added and the mixture was then warmed to ambient temperature. When hydrogen evolution ceased, a solution of isopropyl bromide (17 ml) in N, N-dimethylformamide (50 ml) was added dropwise. The mixture was stirred at ambient temperature for 20 hours and then quenched with water (150 ml). The mixture was extracted with ethyl acetate to give 4-chloro-5-iodo-7-isopropylpyrrolo [2,3-d] pyrimidine.
[314] c) 4-chloro-5-iodo-7-isopropylpyrrolo [2,3-d] pyrimidine (0.57 g), 4-nitrophenylboronic acid (0.30 g), bis (triphenylphosphine) chloride A mixture of palladium (II) (0.126 g), toluene (15 ml), ethanol (2 ml), water (4 ml) and sodium bicarbonate (0.45 g) was heated at 105 ° C. under nitrogen for 8 hours. The mixture was cooled to ambient temperature and then partitioned between brine (50 ml) and ethyl acetate (50 ml). The aqueous layer was further extracted with ethyl acetate and the combined ethyl acetate extracts were washed with water, dried, filtered and evaporated to give a solid which was then flash column chromatographed on silica using cyclohexane as mobile phase with increasing amount of ethyl acetate. Purification by chromatography gave 4-chloro-7-isopropyl-5- (4-nitrophenyl) pyrrolo [2,3-d] pyrimidine.
[315] d) 4-chloro-7-isopropyl-5- (4-nitrophenyl) pyrrolo [2,3-d] pyrimidine (1.0 g), iron powder (1.76 g), ammonium chloride (86 mg), water (8 ml) and a mixture of industrial methylated ethyl alcohol (40 ml) were boiled at reflux for 1 hour. The mixture was filtered and the solvent evaporated. The residue was dissolved in ethyl acetate and washed with water. The ethyl acetate extract was dried, filtered and evaporated to afford 5- (4-aminophenyl) -4-chloro-7-isopropyl-pyrrolo [2,3-d] pyrimidine.
[316] e) Benzenesulfonyl chloride (0.27 g) in dichloromethane (5 ml) was converted to 5- (4-aminophenyl) -4-chloro-7-isopropylpyrrole in dichloromethane (15 ml) at 0 ° C. under nitrogen [ To the solution of 2,3-d] pyrimidine (0.40 g) and triethylamine (155 mg) was added dropwise with stirring. The mixture was stirred at 0 ° C. for 1 hour, then warmed to ambient temperature and stirred at this temperature for 18 hours. Water (20 ml) was added and the mixture extracted with dichloromethane. The combined organic layers were washed with sodium bicarbonate, dried, filtered and evaporated to form N- [4- (4-chloro-7-isopropylpyrrolo [2,3-d] pyrimidin-5-yl) phenyl] benzenesulfonamide Obtained.
[317] f) N- [4- (4-chloro-7-isopropylpyrrolo [2,3-d] pyrimidin-5-yl) phenyl] -benzenesulfonamide (0.34 g), concentrated ammonia (30 ml, SG 0.880) and 1,4-dioxane (30 ml) were heated with stirring in a pressure vessel at 120 ° C. for 16 hours. The mixture was cooled to ambient temperature and the solvent was removed under reduced pressure to give a residue, which was partitioned between water (40 ml) and ethyl acetate (40 ml). The organic layer was separated and the aqueous layer further extracted with ethyl acetate (twice with 40 ml). The combined ethyl acetate extracts were washed, dried, filtered and evaporated to afford a solid which was purified by flash column chromatography on silica using ethyl acetate / cyclohexane (8: 2) as mobile phase. The appropriate fractions were collected, combined and concentrated to give N- [4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenyl] benzenesulfonamide , Melting point 238-240 ° C.
[318] <Example 18>
[319] 4-amino-5- (4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] -pyrimidine (0.20 g), N-chlorosuccinimide (80 mg) and dichloro The mixture of methane (5 ml) was stirred at ambient temperature for 18 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was separated, dried and evaporated to afford an oil which was purified by flash column chromatography on silica using ethyl acetate / triethylamine (95: 5) as mobile phase. Collect the appropriate fractions, combine and evaporate 7- (tert-butyl) -6-chloro-5- (4-phenoxyphenyl) -7H-pyrrolo- [2,3-d] pyrimidin-4-ylamine Obtained, melting point 136.8-137.8 ° C.
[320] <Example 19>
[321] A solution of sodium periodate (0.60 g) dissolved in water (16 ml) was maintained at temperature below 5 ° C. with 4-amino-5- [4- (phenylthio) phenyl] -7 in glacial acetic acid (30 ml). To the solution of-(tert-butyl) pyrrolo [2,3-d] pyrimidine (1.0 g) was added with stirring. The mixture was stirred at ambient temperature for 66 hours. The mixture was filtered and the filtrate was added to water (300 ml). The mixture was basified with solid sodium bicarbonate, filtered to remove a small amount of solid and the filtrate was extracted with ethyl acetate to give a residue, which was purified by silica using ethyl acetate / triethylamine (9: 1) as mobile phase. Purification by flash column chromatography on affords a solid, which is rechromatized under the same conditions to give 7-tert-butyl-5- (4-phenylsulfinylphenyl) -7H-pyrrolo [2,3-d] pyridine. Midin-4-ylamine was obtained, melting point 180-182 ° C.
[322] <Example 20>
[323] A solution of potassium peroxymonosulfate (4.93 g) in water (10 ml) was maintained in 4-amino-5- [4- (phenyl) in methanol (5 ml) and glacial acetic acid (5 ml) while maintaining the temperature below 5 ° C. To the solution of thio) phenyl] -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine (1.0 g) was added dropwise with stirring. The mixture was then stirred at ambient temperature for 3 hours and then diluted with water (50 ml). The mixture was extracted with ethyl acetate to give a solid, which was purified by flash column chromatography on silica using ethyl acetate / triethylamine (9: 1) as mobile phase. Suitable fractions were combined and concentrated to give a solid which was treated with petroleum ether (boiling point 60-80 ° C.) to 7-tert-butyl-5- (4-phenylsulfonylphenyl) -7H-pyrrolo [2,3- d] pyrimidin-4-ylamine was obtained, melting point 222-224 ° C.
[324] <Examples 21a and 21b>
[325] 7- (tert-butyl) -4-amino-5- [4- (4-methoxyphenoxy) phenyl] -7H-pyrrolo- [2,3-d] pyrimidin-4-ylamine (1.1 g , Example 7), glacial acetic acid (25 ml) and a mixture of 48% w / v aqueous hydrobromic acid solution (25 ml) were heated to reflux for 1 hour. The mixture was cooled to ambient temperature and then added to ice water and ethyl acetate. The mixture was stirred with the addition of excess solid sodium bicarbonate slowly. The ethyl acetate layer was separated, washed with water, dried and evaporated to give a solid residue, which was ethyl acetate / triethylamine (19: 1) as mobile phase and flash column chromatography on silica with increasing amount of methanol Purification by chromatography. Collect appropriate fractions, combine and evaporate 4- [4- (4-amino-7-tert-butyl-7H-pyrrolopyrimidin-5-yl) -phenoxy] phenol, melting point 254-255 ° C. (Example 21a) and 4- [4- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenol, melting point 304-305 ° C. (Example 21b) were obtained. .
[326] <Example 22>
[327] 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (0.50 g), ethylene carbonate (0.16 g), N, N-dimethylformamide (20 ml ) And a catalytic amount of sodium hydroxide powder were boiled under reflux for 1 hour. The mixture was evaporated under reduced pressure and the residue was treated with water (30 ml). The mixture was filtered to give a solid, which was purified by flash column chromatography on silica using ethyl acetate / industrial methylated ethylalcohol (9: 1) as mobile phase to afford 2- [4-amino-5- (4-phenoxy). Phenyl) -7H-pyrrolo gave [2,3-d] pyrimidin-7-yl] ethanol, melting point 144.5-145 ° C.
[328] <Example 23>
[329] Sodium hydride (60 mg of 60% dispersion in mineral oil) was added to 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3- in anhydrous N, N-dimethylformamide (20 ml) at ambient temperature under nitrogen. d] was added to the solution of pyrimidin-4-ylamine (302 mg) with stirring. The mixture was stirred at ambient temperature for 30 minutes and cyclopentene oxide (200 mg) was added and the mixture was heated at 150 ° C. for 3 hours and then at 170 ° C. for 1 hour. The mixture was concentrated under reduced pressure and the residue was treated with water and filtered to give a solid. This solid was purified by flash column chromatography on silica using ethyl acetate / industrial methylated ethylalcohol (9: 1) as mobile phase to 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentanol was obtained, melting point 162-162.5 ° C. (after recrystallization from methanol / water).
[330] <Example 24>
[331] 5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine (600 mg) and tetrakis (triphenylphosphine) palladium (40 ml) and anhydrous dimethyl sulfoxide The mixture of seeds (30 ml) was stirred under nitrogen in an ice / water bath, then a solution of cyclopentadiene monoepoxide (200 mg) in tetrahydrofuran (10 ml) was added via syringe at 0 ° C. under nitrogen. . The mixture was stirred at ambient temperature for 66 hours, then tetrahydrofuran was removed under reduced pressure and water was added to the residue. The mixture was left for 18 hours and then extracted with ethyl acetate to give a residue, which was purified by flash column chromatography on silica using ethyl acetate / industrial methylated ethyl alcohol (9: 1) as the mobile phase to give 4 as oil. -[4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopent-2-enol was obtained. The structure was confirmed by ¹ H nmr and mass spectra.
[332] <Example 25>
[333] 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopent-2-enol (110 mg) in ethanol (20 ml Hydrogenated to gaseous hydrogen at atmospheric pressure using 10% palladium on carbon (50 mg) as catalyst. The catalyst was removed by filtration and the filtrate was evaporated to afford 3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentane as an oil. Obtained ol. The structure was confirmed by ¹ H nmr and mass spectra.
[334] <Example 26>
[335] 4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopent-2-enol in tetrahydrofuran (5 ml) ( 188 mg), 4-methylmorpholine-N-oxide (63 mg) was stirred at ambient temperature for 10 minutes. Osmium tetraoxide (0.42 ml of a 2.5% w / v solution in tert-butanol) was added to the mixture. The mixture was stirred at ambient temperature for 3 hours, and then directly chromatographed using flash column chromatography on silica using ethyl acetate / industrial methylated ethylalcohol (9: 1) as mobile phase to give 4- [4-amino as oil. -5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentane-1,2,3-triol was obtained. The structure was confirmed by ¹ H nmr and mass spectra.
[336] <Example 27>
[337] a) 4-chloro-7-cyclopentyl-5-iodopyrrolo [2,3-d] pyrimidine (1.26 g) and potassium (2-phenoxyphenyl) trifluoroborate (1.0 g, J. Phen.brombenzene was reacted with butyllithium in tetrahydrofuran at −70 ° C. by a method similar to that described in Org.Chem. 1995, 60, 3020-3027, followed by triisopropyl borate (IV) , Prepared by reaction with potassium hydrogen fluoride), is stirred in degassed toluene (40 ml), ethanol (10 ml) and water (10 ml), and bis (triphenylphosphine) palladium (II) chloride (0.25 g) was added followed by sodium bicarbonate (2.0 g). The mixture was stirred and heated at 105 ° C. for 16 h and then cooled to ambient temperature. The mixture was separated and the upper layer was evaporated under reduced pressure to give a residue, which was purified by flash column chromatography on silica using petroleum ether / ether (2: 1) as mobile phase to give 4-chloro-7-cyclopentyl-5 -(2-phenoxyphenyl) pyrrolo [2,3-d] pyrimidine was obtained and used directly in the next step of this example.
[338] b) A mixture of the product from a) (0.79 g), 1,4-dioxane (60 ml) and concentrated aqueous ammonia solution (60 ml, SG 0.880) was stirred and heated in a pressure vessel at 120 ° C. for 18 hours. . The mixture was evaporated under reduced pressure and the residue partitioned between water and ethyl acetate. The organic layer was separated, dried and evaporated to give a gum which was crystallized from methanol to give 7-cyclopentyl-5- (2-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine Was obtained, melting point 109-110 ° C.
[339] <Example 28>
[340] This example was carried out in a similar manner to Example 27 except that the initial starting material was 3-phenoxybromobenzene and 4-cyclopentyl-5- (3-phenoxyphenyl) -7H-pyrrolo [2, 3-d] pyrimidin-4-ylamine was obtained, melting point 127.5-128 ° C.
[341] <Example 29>
[342] a) 2-phenyl-1,3-dioxan-3-ol (4.89 g) in anhydrous pyridine (20 ml) is stirred at 0-2 [deg.] C. and anhydrous pyridine prepared as membrane while keeping the temperature below 2 [deg.] C. ( A solution of 4-toluenesulfonyl chloride (5.9 g) in 80 ml) was added dropwise with stirring. The mixture was stirred at 2 ° C for 100 min and then added to water (500 ml). The liquid was decanted and the residual gum dissolved in ether, dried and evaporated to give a residue, which was crystallized from methanol to give 2-phenyl-1,3-dioxan-3-yl-4-toluene sulfonate, Melting point 125.3-125.9 ° C .;
[343] b) Sodium hydride 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] -pyrimidine hydrobromide (0.6 g), sodium hydride (60% dispersion in mineral oil 80 mg ) And anhydrous N, N-dimethylformamide (30 ml) were stirred under nitrogen for 30 minutes. 4-toluene sulfonate (0.76 g) from a) was added and the mixture was heated at 145 ° C. for 16 h. The solvent was removed under reduced pressure and water was added to the residue. The mixture was filtered to give a solid, which was purified by flash column chromatography using ethyl acetate / industrial methylated ethyl alcohol (9: 1) as mobile phase to give 5- (4-phenoxyphenyl) -7- (2-phenyl -1,3-dioxan-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine was obtained. The structure was confirmed by ¹ H nmr and mass spectra.
[344] <Example 30>
[345] Dilute hydrochloric acid (45 ml of 2M solution) to 5- (4-phenoxyphenyl) -7- (2-phenyl-1,3-dioxan-5-yl) -7H-pyrrolo [2,3-d] pyridine Midin-4-ylamine (170 mg) was added and the mixture was heated to boiling under reflux. Propan-1-ol (30 ml) was added and the mixture was boiled at reflux for 6 hours, after which the propanol was distilled off. The mixture was evaporated under reduced pressure to give a residue, which was treated with ethyl acetate and filtered to give a solid which was dissolved in methanol and purified by chromatography to give 2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] propane-1,3-diol was obtained. The structure was confirmed by ¹ H nmr and mass spectra.
[346] <Example 31>
[347] a) Sodium hydride (0.28 g of 60% dispersion in mineral oil) was added to 4-chloro-5-iodo-7H-pyrrolo in anhydrous N, N-dimethylformamide (40 ml) at ambient temperature under nitrogen [2,3 -d] was added to the solution of pyrimidine (1.96 g) with stirring. The mixture was then stirred for 30 minutes and allyl bromide (0.62 ml) was added dropwise. After stirring for 1 h at ambient temperature, further allyl bromide (0.20 ml) was added and the mixture was stirred for 18 h at ambient temperature. The mixture was added to water with stirring, and the precipitated solid was collected by filtration and dried to give 4-chloro-5-iodo-7- (prop-1-en-3-yl) -7H-pyrrolo [2,3- d] -pyrimidine was obtained and used directly in b).
[348] b) The product from a) (2.05 g) was dissolved in tetrahydrofuran (50 ml) and stirred with 4-methylmorpholine N-oxide (850 mg) at ambient temperature before osmium tetraoxide in tert-butanol Solution (5 ml of 2.5% w / v solution) was added. The mixture was left for 18 hours and then evaporated under reduced pressure to give a solid which was dissolved in toluene / propan-2-ol (2: 1), hot filtered and the filtrate was evaporated to 3- [4-chloro-5- Iodo-7H-pyrrolo [2,3-d] pyrimidin-7-yl] propane-1,2-diol was obtained.
[349] c) a mixture of product from b) (1.90 g), 4-phenoxyphenylboronic acid (1.14 g), degassed toluene (100 ml), degassed ethanol (25 ml), degassed water (25 ml) After stirring under nitrogen, bis (triphenylphosphine) palladium (II) chloride (0.40 g) was added and sodium bicarbonate (2.0 g) was added. The mixture was heated to reflux with stirring for 18 hours. The mixture was treated as described in Example 10b) to give an oil which was purified by flash column chromatography on silica using ethyl acetate / industrial methylated ethyl alcohol (9: 1) as mobile phase to give 3- [4-chloro. -5- (4-phenoxyphenyl) -7H-pyrrolo gave [2,3-d] pyrimidin-7-yl] propane-1,2-diol.
[350] d) 3- [4-chloro-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] propane-1,2-diol (0.6 g) It was dissolved in, 4-dioxane (60 ml) and concentrated ammonia water (60 ml, SG 0.880) was added. The mixture was stirred and heated in a pressure vessel at 120 ° C. for 18 hours. The mixture was evaporated under reduced pressure to give a residue, which was partitioned between water and ethyl acetate. The ethyl acetate layer was separated, washed with water, dried and evaporated to give a residue, which was purified by flash column chromatography on silica using ethyl acetate / industrial methylated ethyl alcohol (9: 1) as mobile phase to give 3- [4. Amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] propane-1,2-diol was obtained. The structure was confirmed by ¹ H nmr and mass spectra.
[351] <Example 32>
[352] a) In a similar manner to Example 17b, 4-chloro-5-iodo-7H-pyrrolo [2,3-d] pyrimidine is reacted with sodium hydride in N, N-dimethylformamide at 0 ° C. and then , And reacted with bromocyclopentane to give [2,3-d] pyrimidine with 4-chloro-7-cyclopentyl-5-iodopyrrolo.
[353] b) 2-methoxyaniline is brominated with 2,4,4,6-tetrabromo-2,5-cyclohexadien-1-one to give 4-bromo-2-methoxyaniline, which is tetra The amine group was protected by reaction with di-tert-butyldicarbonate in hydrofuran. The product was treated with butyllithium at −78 ° C. followed by trimethyltin chloride to give 4-tert-butoxycarbonylamino-3-methoxyphenyl trimethyl stanan.
[354] c) The product from a) (4.91 g) and the product from b) (5.45 g) were converted to triphenylarcine (1.07 g) and tris (dibenzylideneacetone) in N, N-dimethylformamide (100 ml). The reaction was carried out with stirring for 18 hours at 65 ° C. under nitrogen in the presence of dipaladium (0) (0.65 g). The mixture was then cooled to ambient temperature and added to water. The mixture was extracted with ethyl acetate to give an oil, which was purified by flash column chromatography on silica using cyclohexane / ethyl acetate (19: 1) as the mobile phase with gradual increase in the amount of ethyl acetate to give 4- as a solid. Chloro-7-cyclopentyl-4- (4-tert-butoxycarbonylamino-3-methoxyphenyl) -pyrrolo [2,3-d] pyrimidine was obtained.
[355] d) The product from c) in dichloromethane (150 ml) (3.58 g) was reacted with trifluoroacetic acid (15 ml) in dichloromethane (50 ml) at 0 ° C. to treat 5- (4-amino as oil after treatment. 3-methoxyphenyl) -4-chloro-7-cyclopentylpyrrolo [2,3-d] pyrimidine was obtained.
[356] e) N- [4- (4-chloro-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-5 after chromatography by reaction of the product from d) (0.5 g) with benzoyl chloride -Yl) -2-methoxyphenyl] -benzamide was obtained. The structure was confirmed by ¹ H nmr and mass spectra.
[357] f) The product from e) (0.42 g) was treated by reacting concentrated aqueous ammonia (30 ml, SG 0.880) in 1,4-dioxane (30 ml) in a pressure vessel at 120 ° C. and chromatographed to give N- [4 -(4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] benzamide was obtained. The structure was confirmed by ¹ H nmr and mass spectra.
[358] <Example 33>
[359] A solution of boron tribromide in dichloromethane (0.9 ml of 1M solution) was added to N- [4- (4-amino-7-cyclopentyl-7H-pyrrolo in dichloromethane (6 ml) which is a solution of the product from Example 32. To a solution of [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] benzamide (130 mg) was added dropwise with stirring at −10 ° C. under nitrogen, and after addition the reaction mixture was warmed to 0 ° C. Then stirred at 0 ° C. for 1.5 h. The reaction mixture was quenched by dropwise addition of saturated aqueous sodium bicarbonate solution (5 ml) at 0 ° C. An exothermic reaction appeared and the temperature of the mixture rose to 10 ° C. The mixture is allowed to warm to ambient temperature and then extracted with dichloromethane to give N- [4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2- Hydroxyphenyl] benzamide was obtained, melting point 173-175 ° C. (decomposition). The structure was confirmed by ¹ H nmr and mass spectra.
[360] <Example 34>
[361] 5- (4-amino-3-methoxyphenyl) -4-chloro-7-cyclopentylpyrrolo [2,3-d] pyrimidine (0.50 g, prepared in a similar manner to Example 32) at 0 ° C Was reacted with benzenesulfonyl chloride (0.31 g) in pyridine (5 ml) and dichloromethane (1 ml) and the product obtained after treatment was reacted with ammonia in a similar manner to Example 32 to give N- [4- (4- Amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] benzenesulfonamide was obtained, melting point 113-115 ° C. The structure was confirmed by ¹ H nmr and mass spectra.
[362] <Example 35>
[363] In a similar manner to Example 33, N- [4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] benzenesulfon The amide was reacted with boron tribromide in dichloromethane at -10 ° C to give N- [4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2 -Hydroxyphenyl] benzenesulfonamide was obtained, melting point 265-267 ° C. The structure was confirmed by ¹ H nmr and mass spectra.
[364] <Examples 36a and 36b>
[365] N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-hydroxyphenyl] -4-tert-butylbenzenesulfonamide, Melting point 278-280 ° C. (Example 36a) was carried out using N- [4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidine-5 in a similar manner to Examples 34 and 35. -Yl) -2-methoxyphenyl] -4-tert-butylbenzenesulfonamide (Example 36b).
[366] <Example 37>
[367] a) In a manner similar to Example 17 c), 4-chloro-5-iodo-7-cyclopentylpyrrolo is used to convert [2,3-d] pyrimidine (1.80 g) to 4- (2-methoxyphenoxy. Reaction with phenylboronic acid to give 4-chloro-7-cyclopentyl-5- [4- (2-methoxy) phenoxyphenyl] -pyrrolo [2,3-d] pyrimidine.
[368] b) The product from a) (1.2 g) was reacted in a pressurized vessel with ammonia (50 ml, SG 0.880) in 1,4-dioxane at 120 ° C. in a 7-cyclopentyl-5- [4- (2-meth Oxyphenoxy) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine was obtained.
[369] <Examples 38a and 38b>
[370] 2- [4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenol, melting point 107-109 ° C. (Example 38a) was carried out. 7-cyclopentyl-5- [4- (2-methoxy) phenoxyphenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine in a similar manner to Example 33 (Example 38b) Prepared from.
[371] <Example 39>
[372] Example N- [4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-hydroxy-phenyl] -4-chlorobenzamide Prepared in a similar manner to 33.
[373] <Example 40>
[374] In a similar manner to Example 18, 7-cyclopentyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2, 3-d] pyrimidin-4-ylamine hemihydrate (2.5 g) was added to dichloromethane. Reacted with N-chlorosuccinimide (0.90 g) in (80 ml) to 6-chloro-7-cyclopentyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine 4-ylamine was obtained.
[375] <Example 41>
[376] 4-Amino-5- (4-phenoxyphenyl) -7- (tert-butyl) pyrrolo [2,3-d] pyrimidine (5.8 g), glacial acetic acid (55 ml) and hydrobromic acid (48% solution 55 ml) was boiled under reflux for 18 hours under nitrogen. The mixture was cooled and the solid collected by filtration. This solid was washed with methanol and then ether to afford 4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidine hydrobromide, melting point 288- 292 ° C. The hydrobromide salt was stirred with dilute sodium hydride solution (100 ml of 5% w / v solution) and ethanol (60 ml) to convert to the free base and distilled to remove ethanol. The mixture was cooled and the solid collected by filtration and washed with water to afford [2,3-d] pyrimidin-4-ylamine with 5- (4-phenoxyphenyl) -7H-pyrrolo.
[377] <Examples 42-48 (General Method)>
[378] Mother liquor in N, N-dimethylformamide (6 g in 24 0 ml) via a Gilson 215 Liquid Autosampler to a mixture of fluorobenzene (1.25 molar equivalents) and potassium carbonate (2 molar equivalents) in a septum sealed tube 4-amino-5- (4-hydroxyphenyl) -7-isopropylpyrrolo [2, 3-d] pyrimidine (1 molar equivalent) was added. The reaction was heated at 120 ° C. for 4 hours with shaking and an additional 1 hour at 140 ° C. and then evaporated to dryness in a centrifugal evaporator.
[379] The reaction residue was dissolved in ethyl acetate / triethylamine (1 ml) (9: 1) and silica pad (3 g SiO ₂ : 12 mm diameter with 9: 1 ethyl acetate / triethylamine (4 times in 2 ml) x 20 mm height). The combined column eluate was evaporated to yield the product as a waxy solid, smear or foam.
[380] Sample amount
[381]
[382] Yield / LCMS
[383]
[384] The compounds prepared in Examples 42-48 are as follows:
[385] <Example 42>
[386] N- {2- [4- (amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -5-nitrophenyl} acetamide;
[387] <Example 43>
[388] 5- [4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -2-nitrobenzoic acid;
[389] <Example 44>
[390] 2- [4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -5-nitrobenzoic acid;
[391] <Example 45>
[392] 7-isopropyl-5- [4- (3-methoxy-4-nitrophenoxy) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine;
[393] <Example 46>
[394] Methyl 4- [4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -3-nitrobenzoate;
[395] <Example 47>
[396] 5- [4- (5-chloro-2-nitrophenoxy) phenyl] -7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine;
[397] <Example 48>
[398] N- {2- [4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -5-nitrophenyl} -2,2- Dimethylpropionamide;
[399] <Example A>
[400] The use of the compounds of the present invention in the preparation of pharmaceutical compositions is indicated by the following description. The term "active compound" in this description refers to any compound of the invention but in particular refers to any compound which is the final product of one of the above examples.
[401] a) capsules
[402] In the preparation of capsules, 10 parts by weight of active compound and 240 parts by weight of lactose were deagglomerated and blended. The mixture is filled into hard gelatin capsules, each capsule containing a unit dose or a portion of a unit dose of the active compound.
[403] b) tablets
[404] Tablets were prepared from the following ingredients:
[405] Parts by weight
[406] Active compound 10
[407] Lactose 190
[408] Corn Starch 22
[409] Polyvinylpyrrolidone 10
[410] Magnesium Stearate 3
[411] The active compound, lactose and some starch were deagglomerated, blended and the resulting mixture was granulated with a solution of polyvinylpyrrolidone in ethanol. The dry granules were blended with magnesium stearate and the remaining starch. The mixture was then compressed in a tablet press to give tablets each containing a unit dose or a portion of a unit dose of the active compound.
[412] c) enteric coated tablets
[413] Tablets were prepared by the method described in (b) above. Tablets were enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1: 1).
[414] d) suppositories
[415] In the preparation of suppositories, 100 parts by weight of the active compound were incorporated into 1300 parts by weight of the base for triglyceride suppositories, and the mixture was formed of suppositories each containing a therapeutically effective amount of the active ingredient.

权利要求:
Claims (30)
[1" claim-type="Currently amended] A compound of formula I and a pharmaceutically acceptable salt thereof.
<Formula I>

Wherein R ₁ is hydrogen, 2-phenyl-1,3-dioxan-5-yl, C _1-6 alkyl group, C _3-8 cycloalkyl group, C _5-7 cycloalkenyl group or (optionally substituted phenyl) C _1-6 alkyl group, wherein the alkyl, cycloalkyl, and cycloalkenyl groups represent one or more groups of formula OR _A wherein R _A represents H or a C _1-6 alkyl group, provided that the group of formula OR _A Is not located at the carbon atom bonded to;
R ₂ represents hydrogen, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, halo, hydroxy, a (optionally substituted phenyl) C _1-6 alkyl group, optionally substituted phenyl or R ₄ ;
R ₃ represents a group of the formula (a);
<Formula (a)>

Wherein the phenyl ring is further optionally substituted, A is NH, O, NHSO ₂ , SO ₂ NH, C _1-4 alkylene chain, NHCO, NHCO ₂ , CONH, NHCONH, CO ₂ or S (O) _p Wherein p is 0, 1 or 2, or A is absent so that R ₅ is directly bonded to the phenyl ring, R ₅ represents optionally substituted phenyl, and further when A is absent, ₅ represents a) a phthalimido group optionally substituted with halo or b) a pyrazolylamino group optionally substituted with at least one of hydroxy or optionally substituted phenyl with pyrazole ring)
R ₄ is thienyl, benzo (b) thienyl, pyridyl, pyrazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, indazolyl (each of which is a C _1-6 alkyl group, C _3-6 cycloalkyl group, C _1-6 alkoxy, C _1-6 alkylthio, hydroxy, optionally substituted phenyl, (optionally substituted phenyl) C _1-6 alkyl, (optionally substituted phenyl) C _1-6 alkylthio group; or (Optionally substituted with one or more of optionally substituted phenyl) C _1-6 alkoxy groups).
Wherein optionally substituted phenyl is a) a C _1-6 alkyl group, b) a C _1-6 alkoxy group, c) phenoxy, d) hydroxy, e) phenyl C _1-6 alkyl, f) halo, g) Groups of NR ₁₀ R ₁₁ , wherein R ₁₀ and R ₁₁ are independently hydrogen, C _1-6 alkyl group, phenyl, C _1-6 alkanoyl group, (C _1-6 alkoxy) carbonyl group, 5-hydroxy-1 -Phenyl-3-pyrazolyl or represent benzoyl optionally substituted with C _1-6 alkyl, C _1-6 alkoxy or halo, h) a group of formula -COR ₉ wherein R ₉ is hydroxy, C _1-6 alkoxy group, phenoxy or a group of formula NR ₁₀ R ₁₁ , wherein R ₁₀ and R ₁₁ are the same as defined above, i) a phthalimido group optionally substituted with halo, j) phenyl Phenyl optionally substituted with one or more of rings (form naphthyl by benz fusion) or k) nitro.
[2" claim-type="Currently amended] The method of claim 1,
R ₁ is a C _1-6 alkyl group, a C _3-8 cycloalkyl group or (optionally substituted phenyl) C _1-6 alkyl group, wherein the alkyl and cycloalkyl group is one or more groups of OR _A , wherein R _A is H or C _1-6 alkyl group, provided that the formula OR _A group is optionally substituted with no carbon located at the carbon bonded to nitrogen;
R ₂ represents hydrogen, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, halo, hydroxy, a (optionally substituted phenyl) C _1-6 alkyl group, optionally substituted phenyl or R ₄ ;
R ₃ represents a group of the formula (a);
<Formula (a)>

[Wherein, the phenyl ring is further optionally substituted, and A is NH, O, NHSO ₂ , SO ₂ NH, C _1-4 alkylene chain, NHCO, NHCO ₂ , CONH, NHCONH, CO ₂ or S (O) _p Wherein p is 0, 1 or 2, or A is absent so that R ₅ is directly bonded to the phenyl ring, R ₅ represents optionally substituted phenyl, and further when A is absent, ₅ represents a) a phthalimido group optionally substituted with halo or b) a pyrazolylamino group, wherein the pyrazole ring is optionally substituted with one or more of hydroxy or optionally substituted phenyl] R ₄ is thienyl, benzo (b) thienyl, pyridyl, pyrazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, indazolyl (each of which is a C _1-6 alkyl group, C _3-6 cycloalkyl group, C _1-6 alkoxy, C _1-6 alkylthio, hydroxy, optionally substituted phenyl, (optionally substituted phenyl) C _1-6 alkyl, (optionally substituted phenyl) C _1-6 alkylthio group; or (Optionally substituted with one or more of optionally substituted phenyl) C _1-6 alkoxy groups).
Wherein optionally substituted phenyl is a) a C _1-6 alkyl group, b) a C _1-6 alkoxy group, c) phenoxy, d) hydroxy, e) phenyl C _1-6 alkyl, f) halo, g) Groups of NR ₁₀ R ₁₁ , wherein R ₁₀ and R ₁₁ are independently hydrogen, C _1-6 alkyl group, phenyl, C _1-6 alkanoyl group, (C _1-6 alkoxy) carbonyl group, 5-hydroxy-1 -Phenyl-3-pyrazolyl or represent benzoyl optionally substituted with C _1-6 alkyl, C _1-6 alkoxy or halo, h) a group of formula -COR ₉ wherein R ₉ is hydroxy, C _1-6 alkoxy group, phenoxy or a group of formula NR ₁₀ R ₁₁ , wherein R ₁₀ and R ₁₁ are as defined above, i) a phthalimido group optionally substituted with halo, or j) Compound meaning phenyl optionally substituted with one or more of the phenyl rings (formed naphthyl by benz fusion).
[3" claim-type="Currently amended] 3. A _compound according to claim 1 or 2 wherein R ₁ represents a C _3-6 alkyl group, a C _3-8 cycloalkyl group or a C _5-7 cycloalkenyl group, wherein the alkyl, cycloalkyl and cycloalkenyl groups are at least one hydroxy group Wherein the hydroxy group is not located in the carbon bonded to nitrogen.
[4" claim-type="Currently amended] The compound according to any one of claims 1 to 3, wherein R ₁ is isopropyl, tert-butyl, 2-hydroxyethyl, cyclopentyl, neopentyl, 2-hydroxycyclopentyl, 4-hydroxycyclopent- 2-enyl, 3-hydroxycyclopentyl, 2,3,4-trihydroxycyclopentyl, 1,3-dihydroxyprop-2-yl or 2,3-dihydroxypropyl .
[5" claim-type="Currently amended] The compound of any one of claims 1-4, wherein R ₂ represents hydrogen or halo.
[6" claim-type="Currently amended] The compound of any one of claims 1-5, wherein R ₂ represents hydrogen or halo.
[7" claim-type="Currently amended] The compound according to any one of claims 1 to 6, wherein R ₃ represents a group of formula (a).
<Formula (a)>

Wherein the phenyl ring is further optionally substituted, A is O, NHSO ₂ , NHCO or S (O) _p , where p is 0, 1 or 2, and R ₅ represents optionally substituted phenyl.
[8" claim-type="Currently amended] 8. The compound of claim 1, wherein A represents NHSO _{2. 9} .
[9" claim-type="Currently amended] The compound of any one of claims 1-8, wherein A represents NHCO.
[10" claim-type="Currently amended] The compound of any one of claims 1-9, wherein A represents O or S. 11.
[11" claim-type="Currently amended] The compound of any one of claims 1-10, wherein A represents O. 12.
[12" claim-type="Currently amended] The compound of claim 1, wherein R ₃ is 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4- (phenylthio) phenyl, 4- (4-methoxy Phenoxy) phenyl, 4- (phenylsulfinyl) phenyl, 4- (phenylsulfonyl) phenyl, 4- (4-hydroxyphenoxy) phenyl, 4- (benzenesulfonamido) phenyl, 4- (benzami Fig.) Phenyl, 4- (4-acetamidophenoxy) phenyl, 4- (2-nitrophenoxy) phenyl, 4- (4-aminophenoxy) phenyl, 4- (3-aminophenoxy) phenyl, 4- (2-aminophenoxy) phenyl, 4- (3-acetamidophenoxy) phenyl, 4- [4- (N-methyl-acetamido) phenoxy] phenyl, 4- (2-acetami Dophenoxy) phenyl, 4- (2-acetamido-4-nitro-phenoxy) phenyl, 4- (3-carboxy-4-nitrophenoxy) phenyl, 4- (2-carboxy-4-nitrophenoxy C), 4- (4-trifluoromethyl-2-nitrophenoxy) phenyl, 4-benzamido-3-methoxyphenyl, 4-benzamido-3-hydroxyphenyl, 4-benzenesulphone Amido-3-methoxyphenyl, 4-benzenesulfonamido-3-hydroxyfe , 3-hydroxy-4- (4-tert-butylbenzenesulfonamido) phenyl, 4- (2-hydroxyphenoxy) phenyl, 4- (4-chlorobenzamido) -3-hydroxy-phenyl 4- (3-methoxy-4-nitrophenoxy) phenyl, 4- (4-methoxycarbonyl-2-nitrophenoxy) phenyl, 4- (4-carboxy-2-nitrophenoxy) phenyl, 4- (5-chloro-2-nitrophenoxy) phenyl or 4- [4-nitro-2- (2,2-dimethylpropionamido) phenoxy] phenyl.
[13" claim-type="Currently amended] The method according to claim 1 or 2,
R ₁ represents methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, benzyl or 2-hydroxyethyl;
R ₂ represents hydrogen, methyl, halo, hydroxy or phenyl,
R ₃ is 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4- (4-chloro-N-phthalimido) -3-tolyl, 3-chloro-4- (3-chlorophenoxy C), 4- (4-methylaminophenylamino) phenyl, 4- (4-methylaminophenylamino) -2-methoxyphenyl, 4- (4-methylaminobenzyl) phenyl, 4-anilino-2 -Methoxyphenyl, 3-hydroxy-4- (4-chlorobenzamido) phenyl, 3-hydroxy-4- (2-methoxybenzamido) phenyl, 4- (4-chlorobenzamido) 3-hydroxyphenyl, 3-hydroxy-4- (2-naphthalenesulfonamido) phenyl, 3-hydroxy-4- [4- (tert-butyl) -benzenesulfonamido] phenyl, 4- [ N- (5-hydroxy-1-phenylpyrazol-3-yl) amino] phenyl or 4-phenoxycarbonylamino-3-hydroxyphenyl.
[14" claim-type="Currently amended] The compound and pharmaceutically acceptable salt thereof according to claim 1, wherein the compound of formula I is represented by formula Ib.
<Formula Ib>

Wherein R ₁ is hydrogen, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, a C _5-7 cycloalkenyl group or (optionally substituted phenyl) C _1-6 alkyl group, wherein alkyl, cycloalkyl and cycloal The kenyl group represents one or more groups of formula OR _A wherein R _A represents H or a C _1-6 alkyl group, provided that the group of formula OR _A is optionally substituted with carbon attached to nitrogen;
R ₂ represents hydrogen or halo;
R _x represents a C _1-6 alkyl group, C _1-4 alkoxy group, halo or hydroxy;
R _y is a C _1-6 alkyl group, C _1-4 alkoxy group, halo, hydroxy, nitro or a group of formula NR ₁₀ R ₁₁ , wherein R ₁₀ and R ₁₁ are independently hydrogen, C _1-6 alkyl group, phenyl , A C _1-6 alkanoyl group, a (C _1-6 alkoxy) carbonyl group), or R _y is a group of the formula -COR ₉ , wherein R ₉ is a hydroxy, a C _1-6 alkoxy group, Phenoxy or a group of formula NR ₁₀ R ₁₁ , wherein R ₁₀ and R ₁₁ are the same as defined above;
m and n are independently 0, 1 or 2.
[15" claim-type="Currently amended] 15. The compound of claim 14, wherein R ₁ is a C _1-6 alkyl group, C _3-8 cycloalkyl group, C _5-7 cycloalkenyl group, wherein the alkyl, cycloalkyl group and cycloalkenyl group is one or more groups of OR _A R _A represents H or a C _1-6 alkyl group, provided that the formula OR _A group is optionally substituted with no carbon attached to nitrogen.
[16" claim-type="Currently amended] The compound according to claim 14 or 15, wherein R ₁ is isopropyl, tert-butyl, 2-hydroxyethyl, cyclopentyl, neopentyl, 2-hydroxycyclopentyl, 4-hydroxycyclopent-2-ethyl, 3-hydroxycyclopentyl, 2,3,4-trihydroxycyclopentyl, 1,3-dihydroxyprop-2-yl or 2,3-dihydroxypropyl.
[17" claim-type="Currently amended] The compound of any one of claims 14-16, wherein R ₂ represents hydrogen or chloro.
[18" claim-type="Currently amended] _{18. The} compound of any one of claims 14-17, wherein R _x represents a hydroxy or C _1-4 alkoxy group.
[19" claim-type="Currently amended] 19. The compound of any one of claims 14-18, wherein R _y is a C _1-4 alkyl group, C _1-4 alkoxy group, nitro, acetamido, amino, N-methylacetamido, carboxy, hydroxy or A compound representing halo.
[20" claim-type="Currently amended] 20. The compound of any of claims 14-19, wherein m is 0 or 1.
[21" claim-type="Currently amended] The compound of claim 20, wherein m represents zero.
[22" claim-type="Currently amended] The compound of any one of claims 14-21, wherein n is 0 or 1.
[23" claim-type="Currently amended] 23. The compound of any of claims 14-22, wherein n represents 0 or 1 and R _y represents hydroxy, amino or acetamido.
[24" claim-type="Currently amended] 7-tert-butyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
7-tert-butyl-6-chloro-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
7-isopropyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
7-cyclopentyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
5- (4-biphenylyl) -7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
7-neopentyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
7-tert-butyl-5- [4- (phenylthio) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
7-tert-butyl-5- [4- (4-methoxyphenoxy) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
7-tert-butyl-5- [4- (phenylsulfinyl) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
7-tert-butyl-5- [4- (phenylsulfonyl) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
4- [4- (4-amino-7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenol
N- [4- (4-amino-7-isopropyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) phenyl] benzenesulfonamide
N- [4- (4-amino-7-isopropyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) phenyl] benzeneamide
N- {4- [4- (4-amino-7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenyl} acetamide
7-isopropyl-5- [4- (2-nitrophenoxy) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
5- [4- (4-aminophenoxy) phenyl] -7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
5- [4- (3-aminophenoxy) phenyl] -7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
5- [4- (2-aminophenoxy) phenyl] -7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
N- {3- [4- (4-amino-7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenyl} acetamide
N- {4- [4- (4-amino-7-tert-butyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenyl} -N-methylacetamide
N- {2- [4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenyl} acetamide
N- {2- [4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -5-nitrophenyl} acetamide
5- [4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -2-nitrobenzoic acid
2- [4- (4-Amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -5-nitrobenzoic acid
2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] ethanol
2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentanol
4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopent-2-enol
6-chloro-7-cyclopentyl-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
5- (4-phenoxyphenyl) -7- (2-phenyl-1,3-dioxan-5-yl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentanol
4- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] cyclopentane-1,2,3-triol
7-cyclopentyl-5- (2-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
7-cyclopentyl-5- (3-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
2- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] propane-1,3-diol
3- [4-amino-5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-7-yl] propane-1,2-diol
N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] benzamide
N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-hydroxyphenyl] benzamide
N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] benzenesulfonamide
N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-hydroxyphenyl] benzenesulfonamide
N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-hydroxyphenyl] -4-tert-butylbenzenesulfonamide
7-cyclopentyl-5- [4- (2-methoxy) phenoxyphenyl] pyrrolo [2,3-d] pyrimidin-4-ylamine
2- [4- (4-amino-7-cyclopentyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] phenol
7-isopropyl-5- [4- (3-methoxy-4-nitrophenoxy) phenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
Methyl 4- [4- (4-amino-7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -3-nitrobenzoate
4- [4- (4-amino-7H-pyrrolo [2,3-d] -pyrimidin-5-yl) phenoxy] phenol
N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-methoxyphenyl] -4-tert-butylbenzenesulfonamide
7-cyclopentyl-5- [4- (2-methoxy) phenoxyphenyl] -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
N- [4- (4-amino-7-cyclopentyl-7 H-pyrrolo [2,3-d] pyrimidin-5-yl) -2-hydroxyphenyl] -4-chlorobenzeneamide
5- (4-phenoxyphenyl) -7H-pyrrolo [2,3-d] pyrimidin-4-ylamine
5- [4- (5-chloro-2-nitrophenoxy) phenyl] -7-isopropyl-7H-pyrrolo [2,3-d] pyrimidin-4-ylamine and
N- {2- [4- (4-amino-7H-pyrrolo [2,3-d] pyrimidin-5-yl) phenoxy] -5-nitrophenyl} -2,2-dimethylpropionamide and its Pharmaceutically acceptable salts.
[25" claim-type="Currently amended] A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a salt thereof according to any one of claims 1 to 24 together with a pharmaceutically acceptable diluent or carrier.
[26" claim-type="Currently amended] A method of treating proliferative disease and / or immune system disease comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula (I) according to any one of claims 1 to 24.
[27" claim-type="Currently amended] The compound of formula I according to any one of claims 1 to 24 for use as a medicament.
[28" claim-type="Currently amended] The compound of formula I according to any one of claims 1 to 24 for use in the treatment of malignant and neoplastic proliferative diseases and immune system diseases.
[29" claim-type="Currently amended] The use according to any one of claims 1 to 24 in the manufacture of a medicament for the treatment of proliferative disease and / or immune system disease.
[30" claim-type="Currently amended] a) the compound of formula II is condensed with formamide in the temperature range of 50 to 250 ° C., optionally in the presence of a catalyst, or
b) reacting a compound of formula (V) with an ammonia or ammonium salt in a temperature range of 15 to 250 ° C., or
c) reacting a compound of formula VIII with a compound of formula R ₅ OH to obtain a compound of formula I wherein R ₃ represents AR ₅ , wherein A represents O, or
d) a compound of formula (IX) comprising the process of reacting a compound of formula (IX) with a compound of formula (R ₅ X in which X represents halo) to obtain a compound of formula (I) in which R ₃ represents AR ₅ , wherein A represents O Process for the preparation of the compound.
<Formula II>

<Formula V>

<Formula VIII>

<Formula IX>

Wherein R ₁ , R ₂ and R ₃ are the same as defined above, Y represents a leaving group and X is halo.

类似技术:

---

公开号 | 公开日 | 专利标题

---

US9662335B2|2017-05-30|Heteroaryl substituted pyrrolo[2,3-B] pyridines and pyrrolo[2,3-B] pyrimidines as janus kinase inhibitors

---

US9556187B2|2017-01-31|Substituted pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidines and JAK inhibitors comprising the same

---

EP2900669B1|2019-09-04|Hexahydropyrrolo[3,4-c]pyrrole derivatives and related compounds as autotaxin | inhibitors and as inhibitors of the lysophosphatidic acid | production for treating e.g. renal diseases

---

KR101994381B1|2019-06-28|Kinase inhibitors

---

US8686005B2|2014-04-01|Tricyclic compound derivatives useful in the treatment of neoplastic diseases, inflammatory disorders and immunomodulatory disorders

---

TWI531572B|2016-05-01|Piperidin-4-yl azetidine derivatives as jak1 inhibitors

---

JP5524171B2|2014-06-18|Kinase inhibitor

---

EP2694509B1|2016-05-18|Pyrrolo[2,3-d]pyrimidine derivatives as inhibitors of tropomyosin-related kinases

---

ES2601226T3|2017-02-14|Imidazole derivatives as IDO inhibitors

---

US9371328B2|2016-06-21|Imidazopyridazinecarbonitriles useful as kinase inhibitors

---

JP5917544B2|2016-05-18|Heterocyclic substituted pyrrolopyridines and pyrrolopyrimidines as JAK inhibitors

---

US8143251B2|2012-03-27|Triazolotriazines as kinase inhibitors

---

RU2536584C2|2014-12-27|Heteroaryl compounds and using them

---

US6387919B1|2002-05-14|Substituted oxindole derivatives as protein tyrosine kinase and as protein serine/threonine kinase inhibitors

---

DE60225563T2|2009-03-26|4-amino-6-phenyl-pyrroloe2,3-dipridine derivatives

---

US6583154B1|2003-06-24|Compounds and methods which modulate feeding behavior and related diseases

---

ES2208397T3|2004-06-16|Imidazo derivatives | piridine and pirazolo | pyridine.

---

US7157460B2|2007-01-02|Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhibitors

---

AU2003276125B2|2007-05-17|Chemical process

---

Norman et al.2000|Structure− activity relationships of a series of pyrrolo [3, 2-d] pyrimidine derivatives and related compounds as neuropeptide Y5 receptor antagonists

---

JP4757491B2|2011-08-24|Phenyl-substituted pyrazolopyrimidines

---

TWI343383B|2011-06-11|Pyrazole derivatives and uses thereof

---

TWI429432B|2014-03-11|Imidazotriazines and imidazopyrimidines as kinase inhibitors

---

EP1343782B1|2009-05-06|Pyrimidineamines as angiogenesis modulators

---

US9371319B2|2016-06-21|Pyrrolopyridineamino derivatives as MPS1 inhibitors

同族专利:

---

公开号 | 公开日

---

US6001839A|1999-12-14|

---

BG64282B1|2004-08-31|

---

CN1259950A|2000-07-12|

---

PT970084E|2003-10-31|

---

SK125999A3|2000-05-16|

---

DE69815317T2|2005-04-07|

---

EP0970084A1|2000-01-12|

---

AU6829398A|1998-10-12|

---

WO1998041525A1|1998-09-24|

---

NO313962B1|2003-01-06|

---

EP0970084B1|2003-06-04|

---

IL131582D0|2001-01-28|

---

JP2001516353A|2001-09-25|

---

NZ337529A|2000-10-27|

---

NO994509D0|1999-09-17|

---

CN1134439C|2004-01-14|

---

PL335685A1|2000-05-08|

---

CA2283961A1|1998-09-24|

---

BG103785A|2000-06-30|

---

NO994509L|1999-09-17|

---

DE69815317D1|2003-07-10|

---

AU748884B2|2002-06-13|

---

TR199902301T2|1999-12-21|

---

DK970084T3|

---

BR9808281A|2000-05-16|

---

AT242245T|2003-06-15|

---

ID24653A|2000-07-27|

---

HU0001507A2|2000-10-28|

---

DK0970084T3|2003-09-29|

---

ES2202827T3|2004-04-01|

---

HU0001507A3|2002-01-28|

引用文献:

---

公开号 | 申请日 | 公开日 | 申请人 | 专利标题

---

法律状态:
1997-03-19|Priority to US4083697P

---

1997-03-19|Priority to US60/040,836

---

1998-03-09|Application filed by 스타르크, 카르크, 바스프 악티엔게젤샤프트

---

2000-12-26|Publication of KR20000076426A

优先权:

---

申请号 | 申请日 | 专利标题

---

US4083697P| true| 1997-03-19|1997-03-19|

---

US60/040,836|1997-03-19|