HK1147745A

HK1147745A - Cgrp antagonists

Info

Publication number: HK1147745A
Application number: HK11101805.0A
Authority: HK
Inventors: Dirk Gottschling; Georg Dahmann; Henri Doods; Annekatrin Heimann; Stephan Georg Mueller; Klaus Rudolf; Gerhard Schaenzle; Dirk Stenkamp
Original assignee: 贝林格尔‧英格海姆国际有限公司
Priority date: 2007-10-18
Filing date: 2008-10-16
Publication date: 2011-08-19

Description

CGRP antagonists

The invention relates to novel CGRP antagonists of general formula (I), wherein U, V, X, Y, R¹、R²And R³As defined below;

their tautomers, isomers, diastereomers, enantiomers, hydrates, mixtures thereof and their salts, as well as hydrates of said salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, the use thereof and processes for the production thereof.

Detailed Description

In a first embodiment, in the above general formula I

R¹A group of the formula IIa or IIb

And is

R²Represents H or C_1-3-alkyl, or

R¹And R²Together with the nitrogen atom to which it is bonded represent a group of the formula IIIa or IIIb

G represents C-R^1.1Or the number of N is greater than the number of N,

t represents N-R^1.2Or an oxygen-containing gas,

R^1.1independently of each other represent

(a)H，

(b) Halogen, C_1-3-alkyl, -OH, -CN, -O-C_1-3-alkyl, -C (O) -O-C_1-3Alkyl radical, C_2-4-alkenyl, -C_2-4-alkynyl, C_1-3-alkyl-S, cyclopropyl, -NH₂、-COOH、-NH-C(O)-O-C_1-3-alkyl, -NH-C (O) -C_1-3-an alkyl group,

(c)C_1-3-alkyl or C_1-3-an alkyl-O-group wherein each methylene group is substituted by up to 2 fluorine atoms and each methyl group is substituted by up to 3 fluorine atoms,

R^1.2independently of each other represent

(a) H or

(b)C_1-3-an alkyl group,

R^1.3to represent

(a)H，

(b)F、-CN、C_1-3-alkyl, -CO₂-R^1.3.1Or

(c)C_1-3-an alkyl group, wherein each methylene group may be substituted by up to 2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine atoms,

R^1.3.1to represent

(a)H，

(b)C_1-6An alkyl group, a carboxyl group,

R³represents a quilt group R^3.1、R^3.2And R^3.3A substituted 6-or 10-membered aryl group, or

Represents a radical R bound via a carbon atom^3.1、R^3.2And R^3.3A substituted 6-membered heteroaryl group, a substituted heteroaryl group,

R^3.1to represent

(a)H，

(b) Halogen, -NH₂、C_1-4-alkyl-NH, (C)_1-4-alkyl groups)₂N、C_1-3alkyl-C (O) -NH, C_1-3-alkyl-S (O)₂)-NH、-CN、-OH、-O-C(O)-NH-C_1-3-an alkyl group,

(c)C_1-4-alkyl, R^3.1.1-C_1-3Alkylene radical, C_2-4-alkenyl, C_2-4-alkynyl, C_1-3-alkyl-O, C_1-3alkyl-S (O)_mA cyclopropyl group,

(d)C_1-3-alkyl or C_1-3-an alkyl-O-group wherein each methylene group is substituted by up to 2 fluorine atoms and each methyl group is substituted by up to 3 fluorine atoms,

(e)-C(O)-R^3.1.2，

(f)-S(O)₂-R^3.1.3，

R^3.1.1to represent

(a)H，

(b)C_3-6Cycloalkyl radical, C_5-6A cycloalkenyl group, a cycloalkyl group,

(c)(R^3.1.1.1)₂N，

(d) at the nitrogen atom by a group R^3.1.1.1Substituted and by one or two radicals R at carbon atoms^3.1.1.2A substituted saturated, monounsaturated or diunsaturated 5-or 6-membered heterocyclic group, or

(e) At carbon atom by a group R^3.1.1.2(ii) a substituted heteroaryl group, wherein,

R^3.1.1.1independently of each other represent

(a)H、C_1-4Alkyl radical, C_3-6A cycloalkyl group,

(b) a heterocyclic group,

(c) aryl-C_0-3Alkylene or heteroaryl-C_0-3-an alkylene group,

R^3.1.1.2independently of each other represent

(a)H、F、C_1-3-alkyl, -CN, -OH, -O-C_1-3Alkyl, -CO (O) R^3.1.1.2.1、H₂N、(C_1-4Alkyl) -NH, (C)_1-4-alkyl groups)₂N，

(b) Phenyl or phenyl-CH₂，

(c)C_1-3-alkyl or-O-C_1-3-alkyl, wherein each methylene group is substituted by up to 2 fluorine atoms and each methyl group is substituted by up to 3 fluorine atoms, or

R^3.1.1.2.1Representation H, C_1-6An alkyl group, a benzyl group,

R^3.1.2represents-O-C_1-3-alkyl, -OH, -NR^3.1.2.1R^3.1.2.2，

R^3.1.2.1Representation H, C_1-3-an alkyl group,

R^3.1.2.2representation H, C_1-3-an alkyl group,

R^3.1.2.1and R^3.1.2.2Together may also form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl,

R^3.1.3represents-O-C_1-3-alkyl, -NR^3.1.3.1R^3.1.3.2，

R^3.1.3.1Representation H, C_1-3-an alkyl group,

R^3.1.3.2representation H, C_1-3-an alkyl group,

R^3.1.3.1and R^3.1.3.2Together may also form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl,

R^3.2to represent

(a)H，

(c)C_1-4alkyl radical, C_2-4-alkenyl, C_2-4-alkynyl, C_1-3-alkyl-O, C_1-3alkyl-S (O)_mA cyclopropyl group,

(e)-C(O)-R^3.2.1，

(f)-S(O)₂-R^3.2.2，

R^3.2.1represents-O-C_1-3-alkyl, -OH, -NR^3.2.1.1R^3.2.1.2，

R^3.2.1.1Representation H, C_1-3-an alkyl group,

R^3.2.1.2representation H, C_1-3-an alkyl group,

R^3.2.1.1and R^3.2.1.2Together may also form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl,

R^3.2.2represents-NR^3.2.2.1R^3.2.2.2，

R^3.2.2.1Representation H, C_1-3-an alkyl group,

R^3.2.2.2representation H, C_1-3-an alkyl group,

R^3.2.2.1and R^3.2.2.2Together may also form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl,

R^3.3to represent

(a)H，

(e)-C(O)-R^3.3.1，

(f)-S(O)₂-R^3.3.2，

R^3.3.1represents-O-C_1-3-alkyl, -OH, -NR^3.3.1.1R^3.3.1.2，

R^3.3.1.1Representation H, C_1-3-an alkyl group,

R^3.3.1.2representation H, C_1-3-an alkyl group,

R^3.3.1.1and R^3.3.1.2Together may also form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl,

R^3.3.2represents-O-C_1-3-alkyl, -NR^3.3.2.1R^3.3.2.2，

R^3.3.2.1Representation H, C_1-3-an alkyl group,

R^3.3.2.2representation H, C_1-3-an alkyl group,

R^3.3.2.1and R^3.3.2.2Together may also form a ring selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, or

R^3.2And R^3.3Together with the carbon atom to which they are bonded form a monounsaturated 5-membered or monounsaturated or diunsaturated 6-membered heterocyclic group or a 5-to 6-membered heteroaryl group, wherein

The heterocyclic ring mentioned previously may contain a carbonyl, thiocarbonyl or cyanoimino group adjacent to the nitrogen atom, and

in each case optionally additionally at one or two nitrogen atoms by a radical R^3.3.3Is substituted, and

in each case optionally additionally at one or two carbon atoms by one or two radicals R^3.3.4The substitution is carried out by the following steps,

R^3.3.3independently of each other represent

(a)C_1-4-alkyl, or

(b)C_3-6A cycloalkyl group,

R^3.3.4independently of each other represent

(a)C_1-4-alkyl, or

(b)C_3-6A cycloalkyl group,

(c) halogen, CN, -O-C_1-3-alkyl, -NH₂，

u represents N, N-oxide or C-R⁴，

V represents N, N-oxide or C-R⁵，

X represents N, N-oxide or CR⁶，

Y represents N or C-R⁷，

And at most three of the previously mentioned groups U, V, X or Y simultaneously represent a nitrogen atom,

R⁴to represent

(a)H，

(b)C_1-6Alkyl or C_1-3An alkyl-O-group, in each case substituted by a radical R^4.1The substitution is carried out by the following steps,

(c)R^4.2R^4.3N、R^4.2R^4.3N-C_1-3an alkylene group or a substituted alkylene group,

(d) halogen, -CN, -OH, -COOH, C_1-3-alkyl-O, C_1-3-alkyl-O-C_1-3Alkylene radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene radical, C_1-3-alkyl-C (O) -O-C_1-3An alkylene group or a substituted alkylene group,

(e)C_1-3-alkyl or C_1-3-an alkyl-O-group wherein each methylene group is substituted by up to 2 fluorine atoms and each methyl group is substituted by up to 3 fluorine atoms,

R^4.1represents H, OH or-O-CH₃，

R^4.2Represents H or C_1-3-an alkyl group,

R^4.3represents H or C_1-3-alkyl, or

R^4.2And R^4.3Together with the nitrogen atom to which they are bound represent a 3-to 6-membered heterocyclic group,

R⁵to represent

(a)H，

(b)C_1-6Alkyl or C_1-3An alkyl-O-group, in each case substituted by a radical R^5.1The substitution is carried out by the following steps,

(c)-NR^5.2R^5.3、NR^5.2R^5.3-C_1-3an alkylene group or a substituted alkylene group,

(d) halogen, -CN, -OH, C_1-3-alkyl-O-C_1-3Alkylene radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene radical, C_1-3-alkyl-C (O) -O-C_1-3An alkylene group or a substituted alkylene group,

(e) aryl-C_0-3-an alkylene-O-group,

(f)C_1-3-alkyl or C_1-3-an alkyl-O-group wherein each methylene group is substituted by up to 2 fluorine atoms and each methyl group is substituted by up to 3 fluorine atoms,

R^5.1represents H, OH or-O-CH₃，

R^5.2Represents H or C_1-6An alkyl group, a carboxyl group,

R^5.3representation H, C_1-6Alkyl or-SO₂-C_1-3-alkyl, or

R^5.2And R^5.3Together with the nitrogen atom to which they are bound represent a 3-to 6-membered heterocyclic group,

R⁶to represent

(a)H，

(b)C_1-6Alkyl or C_1-3An alkyl-O-group, in each case substituted by a radical R^6.1The substitution is carried out by the following steps,

(c)R^6.2R^6.3N、R^6.2R^6.3N-C_1-3an alkylene group or a substituted alkylene group,

R^6.1represents H, OH or-O-CH₃，

R^6.2Represents H or C_1-3-an alkyl group,

R^6.3represents H or C_1-3-alkyl, or

R^6.2And R^6.3Together with the nitrogen atom to which they are bound represent a 3-to 6-membered heterocyclic group, an

R⁷Represents H, halogen or C_1-3-an alkyl group,

their tautomers, diastereomers, enantiomers, hydrates, mixtures thereof and their salts as well as hydrates of said salts, especially their physiologically acceptable salts with inorganic or organic acids or bases.

A second embodiment of the present invention encompasses compounds of formula I as described above, wherein U, V, X, Y, R²And R³As defined above in the first embodiment, and

R¹represents a group selected from:

R^1.1to represent

(a)H，

(b) Halogen, C_1-3-alkyl, -OH, -CN, -O-C_1-3-alkyl, -C (O) -O-C_1-3Alkyl radical, C_2-4-alkenyl, C_2-4-alkynyl, C_1-3-alkyl-S, -NH₂，

(c)C_1-3-alkyl or C_1-3-an alkyl-O-group wherein each methylene group is substituted by up to 2 fluorine atoms and each methyl group is substituted by up to 3 fluorine atoms, and

R^1.2to represent

(a) H, or

(b)CH₃，

A third embodiment of the present invention includes compounds of formula I as described above, wherein U, V, X, Y and R³As defined above in the first embodiment, and

R¹and R²Together with the nitrogen atom to which it is bound, represents a group selected from:

and is

R^1.1To represent

(a)H，

A fourth embodiment of the present invention includes compounds of formula I as described above, wherein U, V, X, Y, R²And R³As defined above in the first embodiment, and

R¹represents a group selected from:

and is

R^1.1To represent

(a)F、CH₃、-OH、-O-CH₃Or is or

(b)CF₃，

A fifth embodiment of the present invention includes compounds of formula I as described above, wherein U, V, X, Y and R³As defined above in the first embodiment, and

R^1.1to represent

(a)F、CH₃、-OH、-O-CH₃Or CF₃，

A sixth embodiment of the present invention includes compounds of formula I as described above, wherein U, V, X, Y, R²And R³As defined above in the first embodiment, and

R¹represents a group selected from:

A seventh embodiment of the present invention includes compounds of formula I as described above, wherein U, V, X, Y and R³As defined above in the first embodiment, and

An eighth embodiment of the present invention includes compounds of formula I as described above, wherein U, V, X, Y, R¹And R²As defined above in the first, second, fourth or sixth embodiments, and

R³a group of the formula IV

A independently of one another represents C-H, C-F or N,

R^3.1to represent

(a)H，

(b) Halogen, -NH₂、C_1-4-alkyl-NH, (C)_1-4-alkyl groups)₂N、C_1-3alkyl-C (O) -NH, C_1-3alkyl-S (O)₂-NH、-CN、-OH、-O-C(O)-NH-C_1-3-an alkyl group,

(c)C_1-4-alkyl, R^3.1.1-C_1-3Alkylene radical, C_2-4-alkenyl, C_2-4-alkynyl, C_1-3-alkyl-O, C_1-3-an alkyl-S group,

(e)-C(O)-R^3.1.2，

(f)-S(O)₂-R^3.1.3，

R^3.1.1to represent

(a)H，

(b)C_3-6Cycloalkyl radical, C_5-6A cycloalkenyl group, a cycloalkyl group,

(c)(R^3.1.1.1)₂N，

R^3.1.1.1independently of each other represent

(a)H、C_1-4Alkyl radical, C_3-6A cycloalkyl group,

(b) a heterocyclic group,

(c) aryl-C_0-3Alkylene or heteroaryl-C_0-3-an alkylene group,

R^3.1.1.2independently of each other represent

(a)H、F、C_1-3-alkyl, -CN, -OH, -O-C_1-3Alkyl, -CO (O) R^3.1.1.2.1、H₂N、(C_1-4-alkyl) -NH, (C)_1-4-alkyl groups)₂N，

(b) Phenyl or phenyl-CH₂，

R^3.1.1.2.1Representation H, C_1-6An alkyl group, a benzyl group,

R^3.1.2represents-O-C_1-3-alkyl, -OH, -NR^3.1.2.1R^3.1.2.2，

R^3.1.2.1Representation H, C_1-3-an alkyl group,

R^3.1.2.2representation H, C_1-3-an alkyl group,

R^3.1.3represents-NR^3.1.3.1R^3.1.3.2，

R^3.1.3.1Representation H, C_1-3-an alkyl group,

R^3.1.3.2representation H, C_1-3-an alkyl group,

R^3.2to represent

(a)H，

(c)C_1-4alkyl radical, C_2-4-alkenyl, C_2-4-alkynyl, C_1-3-alkyl-O, C_1-3-an alkyl-S group,

(e)-C(O)-R^3.2.1，

(f)-S(O)₂-R^3.2.2，

R^3.2.1represents-O-C_1-3-alkyl, -OH, -NR^3.2.1.1R^3.2.1.2，

R^3.2.1.1Representation H, C_1-3-an alkyl group,

R^3.2.1.2representation H, C_1-3-an alkyl group,

R^3.2.2represents-NR^3.2.2.1R^3.2.2.2，

R^3.2.2.1Representation H, C_1-3-an alkyl group,

R^3.2.2.2representation H, C_1-3-an alkyl group,

R^3.3to represent

(a)H，

(e)-C(O)-R^3.3.1，

(f)-S(O)₂-R^3.3.2，

R^3.3.1represents-O-C_1-3-alkyl, -OH, -NR^3.3.1.1R^3.3.1.2，

R^3.3.1.1To representH、C_1-3-an alkyl group,

R^3.3.1.2representation H, C_1-3-an alkyl group,

R^3.3.2represents-O-C_1-3-alkyl, -NR^3.3.2.1R^3.3.2.2，

R^3.3.2.1Representation H, C_1-3-an alkyl group,

R^3.3.2.2representation H, C_1-3-alkyl, or

in each case optionally additionally at one or two carbon atoms by one or two radicals R^3.3.4 of the amino acid sequence is substituted by 4,

R^3.3.3independently of each other represent

(a)C_1-4-alkyl, or

(b)C_3-6A cycloalkyl group,

R^3.3.4independently of each other represent

(a)C_1-4Alkyl radical, C_3-6A cycloalkyl group,

(b) halogen, CN, C_1-3-alkyl-O-, -NH₂，

A ninth embodiment of the present invention includes compounds of formula I as described above, wherein U, V, X, Y, R¹And R²As defined above in the first, second, fourth or sixth embodiments, and

R³a group of the formula IV

A independently of one another represents C-H, C-F or N,

R^3.1to represent

(a)H，

(b) Halogen, -NH₂、C_1-4-alkyl-NH, (C)_1-4-alkyl groups)₂N、C_1-3-alkyl-C (O) -NH, -CN, -OH, -O-C (O) -NH-C_1-3-an alkyl group,

R^3.2to represent

(a)H，

R^3.3to represent

(a)H，

R^3.3.3independently of each other represent

(a)C_1-4-alkyl, or

(b)C_3-6A cycloalkyl group,

R^3.3.4independently of each other represent

(a)C_1-4Alkyl radical, C_3-6A cycloalkyl group,

(b) halogen, CN, C_1-3-alkyl-O-, -NH₂，

A tenth embodiment of the present invention includes compounds of formula I as described above, wherein U, V, X, Y, R¹And R²As defined above in the first, second, fourth or sixth embodiments, and

R³a group of the formula IVa

R^3.1To represent

(a)H，

(b)F、Cl、Br、-NH₂、C_1-3-alkyl-NH, (C)_1-3-alkyl groups)₂N、C_1-3-alkyl-C (O) -NH, -CN, -OH,

R^3.2to represent

(a)H，

(b)F、Cl、Br、H₂N、(C_1-4-alkyl) -NH, (C)_1-4-alkyl groups)₂N、(C_1-3-alkyl) -C (O) -NH, -OH,

(c)C_1-4-an alkyl group,

R^3.3to represent

(a)H，

(c)C_1-4-an alkyl group,

R^3.3.3independently of each other represent

(a)C_1-4-alkyl, or

(b)C_3-6A cycloalkyl group,

R^3.3.4independently of each other represent

(a)C_1-4Alkyl radical, C_3-6A cycloalkyl group,

(b) halogen, CN, C_1-3-alkyl-O-, -NH₂，

R^3.4represents a group of a compound represented by the formula H or F,

An eleventh embodiment of the present invention includes the compounds of formula I above wherein U, V, X, Y, R¹And R²As defined above in the first, second, fourth or sixth embodiments, and

R³represents a group selected from:

A twelfth embodiment of the present invention includes compounds of formula I as described above, wherein U, V, X, Y, R¹And R²As defined above in the first, second, third, fourth, fifth, sixth or seventh implementations, and

R³a group of the formula IVb

R^3.1To represent

(a)H，

The heterocyclic ring mentioned previously containing a carbonyl, thiocarbonyl or cyanoimino group adjacent to the nitrogen atom, and

in each case optionally additionally substituted at one or two nitrogen atoms by a radical R^3.3.3Is substituted, and

can eachOptionally additionally substituted at one or two carbon atoms by one or two radicals R^3.3.4The substitution is carried out by the following steps,

R^3.3.3independently of each other represent

(a)C_1-4-alkyl, or

(b)C_3-6Cycloalkyl radicals, and

R^3.3.4independently of each other represent

(a)C_1-4Alkyl radical, C_3-6A cycloalkyl group,

(b) halogen, -CN, -O-C_1-3-alkyl, -NH₂，

A thirteenth embodiment of the present invention includes compounds of formula I as described above, wherein U, V, X, Y, R¹And R²As defined above in the first, second, third, fourth, fifth, sixth or seventh implementations, and

R³a group of the formula IVb

R^3.1To represent

(a)H，

(b)F、Cl、Br、-NH₂、C_1-3-alkyl-NH, (C)_1-3-alkanesBase)₂N、C_1-3-alkyl-C (O) -NH, -CN, -OH,

R^3.2and R^3.3Together with the carbon atom to which they are bonded form a monounsaturated 5-membered heterocyclic group or a 5-membered heteroaryl group, in which

may each optionally be additionally substituted at one or two nitrogen atoms by a group R^3.3.3Is substituted, and

may each be optionally substituted at one or two carbon atoms by one or two radicals R^3.3.4The substitution is carried out by the following steps,

R^3.3.3independently of each other represent

(a)C_1-4-alkyl, or

(b)C_3-6Cycloalkyl radicals, and

R^3.3.4independently of each other represent

(a)C_1-4Alkyl radical, C_3-6A cycloalkyl group,

(b) halogen, -CN, -O-C_1-3-alkyl, -NH₂，

A fourteenth embodiment of the present invention includes the compounds of formula I, described above, wherein U, V, X, Y, R¹And R²As defined above in the first, second, third, fourth, fifth, sixth or seventh implementations, and

R³a group of the formula IVc

T denotes O, S, CH₂NH or N-R^3.3.3，

R^3.1To represent

(a)H，

(d)C_1-3-alkyl or C_1-3-an alkyl-O-group wherein each methylene group is substituted by up to 2 fluorine atoms and each methyl group is substituted by up to 3 fluorine atoms, and

R^3.3.3independently of each other represent

(a)C_1-4-alkyl, or

(b)C_3-6A cycloalkyl group,

A fifteenth embodiment of the present invention includes the compounds of formula I as described above, wherein U, V, X, Y, R¹And R²As defined above in the first, second, third, fourth, fifth, sixth or seventh implementations, and

R³represents a group selected from:

A sixteenth embodiment of the present invention includes compounds of formula I as described above, wherein Y, R¹、R²And R³As defined above in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiments, and

U-V-X represents a group selected from:

-N＝N-(C-R⁶)＝、-N＝(C-R⁵)-N＝、-N＝(C-R⁵)-(C-R⁶) - (N-oxide) ═ C-R⁵)-(CR⁶)＝、-(CR⁴)＝N-N＝、-(CR⁴)＝N-(CR⁶)＝、-(C-R⁴) N- (oxide) - (C-R)⁶)＝、-(CR⁴)＝(C-R⁵)-N＝、-(CR⁴)＝(C-R⁵) - (N-oxide) - (CR)⁴)＝(C-R⁵)-(CR⁶) Is equal to, and

R⁴to represent

(a)H，

R^4.1represents H, OH or-O-CH₃，

R^4.2Represents H or C_1-3-an alkyl group,

R^4.3represents H or C_1-3-alkyl, or

R⁵to represent

(a)H，

(d) halogen, -CN, -OH, C_1-3-alkyl-O-C_1-3Alkylene radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkylene radical, C_1-3-alkyl-C(O)-O-C_1-3An alkylene group or a substituted alkylene group,

(e) aryl-C_0-3-an alkylene-O-group,

R^5.1represents H, OH or-O-CH₃，

R^5.2Represents H or C_1-6An alkyl group, a carboxyl group,

R^5.3representation H, C_1-6Alkyl or-SO₂-C_1-3-an alkyl group,

R⁶to represent

(a)H，

R^6.1represents H, OH or-O-CH₃，

R^6.2Represents H or C_1-3-an alkyl group,

R^6.3represents H or C_1-3-alkyl, or

R^6.2And R^6.3Together with the nitrogen atom to which they are bound represent a 3-to 6-membered heterocyclic group,

A seventeenth embodiment of the present invention includes compounds of formula I as described above, wherein Y, R¹、R²And R³As defined above in the first, second, third, fourth, fifth, sixth, seventh, eighth, ninth, tenth, eleventh, twelfth, thirteenth, fourteenth or fifteenth embodiments, and

ring (C)Represents a group selected from:

An eighteenth embodiment of the present invention includes compounds of formula I above wherein

R¹Represents a group selected from:

R²the expression "H" is used to indicate the formula,

R³represents a group selected from:

ring (C)Represents a group selected from:

A nineteenth embodiment of the present invention includes compounds of formula I as described above, wherein

R³represents a group selected from:

and a ringRepresents a group selected from:

The following compounds are mentioned as examples of the most particularly preferred compounds of the above general formula I:

their enantiomers, diastereomers, hydrates, mixtures thereof and salts thereof, as well as hydrates of said salts, especially their physiologically acceptable salts with inorganic or organic acids or bases.

Terms and definitions used

The description of the present invention is explained in terms of conventions and rules for chemical bonds.

The compounds included in the present invention are those that are chemically stable.

Unless otherwise indicated, all substituents are independent of each other. If, for example, there are a plurality of C's in a group_1-4Alkyl as a substituent at 3C_1-4In the case of alkyl substituents, then, independently of one another, one may represent methyl, one ethyl and one n-propyl.

Within the scope of the present application, in the definition of possible substituents, these substituents can also be represented in the form of structural formulae. An asterisk (—) in a substituent formula, if present, should be understood as a point of attachment to the rest of the molecule. By way of example, the phenyl group is shown below:

further, the atom of the substituent subsequent to the point of attachment is regarded as the atom at the number 1 position.

The subject matter of the invention also includes the compounds of the invention (including salts thereof) in which one or more hydrogen atoms (e.g. 1, 2, 3, 4 or 5 hydrogen atoms) are replaced by deuterium.

The term "C_1-3Alkyl "(including those C as part of other groups)_1-3-alkyl) refers to branched and straight-chain alkyl groups having 1 to 3 carbon atoms, the term "C_1-4-alkyl "refers to branched and straight-chain alkyl groups having 1 to 4 carbon atoms, and the term" C_1-6Alkyl "refers to branched and straight chain alkyl groups having 1 to 6 carbon atoms. Fruit of Chinese wolfberryExamples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, neopentyl or n-hexyl. The abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may also be optionally used for the above-mentioned groups. Unless otherwise indicated, the definitions propyl and butyl include all possible isomeric forms of the groups. Thus, for example, propyl includes n-propyl and isopropyl, and butyl includes isobutyl, sec-butyl, tert-butyl, and the like.

The term "C_1-6Alkylene "(including those C as part of other groups)_1-6Alkylene) refers to branched and straight chain alkylene groups having 1 to 6 carbon atoms, and the term "C_1-3By alkylene is meant both branched and straight chain alkylene groups having from 1 to 3 carbon atoms. Examples include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1-dimethylethylene, 1, 2-dimethylethylene, pentylene, 1-dimethylpropylene, 2-dimethylpropylene, 1, 3-dimethylpropylene or hexylene. Unless otherwise indicated, the definition propylene includes all possible isomeric forms of the groups having the same carbon number. Thus, for example, propylene also includes 1-methylethylene and butylene includes 1-methylpropylene, 1-dimethylethylene, 1, 2-dimethylethylene.

C₀The definition of alkylene represents a chemical bond.

The term "C_2-6Alkenyl "(including those C as part of other groups)_2-6-alkenyl) means branched and straight-chain alkenyl groups having 2 to 6 carbon atoms, the term "C_2-4-alkenyl "means branched and straight chain alkenyl groups having 2 to 4 carbon atoms, provided that they contain at least one double bond. Alkenyl groups having 2 to 4 carbon atoms are preferred. Examples include: vinyl (ethenyl or vinyl), propenyl, butenyl, pentenyl or hexenyl. Unless otherwise indicated, the definitions propenyl, butenyl, pentenyl and hexenyl include all possible isomeric forms of the groups described. Thus, for exampleThe propenyl group includes 1-propenyl group and 2-propenyl group, and the butenyl group includes 1-butenyl group, 2-butenyl group and 3-butenyl group, 1-methyl-1-propenyl group, 1-methyl-2-propenyl group and the like.

The term "C_2-6Alkynyl "(including those C as part of other groups)_2-6-alkynyl) means branched and straight chain alkynyl groups having 2 to 6 carbon atoms, the term "C_2-4-alkynyl "means branched and straight chain alkynyl groups having 2 to 4 carbon atoms, provided that they contain at least one triple bond. Examples include: ethynyl, propynyl, butynyl, pentynyl or hexynyl. Unless otherwise indicated, the definitions propynyl, butynyl, pentynyl and hexynyl include all possible isomeric forms of the radicals in question. Thus, for example, propynyl includes 1-propynyl and 2-propynyl, butynyl includes 1-butynyl, 2-butynyl and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl and the like.

The term "C_3-6Cycloalkyl "(including those C as part of other groups)_3-6Cycloalkyl) refers to a cyclic alkyl group having 3 to 6 carbon atoms, and the term "C_5-6Cycloalkyl "refers to a cyclic alkyl group having 5 to 6 carbon atoms. Examples include: cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Unless otherwise specified, the cyclic alkyl group may be substituted with one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluoro, chloro, bromo, and iodo.

The term "C_5-6Cycloalkenyl "(including those C as part of other groups)_5-6Cycloalkenyl) means a cyclic alkenyl group having 5 or 6 carbon atoms, which contains an unsaturated bond. Examples include: cyclopentenyl or cyclohexenyl. Unless otherwise specified, a cyclic alkenyl group may be substituted with one or more groups selected from methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluoro, chloro, bromo, and iodo.

Unless otherwise described in the definitions, the term "heterocyclyl" or "heterocyclic group" refers to a stable 5-, 6-or 7-membered monocyclic heterocyclic ring system or an 8-, 9-, 10-or 11-membered bicyclic heterocyclic ring system which does not form an aromatic ring system in at least one ring and which may carry, in addition to carbon atoms, from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. Both the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may be quaternized. The heterocyclic ring may contain one or two carbonyl, thiocarbonyl or cyanoimino groups adjacent to the nitrogen atom. The heterocyclic ring mentioned previously may be attached to the rest of the molecule through a carbon or nitrogen atom.

Unless otherwise indicated, the heterocycle may be substituted with one or more groups selected from:

(a)OH、NO₂、CN、OCF₃、OCHF₂、OCH₂F、NH₂，

(b) the halogen, preferably fluorine or chlorine,

(c)C_1-6alkyl, preferably C_1-3Alkyl, particularly preferably ethyl, methyl, isopropyl or tert-butyl,

(d)-SO₂-O-C_1-3-alkyl, preferably-O-methyl,

(e)-O-C_1-3-alkyl, preferably-O-methyl or-O-ethyl,

(f)COOH、COO-C_1-3alkyl, preferably CO-O-methyl or CO-O-ethyl,

and the groups may be the same or different.

The following compounds are mentioned by way of example, but the invention is not limited to them: azetidine, oxetane, thietane dioxide (thietane dioxide), tetrahydrofuran, dihydrofuran, dioxolane, imidazolidine, imidazoline, imidazolidinone, dihydroimidazolone, oxazoline, oxazolidine, oxazolidinone, pyrroline, pyrrolidine, morpholine, tetrahydropyridine, dihydropyran, tetrahydropyran, dioxane, piperazine, piperidine, piperazinone, piperidone, pyran, thiomorpholine-S-oxide, thiomorpholine-S-dioxide, thiomorpholine, dihydrooxazine, morpholineDiketones, morpholinothiones, perhydrothiazinedioxides,Caprolactam, oxazepanone (oxazepanone), diazepanone (diazepanone), thiazepanone (thiazepanone), perhydroazepanoneDihydroquinazolinone, indoline, isoindoline, benzoxazolone, benzimidazolone, chroman-4-one (chromanone), tetrahydroquinoline, tetrahydrobenzoxazole, tetrahydrobenzisoxazole, tetrahydrobenzothiophene, tetrahydrothienopyridine, tetrahydrobenzofuran, tetrahydrooxazolopyridine, tetrahydroisoxazolopyridine.

According to the invention, the following heterocycles are preferred:

the term "aryl" (including those aryl groups that are part of other groups) refers to a monocyclic aromatic ring system having 6 carbon atoms or a bicyclic aromatic ring system having 10 carbon atoms. Examples include phenyl, 1-naphthyl or 2-naphthyl; preferably aryl is phenyl.

Unless otherwise indicated, aryl groups may be substituted by one or more groups selected from:

(a)OH、NO₂、CN、OCF₃、OCHF₂、OCH₂F、NH₂，

(b) the halogen, preferably fluorine or chlorine,

(d)-SO₂-O-C_1-3-alkyl, preferably-O-methyl,

(e)-O-C_1-3-alkyl, preferably-O-methyl or-O-ethyl,

(f)COOH、CO-O-C_1-3alkyl, preferably CO-O-methyl or CO-O-ethyl,

and the groups may be the same or different.

The term "heteroaryl" refers to a stable 5-or 6-membered heterocyclic aromatic group or an 8-to 10-membered bicyclic heteroaromatic ring which may contain 1, 2 or 3 heteroatoms selected from oxygen, sulfur and nitrogen in each ring, and additionally sufficient conjugated double bonds to form an aromatic system. Examples of 5-or 6-membered heterocyclic aromatic groups are as follows (although the invention is not limited to these heterocyclic aromatic groups):

furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, thiazole, isothiazole, isoxazole, oxadiazole, triazole, tetrazole, furazan, thiadiazole, pyridine, pyrimidine, pyrazine, pyridazine, triazine.

According to the invention, the following 5-membered heterocyclic aromatic groups are preferred:

according to the invention, the following 6-membered heterocyclic aromatic groups are preferred:

examples of 9-or 10-membered bicyclic heteroaromatic rings are as follows (although the invention is not limited to these bicyclic heteroaromatic rings):

indole, isoindole, indazole, indolizine, benzofuran, benzothiophene, benzimidazole, benzoxazole, benzothiazole, benzotriazole, benzisoxazole, benzisothiazole, quinoline, isoquinoline, cinnoline, phthalazine, quinoxaline, quinazoline, pyridopyrimidine, pyridopyrazine, pyridopyridazine, pyrimidopyrimidine, pteridine, purine, quinolizine, benzoxazole nitrile, quinoline, isoquinoline, quinolizine, pteridine, purine, quinolizine, benzoxazole nitrile.

According to the invention, the following bicyclic heteroaromatic rings are preferred:

unless otherwise indicated, the heteroaryl groups previously mentioned may be substituted by one or more groups selected from:

(a)OH、NO₂、CN、OCF₃、OCHF₂、OCH₂F、NH₂，

(b) the halogen, preferably fluorine or chlorine,

(d)-SO₂-O-C_1-3-alkyl, preferably-O-methyl,

(e)-O-C_1-3-alkyl, preferably-O-methyl or-O-ethyl,

(f)COOH、CO-O-C_1-3alkyl, preferably CO-O-methyl or CO-O-ethyl,

and the groups may be the same or different.

Bicyclic heteroaromatic rings may preferably be substituted at the phenyl group.

The term "halogen" refers to a fluorine, chlorine, bromine or iodine atom.

The compounds of the general formula I can have acidic groups (predominantly carboxyl groups) and/or basic groups (e.g.amino functions). The compounds of the general formula I can thus be present in the form of internal salts, either as salts with pharmaceutically usable inorganic acids, such as hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or as salts with organic acids, such as malic acid, succinic acid, acetic acid, fumaric acid, maleic acid, mandelic acid, lactic acid, tartaric acid, citric acid; pharmaceutically usable bases are, for example, alkali metal or alkaline earth metal hydroxides (e.g. sodium hydroxide or potassium hydroxide) or carbonates, ammonia, zinc hydroxide or ammonium hydroxide, or salts of organic amines (e.g. diethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine).

The compounds of the invention may exist as racemates, provided that they have only one chiral element, but may also be obtained as pure enantiomers (i.e. in (R) or (S) form).

The compound having a carbon-carbon double bond may exist in both forms E and Z.

The following nitrogen-containing heteroaryl groups may exist in different tautomeric forms:

this means that the compounds prepared in each case are not limited to one tautomeric form but include all tautomeric forms.

However, the present application also includes the diastereoisomeric pairs of the individual enantiomers or mixtures thereof (if obtained in the presence of more than one chiral element in the compound of formula I), as well as the individual optically active enantiomers which constitute the racemates mentioned above.

The invention relates to said compounds, optionally in the form of mixtures of individual optical isomers, individual enantiomers or racemates, in the form of tautomers and in the form of free bases or of the corresponding acid addition salts with pharmacologically acceptable acids.

The invention also encompasses so-called prodrugs of the compounds of the general formula I. The term prodrug is used to denote any molecule that releases the active ingredient of formula I in vivo upon administration to a mammal. The prodrug itself may have little or no pharmacological activity, but upon administration releases the active ingredient of formula I in vivo and this active ingredient has the activity described. Prodrugs of compounds of formula I may be prepared by modifying appropriate functional groups in compounds of formula I, as is well known to those skilled in the art (H.Bundgaard (eds.), Design of produgs. (1986), Elsevier).

The invention also includes those metabolites derived from compounds of formula I. In this context, metabolite means a compound formed in vivo from a compound of formula I after administration. Examples of metabolites include:

the methyl group of the compound of the formula I can be converted into the corresponding hydroxymethyl group (-CH)₃-＞-CH₂OH)；

-the alkoxy group of the compound of formula I can be converted into the corresponding hydroxy group (-OR- > -OH);

the conversion of secondary amines of the compounds of the formula I into the corresponding primary amines (-NR)₁R₂-＞-NHR₁or-NHR₂)；

The nitrogen atom of the compounds of the formula I can be converted into the corresponding nitroxide (═ N- - > - -) N⁺-(O^-)-)。

Preparation method

The invention also relates to a method for producing compounds of the general formula I, wherein the substituents have the previously specified meanings.

Some methods for preparing the compounds of formula I of the present invention are illustrated in the following synthesis equations and examples:

u, V, X, Y, R therein¹、R²And R³As defined above.

In some cases, the order in which the reaction equations are carried out may be changed to simplify the reaction or to prevent unwanted byproducts. The following examples are provided to facilitate understanding of the invention. These examples are intended to illustrate the invention and should not be construed as limiting the invention in any way.

In some cases, the final product may be further derivatized, for example, by utilizing substituents. Such means are generally well known to those skilled in the art, such as, but not limited to, oxidation, reduction, alkylation, acylation, and hydrolysis.

The starting compounds are prepared by methods known in the art or described herein. Before the reaction is carried out, the corresponding functional groups in the compounds can be protected by conventional protecting groups. These can be removed again at a suitable stage in the reaction sequence using methods known in the art (p.g.m.wuts, t.w.greene "Greene's Protective Groups in Organic Synthesis", fourth edition, Wiley Interscience).

The compounds of the present invention can be prepared using known and/or available starting materials, reagents and conventional synthetic methods according to the reaction equations provided and the specific examples or modifications accordingly. Variations to these reactions that are known to those skilled in the art but not described in detail herein may also be implemented.

The following processes for preparing the compounds of the general formula I according to the invention and their precursors have proven particularly suitable:

the starting compounds are commercially available or can be prepared by methods described in the literature, known to the person skilled in the art or described herein. Any corresponding functional groups in the compounds may be protected with conventional protecting groups prior to carrying out the reaction. These protecting groups may be removed again at a suitable stage in the reaction sequence using methods known in the art.

In the reactions described below, any reactive groups present, such as hydroxyl, carboxyl, amino, alkylamino, amido or imino, may be protected during the reaction by conventional protecting groups which are then removed after the reaction.

For example, in the case of

Suitable protecting groups for hydroxyl groups may be methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert-butyl, tribenzyl, benzyl or tetrahydropyranyl,

suitable protecting groups for the carboxyl group may be trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl, and

suitable protecting groups for the amido group may be N-methoxymethyl (MOM), N-Benzyloxymethyl (BOM), N- (trimethylsilyl) ethoxymethyl (SEM), N-tert-butyldimethylsilyloxymethyl, N-tert-butyldimethylsilyl (TBDMS), N-Triisopropylsilyl (TIPS), N-benzyl, N-4-methoxybenzyl (PMB), N-triphenylmethyl (Trt), N-tert-Butoxycarbonyl (BOC), N-benzyloxycarbonyl (Cbz) or N-trimethylsilylethylsulfonyl (SES),

suitable protecting groups for amino, alkylamino or imino groups can be acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2, 4-dimethoxybenzyl, and also phthaloyl for amino groups.

Other protecting groups and their removal are described in t.w.greene, p.g.m.wuts, "protective groups in Organic Synthesis", Wiley, 2006.

Any protecting groups used are optionally subsequently removed, for example by hydrolysis in an aqueous solvent, for example in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or by ether cleavage, for example in the presence of trimethyliodosilane at a temperature between 0 ℃ and 100 ℃, preferably between 10 ℃ and 50 ℃.

However, benzyl, methoxybenzyl or benzyloxycarbonyl (for example) is removed hydrogenolytically with hydrogen in the presence of a catalyst such as palladium on charcoal in e.g. methanol, ethanol, ethyl acetate, dimethylformamide/acetone or glacial acetic acid, optionally with addition of an acid such as hydrochloric acid, at a temperature between 0 ℃ and 50 ℃, but preferably at ambient temperature and at a hydrogen pressure of 1 to 7 bar, but preferably 1 to 5 bar.

The methoxybenzyl group may also be removed in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as dichloromethane, acetonitrile or acetonitrile/water at a temperature between 0 ℃ and 50 ℃, but preferably at ambient temperature.

The methoxy group is suitably decomposed in the presence of boron tribromide in a solvent such as dichloromethane at a temperature between-35 ℃ and-25 ℃.

The 2, 4-dimethoxybenzyl group is preferably decomposed in trifluoroacetic acid in the presence of anisole.

The tert-butyl or tert-butoxycarbonyl group is preferably removed by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as dichloromethane, dioxane or diethyl ether.

The phthalyl group is preferably removed in the presence of hydrazine or a primary amine (such as methylamine, ethylamine or n-butylamine) in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at a temperature between 20 ℃ and 50 ℃.

The methoxymethyl group can be removed in a solvent such as dimethoxyethane in the presence of an acid such as concentrated hydrochloric acid. Alternatively, an acid such as trifluoroacetic acid can also be used without a solvent.

The N- (trimethylsilyl) ethoxymethyl group can be removed in the presence of TBAF and 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone. Alternatively, the SEM protecting groups may also be removed with an acid such as hydrogen chloride in an organic solvent such as dioxane or ethanol.

The allyloxycarbonyl group is removed by treatment with a catalytic amount of tetrakis- (triphenylphosphine) -palladium (0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine, at a temperature between 0 ℃ and 100 ℃, preferably at ambient temperature and under an inert gas, or by treatment with a catalytic amount of tris- (triphenylphosphine) -rhodium (I) chloride at a temperature between 20 ℃ and 70 ℃ in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1, 4-diazabicyclo [2, 2, 2] octane.

the final compound of formula I (wherein U, V, X, Y, R)¹、R²And R³As defined above) can be obtained by reacting a compound of the general formula (1-1) with an electron-deficient compound of the general formula (1-2) having a leaving group LG. Halogen (preferably chlorine and bromine), -SO₂CH₃、-OSO₂CH₃、-OSO₂C₆H₄-CH₃or-S-CH₃(-S-CH₃Requiring further reaction with an organic peroxide to be converted into an actual leaving group), etc. may be used as the leaving group LG, but is not limited thereto. The use of chlorine is most particularly preferred.

Reaction equation 1:

the reaction can be carried out by nucleophilic aromatic substitution in an inert solvent using an auxiliary base at a temperature in the range of 0 ℃ to the reflux temperature of the solvent. The reaction is carried out in a suitable inert solvent such as tetrahydrofuran, toluene, xylene, dialkylformamide (particularly preferably dimethylformamide), cyclic amides (particularly preferably N-methyl-pyrrolidone), 1, 4-dioxane, acetonitrile or in a mixture of inert solvents. Suitable auxiliary bases include tertiary amines such as triethylamine or ethyldiisopropylamine, alkali metal carbonates such as potassium carbonate or sodium carbonate, sodium hydride (NaH) or Lithium Diisopropylamide (LDA). The inert solvent used must be compatible with the base used. The reaction is preferably carried out in dimethylformamide in the presence of a tertiary amine base at a temperature between ambient temperature and the reflux temperature of the solvent.

Alternatively, a structure of the general formula (1-3) (wherein U, V, X, Y, R is shown in reaction formula 1¹、R²And R³As defined above) may be synthesized by a transition metal catalyzed reaction. The compound of the general formula (1-1) can be reacted with the compound of the general formula (1-2) having a leaving group LG in an inert solvent in the presence of a catalyst and an auxiliary base. In addition, the catalyst may employ a suitable ligand. Chloride, bromide, iodide, trifluoroacetate, triflate, methanesulfonate and toluenesulfonate, but are not limited thereto. Xylene, tetrahydrofuran, dimethylformamide, dimethoxyethane, toluene, benzene, 1, 4-dioxane, acetonitrile or solvent mixtures can be used as inert solvents. The preferred solvent is xylene. Suitable bases are especially amine bases such as triethylamine or diisopropylethylamine or inorganic bases such as cesium carbonate, cesium acetate, potassium carbonate, sodium carbonate or potassium phosphate. At normal pressure, the reaction temperature is preferably from room temperature to the reflux temperature of the solvent. Typical catalysts are, for example, transition metal catalysts, such as tris (dibenzylideneacetone) -dipalladium (0), tetrakis- (triphenylphosphine) -palladium (0), palladium (II) acetate, Pd (PPH)₃)₂Cl₂、Pd(CH₃CN)₂Cl₂、Pd(dppf)Cl₂Or palladium (II) chloride type palladium catalysts. Typical ligands are, for example, triphenylphosphine, triphenylarsine, BINAP, XPhos, XantPhos or 2- (di-tert-butylphosphino) biphenyl.

The compound of the general formula (2-4) (wherein U, V, X, Y, R is shown in the reaction scheme 2) can be prepared¹、R²And R³As defined above).

Reaction equation 2:

the reaction starts from a compound of formula (2-1) wherein Hal represents a halogen atom, preferably chlorine, bromine or iodine. Grignard (Grignard) or lithiated compounds of the general formula (2-2) can be prepared from the corresponding halogenated compounds of the general formula (2-1) by so-called halogen-metal exchange or by insertion of a metal into a halogen-carbon bond. For the synthesis of the corresponding lithiated compounds of the general formula (2-2), halogen-metal exchanges can be carried out, for example, with organo-lithium compounds such as n-butyllithium, sec-butyllithium or tert-butyllithium. The corresponding magnesium compounds (grignard compounds) can also be obtained by halogen-metal exchange with or in the presence of the corresponding grignard reagent such as isopropyl or sec-butyl magnesium bromide or isopropyl or sec-butyl magnesium chloride or diisopropyl or di-sec-butyl magnesium chloride together with a salt such as lithium chloride which accelerates the metallization process. Corresponding metal-transferred organomagnesium compounds can also be synthesized in situ from the corresponding precursors (see, for example, Angew. chem.2004, 116, 3396-3399 and Angew. chem.2006, 118, 165-169 and the references contained therein). In addition, acid-based complexes of organomagnesium compounds, which result from the mixing of, for example, butylmagnesium chloride or butylmagnesium bromide or isopropylmagnesium chloride or isopropylmagnesium bromide with butyllithium, can also be used (see Angew. chem.2000, 112, 2594-. The halogen-metal exchange is preferably carried out at a temperature of between-100 ℃ and 40 ℃ (particularly preferably in the temperature range from-80 ℃ to 10 ℃), in an inert solvent, preferably an alkyl ether (particularly preferably diethyl ether), a cyclic ether (particularly preferably 1, 4-dioxane or tetrahydrofuran), toluene, hexane or a solvent mixture thereof. The magnesium or organolithium compound thus obtained can optionally be transmetalated with a metal salt such as cerium trichloride, zinc chloride or zinc bromide, indium chloride or indium bromide to synthesize alternative organometallic compounds of the general formula (2-2) which are also suitable for the reaction. Alternatively, the organometallic compound (2-2) can also be prepared by inserting a metal into a carbon-halogen bond. Lithium or magnesium are suitable elemental metals for this conversion. The insertion reaction is preferably carried out between-80 ℃ and 100 ℃ (and particularly preferably at a temperature in the range from-70 ℃ to 40 ℃), in an inert solvent, preferably an alkyl ether (particularly preferably diethyl ether), a cyclic ether (particularly preferably 1, 4-dioxane or tetrahydrofuran), toluene, hexane or a solvent mixture thereof. In cases where spontaneous reactions do not occur, it may be desirable to activate the metal with, for example, 1, 2-dibromoethane, iodine, trimethylchlorosilane, acetic acid, hydrogen chloride, or ultrasound. The reaction of the organometallic compound of the general formula (2-2) with the compound (2-3) is preferably carried out at a temperature ranging from-100 ℃ to 100 ℃, and a temperature ranging from-80 ℃ to 50 ℃ is particularly preferred. The reaction is carried out in an inert solvent such as preferably an alkyl ether (particularly preferably diethyl ether, dimethoxyethane), a cyclic ether (particularly preferably 1, 4-dioxane or tetrahydrofuran), an aromatic hydrocarbon (particularly preferably toluene or benzene), hexane or a solvent mixture thereof. All reactions can be carried out in air, but it is preferably carried out in a protective gas atmosphere such as argon or nitrogen. It has proven advantageous to temporarily protect the functional groups in the compounds (2-3).

The lithium-substituted or magnesium-substituted compound of the general formula (2-2) may be reacted with the compound of the general formula (2-3) containing a carboxyl group or a derivative thereof such as an ester, nitrile, acid chloride or amide such as grapevine amide in a desired manner. These reactions can generally be carried out without any additional transition metal catalyst or transmetallation with another metal such as cerium, indium or zinc. However, in some cases, the two mentioned variations also prove to be advantageous. Aromatic boronic acids, esters derived therefrom, dialkylarylboranes or aryltrifluoroborates can be reacted with acid chlorides or carboxylic acids in the presence of transition metals such as palladium as catalysts to give the corresponding ketones (V.Polackova, St.Toma, I.Augustinova, Iveta; Tetrahedron; 2006; 62; 50; 11675-.

The corresponding boron-substituted compounds, such as boronic acids, dialkylarylboranes or boronic esters, are synthesized from self-metallizable materials by reaction with, for example, a boronic electrophile boronic ester or derivative thereof. Boron substituted compounds can also be synthesized from halogenated or pseudohalogenated precursor molecules using transition metal catalysts, preferably palladium, and boron (boron) or borolane (borolan) compounds (Tetrahedron lett.2003, 4895-4898 and references cited therein).

The metallization and/or coupling reactions can also be carried out in microreactors and/or in micromixers. The addition reaction can be carried out without any further addition or, in the case of inactive reactants, it is also possible to add, for example, BF₃*OEt₂(see M.Schlosser, Organometallics in Synthesis, John Wiley)& Sons，Chichester/New York/Brisbane/Toronto/Singapore，1994)。

Halogenated compounds of formula (2-1) are commercially available or can be synthesized by methods described in the specialist literature known in the art of organic chemistry (see, for example, j. march, Advanced organic Reactions, Reactions Mechanism, and Structure, fourth edition, John Wiley & Sons, chicchester/New York/Brisbane/Toronto/Singapore, 1992 and the references cited therein). Transition Metals and organometallic compounds for synthetic use are described in detail in monographs (see, for example, L.Brandsma, S.F.Vasievsky, H.D.Verkruijsse, Application of Transition Metals Catalysts in Organic Synthesis, Springer-Verlag, Berlin/Heidelberg, 1999; M.Schloser, organometallics Synthesis, John Wiley & Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1994; P.J.Stang, F.Diederich, Metal-catalyst Cross-coupling reactions, Wiley-VCH, Weinheim, 1997 and references cited therein).

The synthesis of compounds of general formula (3-4) (wherein U, V, X, Y and R are as shown in reaction scheme 3) is illustrated schematically³As defined above).

Reaction equation 3:

starting from halogenated compounds of the general formula (3-1), particularly preferred are chlorides, bromides and iodides, the corresponding lithium-or magnesium-substituted compounds can be synthesized, for example, by halogen-metal exchange reactions with butyllithium, isopropylmagnesium halide or diisopropylmagnesium or by insertion of elemental metals into halogen-carbon bonds. The corresponding boron-substituted compounds, such as boronic acids, dialkylarylboranes or boronic esters, are synthesized from self-metallizable materials by reaction with a boron electrophile, such as a boronic ester or derivative thereof. Boron substituted compounds can also be synthesized from halogenated or halogenated-like precursor molecules using a transition metal catalyst, preferably palladium, and a boron or borolane compound (Tetrahedron lett.2003, 4895-4898 and references cited therein). The lithium-substituted or magnesium-substituted compound of the general formula (3-2) may be added to the compound of the general formula (3-3) containing a carboxyl group or a derivative thereof such as an ester, nitrile, acid chloride or amide such as grapevine amide. These reactions can generally be carried out without any additional transition metal catalyst or transmetallation with another metal such as cerium, indium or zinc. However, in some cases, the two mentioned variations also prove to be advantageous. Aromatic boronic acids, esters derived therefrom, dialkylarylboranes or aryltrifluoroborates can be reacted with acid chlorides or carboxylic acids in the presence of transition metals such as palladium as catalysts to give the corresponding ketones (V.Polackova, St.Toma, I.Augustinova, Iveta; Tetrahedron; 2006; 62; 50; 11675-.

The compound of the general formula (4-3) (wherein U, V, X, Y and R are³As defined above).

Reaction equation 4:

hal ═ halogen

The compound of the general formula (4-1) having a leaving group LG and an acid halide group can be reacted with the aromatic compound of the general formula (4-2) under Friedel-Crafts acylation conditions or a variation thereof. The Friedel-Crafts reaction is carried out in the presence of a catalyst used in catalytic or stoichiometric amounts. In particular, a suitable catalyst is AlCl₃、FeCl₃Iodine, iron, ZnCl₂Sulfuric acid or trifluoromethanesulfonic acid. Instead of the acid halides, the corresponding carboxylic acids, anhydrides, esters or nitriles can also be used. The reaction is preferably carried out in a halogenated hydrocarbon. Methylene chloride and 1, 2-dichloroethane are particularly preferred. The Friedel-Crafts reaction is carried out at a temperature in the range of-30 ℃ to 120 ℃, preferably 30 ℃ to 100 ℃. However, the reaction can also be carried out without solvent. The reaction can also be carried out in a microwave.

A compound of the general formula (5-3) (wherein U, V, X, Y, R is present) can be prepared as shown in reaction scheme 5¹、R²And R³As defined above).

Reaction equation 5:

in analogy to the process of t.ishiyama et al (j.org.chem., 1998, 63, 4726), a compound of formula (5-1) having a leaving group LG may be (preferably) reacted with a boron-substituted compound such as a boronic acid (R ═ H), a boronic ester (R ═ alkyl), a dialkylarylborane in the presence of a catalyst and a base in an inert solvent and carbon monoxide atmosphere, at a temperature ranging from ambient temperature to the reflux temperature of the solvent. Preferably, high reaction temperatures of 80 ℃ to 110 ℃ are used at high carbon monoxide pressures. In addition, for catalysisSuitable ligands may also be used. Alkali metal iodides such as sodium iodide or potassium iodide may be added as additives. As the leaving group LG, bromide, iodide, trifluoroacetate, trifluoromethanesulfonate, methanesulfonate and toluenesulfonate may be used, but are not limited thereto. The inert solvent used may be xylene, tetrahydrofuran, dimethylformamide, dimethoxyethane, toluene, benzene, anisole, 1, 4-dioxane, acetonitrile or solvent mixtures. The preferred solvent is anisole. Suitable bases are inorganic bases such as cesium carbonate, cesium acetate, potassium carbonate, sodium carbonate or potassium phosphate. The reaction is carried out in a carbon monoxide atmosphere, wherein the carbon monoxide pressure may be from 1 bar to 50 bar. Typical catalysts are, for example, palladium catalysts, such as tris (dibenzylideneacetone) -dipalladium (0), tetrakis- (triphenylphosphine) -palladium (0), palladium- (II) acetate, Pd (PPH)₃)₂Cl₂、Pd(CH₃CN)₂Cl₂、Pd(dppf)Cl₂Or palladium (II) chloride. Typical ligands are, for example, triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, triphenylarsine, 2 '-bis (diphenylphosphino) -1, 1' -Binaphthyl (BINAP), 2-di-tert-butylphosphino-2 ', 4', 6 '-triisopropylbiphenyl (XPhos), 4, 5-bis-diphenylphosphino (diphenylphosphino) -9, 9-dimethyl-9H-dibenzopyran (XantPhos) or 2- (di-tert-butylphosphino) biphenyl, 1' -bis (diphenylphosphino) ferrocene (Dppf), 1, 2-bis (diphenylphosphino) ethane (dppe), 1, 3-bis (diphenylphosphino) propane (dPPP) and 1, 4-bis (diphenylphosphino) butane (dppb).

Pd (PPH) is particularly preferably used₃)₂Cl₂As catalyst, potassium carbonate as base, 1 bar carbon monoxide, potassium iodide as additive and anisole as solvent. The corresponding boron-substituted compounds are commercially available or can be synthesized from metallated compounds by reaction with a boron electrophile, such as a borate ester or derivative thereof. In addition, boron-substituted compounds can be prepared from the corresponding halogenated or halogenated-like precursor molecules in transition metal-catalyzed reactions using, for example, palladium and diboronoranes (diborolones) or borolane compounds (Tetrahedron Lett.2003, 4895-.

Shown in reaction equation 6 is the synthesis of a compound of general formula (6-3) (wherein U, V, X, Y and R³As defined above).

Reaction equation 6:

in analogy to the process of A.Miyashita et al (Heterocycles, 1997, vol.45, No. 11, 2159-2173), a compound of the formula (6-1) having a leaving group LG can be reacted with an aromatic aldehyde in the presence of a catalyst and a base in an inert solvent to give a compound of the formula (6-3). Fluoride ion, chloride ion, bromide ion, iodide ion, trifluoromethanesulfonate group, methanesulfonate group, and tosylate group may be used as the leaving group LG, but are not limited thereto. Particularly preferred are chloride and bromide. Cyclic ethers (preferably tetrahydrofuran) and alkyl formamides (preferably dimethylformamide) may be used as inert solvents. Suitable catalysts are azolium salts, such as 1, 3-dimethylimidazolium iodide or 1, 3-dimethylbenzylimidazolium iodide. Suitable bases are metal hydrides. Sodium hydride is particularly preferred. The reaction is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent. High temperatures are preferred.

It is also possible to carry out the reaction at elevated temperature using sodium p-toluenesulfinate instead of the azolium salt and the base in the presence of an alkali metal cyanide, preferably potassium cyanide, in an inert solvent (A. Miyashita et al, Heterocycles, 1998, vol.47, stage 1, 407-414).

The compounds of formula (7-4) wherein U, V, X, Y and R are U, V, X, Y can be prepared analogously to A.Miyashita et al (Heterocycles, 1997, vol.45, No. 11, 2159-2173) and the references cited therein, as shown in equation 7³As defined above).

Reaction equation 7:

reacting the compound of the general formula (7-1) having a leaving group LG with 2-arylacetonitrile or 2-heteroarylacetonitrile in an inert solvent in the presence of a base to obtain a compound of the general formula (7-3). Fluorine, chlorine, bromine, iodine, trifluoromethanesulfonate, methanesulfonate and tosylate may be used as the leaving group LG, but are not limited thereto. Especially preferred are chlorine and bromine. The inert solvent may be a dialkylformamide (preferably dimethylformamide). Metal hydrides are suitable as bases. Sodium hydride is particularly preferred. The reaction is carried out at a temperature ranging from room temperature to the reflux temperature of the solvent. The reaction is preferably carried out at elevated temperature. The compound of the general formula (7-4) is synthesized by oxidation decyanation of the compound of the general formula (7-3). The oxidative decyanation reaction is carried out in the presence of a base in an inert solvent through which oxygen is passed. Cyclic ethers, preferably tetrahydrofuran, may be used as inert solvents. Suitable bases are metal hydrides. Sodium hydride is particularly preferred. The reaction is carried out at a temperature ranging from-20 ℃ to the reflux temperature of the solvent. The reaction is preferably carried out at room temperature.

The novel compounds of the general formula I according to the invention may contain one or more chiral centers. If, for example, two chiral centers are present, the compounds may exist as two diastereomeric enantiomeric pairs. The present invention includes individual isomers as well as mixtures thereof. Diastereomers may be separated on the basis of their different physicochemical properties (for example) by fractional crystallization from a suitable solvent, by high pressure liquid chromatography or column chromatography, using a chiral or (preferably) achiral stationary phase.

Racemates encompassed by formula I can be separated, for example, by HPLC on a suitable chiral stationary phase (e.g., chiral AGP, Chiralpak AD). Racemates containing basic or acidic functions may also be separated by diastereomeric, optically active salts, which may be produced by reaction with an optically active acid, such as (+) or (-) -tartaric acid, (+) or (-) -diacetyltartaric acid, (+) or (-) -monomethyl tartrate or (+) or (-) -camphorsulfonic acid, or an optically active base, such as (R) - (+) -1-phenylethylamine, (S) - (-) -1-phenylethylamine or (S) -strychnine.

According to the conventional method for separating isomers, a racemate of a compound of the general formula I is reacted with one of the above-mentioned optically active acids or bases in an equimolar amount in a solvent, and the resulting crystalline, diastereomeric optically active salt is separated by utilizing its different solubility. The reaction can be carried out in any type of solvent, provided that the solubility of the solvent for the salt is significantly different. Preferably, methanol, ethanol or mixtures thereof (e.g., 50: 50 by volume) are used. Each optically active salt is then dissolved in water, carefully neutralized with a base such as sodium or potassium carbonate or with a suitable acid such as dilute aqueous hydrochloric or methanesulfonic acid, and in this way the corresponding free compound is obtained in (+) or (-) form.

The individual (R) or (S) enantiomers or mixtures of two optically active diastereoisomers encompassed by the general formula I can be obtained by carrying out the synthesis described above with suitable reaction components of the (R) or (S) configuration.

The novel compounds of the general formula I and their physiologically acceptable salts have important pharmacological properties on the basis of their selective CGRP-antagonistic properties. The invention also relates to pharmaceutical compositions containing these compounds, to their use and to their preparation.

The novel compounds mentioned above and their physiologically acceptable salts have CGRP-antagonistic properties and show good affinity in studies of the binding of CGRP receptors. These compounds show CGRP-antagonistic properties in the pharmacological test system described below.

The following experiments were carried out to demonstrate the affinity of the above mentioned compounds for the human CGRP-receptor and their antagonistic properties:

binding studies of SK-N-MC cells (expressing the human CGRP receptor)

SK-N-MC cells were cultured in "Dulbecco's modified Eagle Medium". The medium was removed from the confluent culture. PBS buffer for cells (1)Gibco 041-04190M), the cells were detached by adding PBS buffer mixed with 0.02% EDTA, and separated by centrifugation. Resuspended in 20ml "balanced salt solution" [ BSS (in mM): NaCl 120, KCl 5.4, NaHCO₃ 16.2，MgSO₄ 0.8，NaHPO₄ 1.0，CaCl₂1.8, D-glucose 5.5, HEPES30, pH 7.40]After neutralization, the cells were centrifuged twice at 100 × g and resuspended in BSS. After determination of the cell number, the cells were homogenized using an Ultra-Turrax and centrifuged at 3000 Xg for 10 min. The supernatant was discarded and the pellet was plated in Tris buffer (10mM Tris, 50mM NaCl, 5mM MgCl) enriched with 1% bovine serum albumin and 0.1% bacitracin₂1mM EDTA, pH 7.40) and resuspended (1 ml per 1000000 cells). The homogenized product was frozen at-80 ℃. The film formulations were stable under these conditions for more than 6 weeks.

After thawing, the homogenized product was washed with test buffer (50mM Tris, 150mM NaCl, 5mM MgCl)₂1mM EDTA, pH 7.40) at 1: 10 and homogenized for 30 seconds with an Ultra-Turrax. 230. mu.l of the homogenized product were mixed with 50pM¹²⁵I-iodotyrosyl-calcitonin-gene-related peptide (Amersham) and an overall 250. mu.l increasing concentration of test substance were incubated for 180 minutes at ambient temperature. The culture was terminated by rapid filtration through polyethyleneimine (0.1%) treated GF/B glass fiber filters using a cell harvester. White matter binding radioactivity was measured using a gamma counter. Non-specific binding was defined as the bound radioactivity in the presence of 1 μ M human CGRP- α during culture.

Concentration binding curves were analyzed using computer-assisted nonlinear curve fitting.

The compounds mentioned above showed Ki values of ≦ 50 μ M in the test.

B. CGRP antagonism in SK-N-MC cells

SK-N-MC cells (1 million cells) were washed 2 times with 250. mu.l of culture buffer (Hanks' HEPES, 1mM 3-isobutyl-1-methylxanthine, 1% BSA, pH 7.4) andthe cells were incubated at 37 ℃ for 15 minutes in advance. In increasing concentrations (10)^-11M to 10^-6M) CGRP (10 μ l) was added as an agonist or in addition 3 to 4 different concentrations of substances, and the mixture was incubated for a further 15 minutes.

Intracellular cAMP was then extracted by addition of 20. mu.l of 1M HCl and centrifugation (2000 Xg, 4 ℃, 15 min). The supernatant was frozen in liquid nitrogen and stored at-20 ℃.

cAMP content of the sample was determined by radioimmunoassay (messrs. amersham) and the pA2 value of the antagonistic agent was determined graphically.

In the in vitro test model, the compounds of the invention are at 10^-12M and 10^-4The dose range between M shows CGRP-antagonistic properties.

To demonstrate that the compounds of general formula I show good to excellent CGRP-antagonistic activity under different structural moieties, the following table provides K obtained according to the test procedure described above_iThe value is obtained. It should be noted that the compounds are selected for their different moieties, and not to emphasize a particular compound:

examples	K_i[nM]
examples	K_i[nM]	(1)	6
(2)	27	(1)	6

Indications of

In view of their pharmacological properties, the compounds according to the invention and their salts with physiologically acceptable acids are suitable for the acute and prophylactic treatment of headaches (in particular migraine or cluster headaches as well as tension headaches). Furthermore, the compounds according to the invention also have a positive effect on: non-insulin dependent diabetes mellitus ("NIDDM"), cardiovascular disease, morphine tolerance, diarrhoea caused by clostridium toxin (diarrheea used by clinical hypertension), skin diseases, in particular heat and radiation-induced skin damage including sunburn, lichen disease (lichen), prurigo (pruritis), pruritic toxic dermatitis (pruritic dermatitis) and severe itching irritation, inflammatory diseases, for example inflammatory diseases of the joints (osteoarthritis, rheumatoid arthritis, neuroarthritis), systemic soft tissue rheumatism (generalized soft-tissue lung inflammation) (fibromyalgia), neuroinflammation of the oral mucosa, inflammatory diseases, allergic rhinitis, asthma, COPD, diseases caused by excessive vasodilation and a resulting decrease in blood supply to the tissues, for example shock and sepsis, chronic pain, for example, diabetic neuropathy, neuropathy caused by chemotherapy, neuropathy caused by HIV, neuropathy after herpes, neuropathy caused by tissue trauma, trigeminal neuralgia, temporomandibular dysfunction, CRPS (complex regional pain syndrome), back pain, and visceral diseases such as Irritable Bowel Syndrome (IBS), inflammatory bowel syndrome. In addition, the compounds according to the invention have a general pain-relieving effect. The symptoms of menopausal hot flashes in women with estrogen deficiency and in hormone-treated prostate cancer patients and castrated men due to vasodilation and increased blood flow are favorably influenced by the prophylactic and acute therapeutic use of the CGRP antagonists of the present application, a treatment modality which is distinguished from hormone replacement by no side effects.

The dosage required to achieve the corresponding effect is suitably from 0.0001 to 3 mg/kg of body weight, preferably from 0.01 to 1 mg/kg of body weight, when administered intravenously or subcutaneously, and from 0.01 to 10 mg/kg of body weight, preferably from 0.1 to 10 mg/kg of body weight, when administered orally, nasally or by inhalation, in each case from 1 to 3 times per day.

If treatment with CGRP antagonists and/or CGRP release inhibitors is used to supplement conventional hormone replacement, it is advisable to lower the above indicated dose, in which case the dose may be 1/5 from the above lower limit up to 1/1 from the indicated upper limit.

The invention further relates to the use of the compounds of the invention as valuable adjuvants in the manufacture and purification (affinity chromatography) of antibodies and in RIA and ELISA assays, for example by tritiation of suitable precursors (for example by catalytic hydrogenation of tritium or replacement of the halogen atom by tritium) after suitable radiolabelling, and as diagnostic or analytical aids in neurotransmitter research.

Combination of

Active substance classes which can be used in combination include antiemetics, prokinetic (prokinetic), neuroleptics, antidepressants, neurokinin antagonists, antispasmodics, histamine-H1-receptor antagonists, beta-blockers, alpha-agonists and alpha-antagonists, ergot alkaloids, mild analgesics, non-steroidal anti-inflammatory agents, corticosteroids, calcium antagonists, 5-HT_1B/1DAgonists or other antimigraine agents which may be formulated into conventional galenic formulations such as plain or coated tablets, capsules, powders, suspensions, solutions, metered dose aerosols or suppositories, together with one or more conventional inert carriers and/or diluents such as, for example, maize starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or suitable mixtures thereof.

Thus, other active substances which may be used in the above combinations include, for example, the non-steroidal anti-inflammatory agents aceclofenac, acemetacin, acetylsalicylic acid, acetamidophenol (paracetamol), azathioprine, diclofenac, diflunisal, fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, leflunomide, lornoxicam, mefenamic acid, naproxen, phenylbutazone, piroxicam, sulfasalazine, zomepirac or a pharmaceutically acceptable salt thereof and meloxicam and other selective COX 2-inhibitors, such as, for example, rofecoxib, valdecoxib, parecoxib, etoricoxib and celecoxib, as well as substances which inhibit the early or late stages of prostaglandin synthesis or prostaglandin receptor antagonists such as EP 2-receptor antagonists and IP-receptor antagonists.

Ergotamine, dihydroergotamine, metoclopramide, domperidone, diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrin, timolol, isometheptene, thiothidine, botulinum toxin (botox), gabapentin, pregabalin, duloxetine, topiramate, riboflavin (riboflavin), montelukast, lisinopril, telmisartan, norgestrel (prochloroperazine), dexamethasone, flunarizine, dexpropoxyphene, pethidine, metoprolol, propranolol, nadolol, atenolol, clonidine, indoramine, carbamazepine, phenytoin, sodium valproate, amitriptyline (amitriptiline), imipramine, venlafaxine, lidocaine or diltiazemAnd other 5-HT_1B/1DAgonists such as almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan.

In addition, CGRP-antagonists can be added as well as the following: vanilloid (vanilloid) receptor antagonists such as VR-1 antagonists, glutamate receptor antagonists such as MGlu 5-receptor antagonists, MGlu 1-receptor antagonists, iGlu 5-receptor antagonists, AMPA-receptor antagonists, purine receptor blockers such as P2X3 antagonists, NO-synthase inhibitors such as INOS inhibitors, calcium channel blockers such as PQ-type blockers, N-type blockers, potassium channel openers such as KCNQ channel openers, sodium channel blockers such as PN3 channel blockers, NMDA-receptor antagonists, acid-sensitive ion channel antagonists such as ASIC3 antagonists, bradykinin receptor antagonists such as B1-receptor antagonists, cannabinoid receptor agonists such as CB2 agonists, CB1 agonists, somatostatin receptor agonists such as sst2 receptor agonists.

The dosage of these actives is suitably 1/5 at the lowest generally recommended dose to 1/1 at the generally recommended dose, i.e. for example 20mg to 100mg sumatriptan (sumatriptan).

Preparation

The compounds prepared according to the invention can be administered by intravenous, subcutaneous, intramuscular, intraarticular, intrarectal, intranasal route, by inhalation, topically, transdermally or orally, alone or optionally in combination with other active substances for the treatment of migraine, whereas aerosol formulations are particularly suitable for inhalation. The compositions may be administered simultaneously or sequentially.

Suitable forms for administration are, for example, tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. In each case, the proportion of the pharmaceutically active compounds should be in the range from 0.1 to 90% by weight, preferably from 0.5 to 50% by weight, of the total composition, i.e. in an amount sufficient to achieve the dosage ranges mentioned below.

Oral administration may be in the form of tablets, powders in capsules (e.g., hard gelatin capsules), or as solutions or suspensions. When administered by inhalation, the active substance combination can be administered as a powder, an aqueous or aqueous-alcoholic solution or via a propellant gas formulation.

Accordingly, a preferred pharmaceutical preparation is characterized in that it contains one or more compounds according to the invention.

It is particularly preferred if the compounds of the formula I are administered orally, and also particularly preferred if they are administered once or twice a day. Suitable tablets may, for example, be obtained by mixing the active substance with known excipients, for example inert diluents, such as calcium carbonate, calcium phosphate or lactose, disintegrating agents, for example corn starch or alginic acid, binding agents, for example starch or gelatin, lubricating agents, for example magnesium stearate or talc and/or agents delaying release, such as carboxymethylcellulose, ethylcellulose, or polyvinyl acetate.

Coated tablets may be prepared by coating a core, manufactured analogously to the tablets, with the substances normally used for tablet coatings, such as collidone or shellac, gum arabic, talc, titanium dioxide or sugar. The core may also be composed of multiple layers for delayed release or to prevent incompatibilities. Similarly, to achieve delayed release the tablet coating may consist of multiple layers, and the excipients mentioned above for tablets may be used.

Syrups containing the active substance or a combination thereof according to the invention may additionally contain sweetening agents, for example saccharin, cyclamate, glycerol or sugar, and taste enhancers (for example, aromatics such as vanillin or orange extract (orange extract), it may furthermore also contain suspension auxiliaries or thickeners such as sodium carboxymethylcellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

Capsules containing one or more active substances or combinations of active substances may be prepared, for example, by mixing the active substances with inert carriers, such as lactose or sorbitol, and encapsulating them in gelatin capsules.

Suitable suppositories may be prepared, for example, by mixing them with carriers suitable for the purpose, such as neutral fats or polyethylene glycols or derivatives thereof.

Excipients that may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g., petroleum fractions), vegetable oils (e.g., peanut or sesame oil), mono-or polyhydric alcohols (e.g., ethanol or glycerol), carriers such as natural mineral powders (e.g., kaolin, clay, talc, chalk), synthetic mineral powders (e.g., highly dispersed silicic acid and silicates), sugars (e.g., sucrose, lactose and glucose), emulsifiers (e.g., lignin, spent sulfite liquor, methyl cellulose, starch and polyvinylpyrrolidone), and lubricants (e.g., magnesium stearate, talc, stearic acid and sodium lauryl sulfate).

For oral administration, these tablets may, of course, contain, in addition to the aforementioned specified carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate in combination with various additives such as starch (preferably potato starch), gelatin and the like. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc may be used when making tablets. In the case of aqueous suspensions, the active substances may be mixed with various odorants or colorants in addition to the above-mentioned excipients.

It is also preferred if the compounds of the invention are administered by inhalation, especially if they are administered once or twice a day. To achieve this, the compounds of the present invention must be formulated in a form suitable for inhalation. Inhalable formulations include inhalable powders, propellant-containing metered dose aerosols or propellant-free inhalable solutions, optionally mixed with conventional physiologically acceptable excipients.

Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile ready-to-use inhalable solutions. The formulations that can be used according to the invention are described in more detail in the next part of the description.

Experimental part

Typically, IR, 1H-NMR and/or mass spectra of the prepared compounds are obtained. Unless otherwise stated, R was determined using a preformed TLC silica gel plate 60F254(E.Merck, Darmstadt, project No.: 1.05714) without expansion tank saturation_fThe value is obtained.

The eluent ratio given is for a volume unit of a particular solvent. Given NH₃Volume unit of (2) for NH₃Concentrated solution in water.

Unless otherwise specified, the acid, base and salt solutions used to treat the reaction solutions are aqueous solutions of the indicated concentrations. Silica gel (MATREXTM, 35 μm to 70 μm) made of Millipore was used for the chromatographic purification.

The HPLC data provided are under the parameters listed below and determined using the column mentioned.

Column used:

(column temperature: 30 ℃ C.; injection volume: 5. mu.L; detection at 254 nm)

S1	Zorbax column (Agilent Technologies), SB (Stable bond) C18; 3.5 μm; 4.6X 75mm
S1		S2	Zorbax column (Agilent Technologies), SB (Stable bond) C18; 1.8 μm; 3.0X 30mm
S3	Zorbax column (Agilent Technologies), SB (Stable bond) C18; 5 μm; 4.6X 75mm	S2
S3		S4	Xbridge(Waters)C18；3.0×30mm，2.5μm
S5	Sunfire C18(Waters)；3.5μm；4.6×75mm	S4	Xbridge(Waters)C18；3.0×30mm，2.5μm
S5	Sunfire C18(Waters)；3.5μm；4.6×75mm	S6	Symmetry C18(Waters)；4.6×75mm，3.5μm

Solvents used:

solvent A: water (containing 0.1% formic acid); solvent B: acetonitrile (containing 0.1% formic acid); solvent C: water (containing 0.1% ammonia); and (3) solvent D: acetonitrile (containing 0.1% ammonia), percentages being based on total volume.

Gradient:

the method comprises the following steps:

in preparative HPLC purification, the same gradient as used to obtain analytical HPLC data is typically used. The product was collected under mass spectrometry control and the product containing fractions were combined and freeze dried.

In the absence of any more information about the configuration, it is unclear whether pure enantiomers are involved or whether partial or even complete racemization has occurred.

The following abbreviations are used in the test description:

AcOH acetic acid

BINAP 2, 2 '-bis (diphenylphosphino-) 1, 1' -binaphthyl

BOC tert-butoxycarbonyl

CDI 1, 1' -carbonyldiimidazole

cvc cyclohexane

DCM dichloromethane

DIPE diisopropyl ether

DIPEA diisopropylethylamine

DMF N, N-dimethylformamide

of theoretical value of th.

d-water deionized water

EI electric impact ionization (MS middle)

ESI electrospray ionization (MS middle)

EtOAc ethyl acetate

EtOH ethanol

el. eluent

HCl hydrochloric acid

HCOOH formic acid

HPLC high performance liquid chromatography

HPLC-MS HPLC combined mass spectrum

HV high vacuum

Vac. under vacuum (in vacuum)

con. dense

MeOH methanol

MS Mass Spectrometry

MW molecular weight [ g/mol ]

NaOH sodium hydroxide

NH₄OH ammonium hydroxide (Ammonia solution, 30%)

NMP N-methyl-2-pyrrolidines

Pd₂dba₃Bis (dibenzylideneacetone) palladium- (0)

PE Petroleum Ether

Rf Retention coefficient (in TLC)

RT ambient temperature

Rt Retention time (in HPLC)

TEA Triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

DC drying cabinet

CAD circulating air dryer

Preparation of the starting Compounds

Intermediate 1

6-chloropyrimidine-4-carbonyl chloride

Step 1: 6-hydroxypyrimidine-4-carboxylic acid

63.5g (287mmol) diethyl oxaloacetate sodium (sodium dimethyl-oxalacetate) and 30.2g (287mmol) formamidine acetate were added to 24.1g (0.597mol) NaOH in 3.6L water. The mixture was stirred at room temperature overnight. Activated carbon was then added and the mixture was refluxed for 1 hour. It was filtered hot and, after cooling, acidified with aqueous HCl. The solution was concentrated to dryness by rotary evaporation. The residue contained the desired product and was used in the next step without any further purification.

Yield: 83.0g

Step 2: 6-chloropyrimidine-4-carbonyl chloride

50g (0.352mol) of 6-hydroxypyrimidine-4-carboxylic acid were taken, and 500mL of phosphorus oxychloride (phosphorus oxychloride) was added thereto. Subsequently, 150g (0.720mol) of phosphorus pentachloride (phosphorus pentachloride) are added in portions with stirring. The reaction mixture was refluxed for 5 hours. The oxyphosphorus chloride was distilled off and the residue was purified by distillation under column vacuum.

Yield: 52 (83% of theoretical)

EI-MS：m/z＝176/178/180(M)⁺(2Cl)

Intermediate 2

4-methyl-3H-benzoxazol-2-ones

25.0g (200mmol) of 2-amino-m-methylphenol and 70.4mL (400mmol) of DIPEA were placed in 1.0L DCM and cooled to 0 ℃. Over 30 minutes, a solution of 38.0g (227mmol) of 1, 1' -carbonyldiimidazole is added dropwise thereto. The mixture was stirred at 0 ℃ for 30 minutes, followed by stirring at room temperature overnight. After the reaction mixture was evaporated to half of its volume in vacuo, the aqueous phase was washed with water (2X 250mL), 1M aqueous potassium bisulfate (1X 250mL), and then with water (1X 250 mL). The organic phase was evaporated in vacuo. The residual crude product was triturated as a solid with a mixture of diethyl ether and PE, the precipitated solid was filtered off with suction, washed with PE and dried under vacuum.

Yield: 25.0g (86% of theory)

ESI-MS：m/z＝150(M+H)⁺

Rt (hplc) 2.67 min (method C)

Intermediate 3

6- (6-chloropyrimidine-4-carbonyl) -4-methyl-3H-benzoxazol-2-one

2.34g (13.2mmol) of 6-chloropyrimidine-4-carbonyl chloride, 8.00g (60.0mmol) of aluminum trichloride and 1.79g (12.0mmol) of 4-methyl-3H-benzoxazol-2-one are heated to 130 ℃ for 1.5 hours. After cooling to room temperature, the mixture is mixed with ice-water and extracted with ethyl acetate, the organic phase is dried over sodium sulfate and evaporated in vacuo. The crude product remaining as a solid was triturated with ether, filtered off with suction and dried under air.

Yield: 2.00g (52% of theory)

ESI-MS：m/z＝290/292(M+H)⁺(Cl)

Rt (hplc) 3.17 min (method C)

Intermediate 4

6- (6-chloropyrimidine-4-carbonyl) -3, 4-dimethyl-3H-benzoxazol-2-one

0.35g (8.0mmol) of sodium hydride (55% suspension in mineral oil) is added to 2.2g (7.6mmol) of 6- (6-chloropyrimidine-4-carbonyl) -4-methyl-3H-benzoxazol-2-one in 10mL of DMF. The reaction mixture was stirred at room temperature for 30 minutes. Then 0.95mL (15.0mmol) of iodomethane was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was mixed with ice water and the aqueous phase was extracted several times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and evaporated to dryness by rotary evaporation. The residue is triturated with diethyl ether, filtered off with suction and dried.

Yield: 1.6g (69% of theory)

ESI-MS：m/z＝304/306(M+H)⁺

Rt (hplc): 3.55 minutes (method C)

Intermediate 5

1 'H-spiro [ piperidine-4, 4' -quinazoline ] -2 '(3' H) -one

This compound and its precursors were synthesized as described in WO 2003/104236.

ESI-MS：m/z＝218(M+H)⁺

Rf: 0.08 (silica gel, DCM/cyc/MeOH/NH4OH ═ 70/15/15/2)

Intermediate 6

Spiro [ benzo [ d ] [1, 3] oxazine-4, 4' -piperidin ] -2(1H) -one hydrochloride

This compound and its precursors were synthesized as described in US 6,436,962.

ESI-MS：m/z＝219(M+H)⁺

Rf: 0.14 (silica gel, DCM/cyc/MeOH/NH4OH ═ 70/15/15/2)

Intermediate 7

Spiro [ piperidine-4, 4 ' -pyrido [2, 3-d ] [1, 3] oxazine ] -2 ' (1 ' H) -one hydrochloride

Step 1: (6-chloro-pyridin-2-yl) -carbamic acid tert-butyl ester

A solution of 32.7g (0.150mol) of BOC anhydride in 100mL of THF is added dropwise at room temperature under a nitrogen atmosphere to a mixture of 17.4g (0.135mol) of 6-chloropyridin-2-ylamine and 300mL (0.300mol) of sodium bis (trimethylsilane) amide solution (1M in THF) in 200mL of THF. The reaction mixture was stirred at room temperature overnight and evaporated under vacuum. The residue was stirred between EtOAc and 1N aqueous hydrochloric acid. The organic phase was separated and the aqueous phase was extracted with EtOAc. The combined organic phases were washed with saturated sodium bicarbonate solution, dried and evaporated. The residue was recrystallized from EtOH, the solid was filtered off with suction and dried.

Yield: 29.2g (95% of theory)

ESI-MS：m/z＝228(M+)

Rt (hplc): 1.70 minutes (method B)

Step 2: 7 ' -chloro-2 ' -oxo-1 ', 2 ' -dihydrospiro [ piperidine-4, 4 ' -pyrido [2, 3-d ] [1, 3] oxazine ] -1-carboxylic acid benzyl ester

26.0mL (173mmol) of N, N, N, N-tetramethylene-ethylenediamine in 180mL of THF was cooled to-20 deg.C under nitrogen and mixed with 70.0mL (175mmol) of a 2.5M solution of butyllithium. After stirring for 30 min, the reaction mixture was cooled to-78 ℃ and 17.8g (78.0mmol) of (6-chloro-pyridin-2-yl) -carbamic acid tert-butyl ester in 120mL THF were slowly added dropwise at this temperature. The reaction mixture was stirred at-78 ℃ for 2.5 h and then combined with 27.2g (117mmol) of Cbz-protected piperidone in 60mL of THF. After 1 hour at-78 ℃, the mixture was warmed to room temperature and then stirred at 40 ℃ for 18 hours. The reaction mixture was decomposed by dropwise addition of 150mL of a saturated sodium bicarbonate solution. It was then extracted with DCM. The combined organic phases were washed with water, dried and evaporated. The residue was triturated with PE/EtOAc (1/1), and the precipitate formed was filtered off with suction, washed with PE/EtOAc (1/1), and dried.

Yield: 16.4g (54% of theory)

ESI-MS：m/z＝388(M+H)⁺

Rt (hplc): 1.57 minutes (method B)

And step 3: spiro [ piperidine-4, 4 ' -pyrido [2, 3-d ] [1, 3] oxazine ] -2 ' (1 ' H) -one hydrochloride

16.4g (42.0mmol) of benzyl 7 ' -chloro-2 ' -oxo-1 ', 2 ' -dihydrospiro [ piperidine-4, 4 ' -pyrido [2, 3-d ] [1, 3] oxazine ] -1-carboxylate and 2.00g palladium on charcoal (Pd/C10%) in 500mL EtOH were hydrogenated at room temperature under a hydrogen atmosphere for 6 hours. 1.0g of palladium on charcoal (Pd/C10%) are then added and the reaction mixture is hydrogenated for a further 3 hours at room temperature under a hydrogen atmosphere. After filtration of the reaction mixture, the solvent was removed in vacuo. The residue was triturated with EtOH and the precipitate formed was filtered off with suction, washed with EtOH and dried.

Yield: 5.40g (50% of theory)

ESI-MS：m/z＝220(M+H)⁺

Rt (hplc): 0.90 min (method C)

Intermediate 8

6- (6-chloro-2-methyl-pyrimidine-4-carbonyl) -4-methyl-3H-benzoxazol-2-one

Step 1: 6-chloro-2-methyl-pyrimidine-4-carbonyl chloride

2.00g (13.0mmol) of 6-hydroxy-2-methylpyrimidine-4-carboxylic acid are refluxed with 11.9mL (130mmol) of phosphorus oxychloride for 2 hours. After cooling to room temperature, 2.70g (13.0mmol) of phosphorus (V) chloride were added and the mixture was boiled for 2 hours. The reaction mixture was cooled to room temperature and evaporated to dryness in vacuo. And azeotroped with toluene 2 times. The residue was triturated several times with DCM and the excess DCM was decanted off. The combined DCM phases were evaporated and the residue was further reacted as crude product.

Yield: 2.48g (quantitative)

Step 2: 6- (6-chloro-2-methyl-pyrimidine-4-carbonyl) -4-methyl-3H-benzoxazol-2-one

2.48g (13.0mmol) of 6-chloro-2-methyl-pyrimidine-4-carbonyl chloride, 1.94g (13.0mmol) of 4-methyl-3H-benzoxazol-2-one and 6.93g (52.0mmol) of aluminium trichloride are heated to 125 ℃ for 1.5 hours with stirring. The mixture was mixed with ice-water and the precipitate formed was filtered off with suction and washed with water. The precipitate was then dissolved in MeOH/DCM and filtered off with suction through silica gel. The filtrate was evaporated and the residue was purified by flash chromatography. The product containing fractions were mixed, evaporated and triturated with ether. The precipitate is filtered off with suction, washed with diethyl ether and dried under vacuum.

Yield: 0.600g (15% of theory)

ESI-MS：m/z＝304(M+H)⁺

Rt (hplc): 1.42 minutes (method B)

Intermediate 9

6- (6-chloro-2-methyl-pyrimidin-4-yl) -3, 4-dimethyl-3H-benzoxazol-2-one

59mg (1.4mmol) of sodium hydride (55% suspension in mineral oil) are added at room temperature to 0.37g (1.2mmol) of 6- (6-chloro-2-methyl-pyrimidine-4-carbonyl) -4-methyl-3H-benzoxazol-2-one in 5.0mL of DMF. The reaction mixture was stirred at room temperature for 30 minutes. Then 0.10mL (1.60mmol) of iodomethane was added, and the mixture was stirred at room temperature for 1 hour. Then, 0.10mL (1.60mmol) of iodomethane was further added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ice water and the precipitate formed was filtered off with suction. The residue was washed with water and dried under vacuum.

Yield: 0.37g (96% of theory)

ESI-MS：m/z＝318(M+H)⁺

Rt (hplc): 1.53 minutes (method B)

Intermediate 10

(6-chloro-pyrimidin-4-yl) - (7-methyl-2, 3-dihydro-benzofuran-5-yl) -methanone

Step 1: 7-methyl-2, 3-dihydro-benzofuran-3-ol

Under a nitrogen atmosphere, 0.945g (7.35mmol) of trimethylsulfoxide chloride (trimethylulphosoxonium chloride) is placed in 20mL of THF and mixed in portions with 0.300g (7.50mmol) of sodium hydride (55%, suspension in mineral oil). The reaction mixture was refluxed for 2 hours. Next, 1.00g (7.35mmol) of 2-hydroxy-3-methylbenzaldehyde in 20mL of THF was added dropwise to the reaction mixture, and refluxed overnight. PE was then added and the resulting suspension was filtered. The filtrate was evaporated in vacuo and purified by flash chromatography. The product containing fractions were mixed and evaporated.

Yield: 0.615g (56% of theory)

ESI-MS：m/z＝133(M-H₂O+H)⁺

Rt (hplc): 1.09 minutes (method B)

Step 2: 7-methyl-2, 3-dihydro-benzofurans

0.610g (4.06mmol) of 7-methyl-2, 3-dihydro-benzofuran-3-ol in 5mL of acetic acid is refluxed with 770. mu.L (8.16mmol) of acetic anhydride under nitrogen for 2 hours. After cooling to room temperature, 60mg of palladium on charcoal (Pd/C10%) were added and the mixture was hydrogenated under a hydrogen atmosphere (3 bar) for 3.5 hours. The catalyst was filtered off and the solvent was evaporated.

Yield: 0.350g (64% of theory)

MS：m/z＝134(M⁺)

And step 3: (6-chloro-pyrimidin-4-yl) - (7-methyl-2, 3-dihydro-benzofuran-5-yl) -methanone

0.396g (2.24mmol) of 6-chloropyrimidine-4-carbonyl chloride and 0.328g (2.46mmol) of aluminum trichloride in 10mL of DCM are stirred for 20 minutes at room temperature. 0.300g (2.24mmol) of 7-methyl-2, 3-dihydro-benzofuran in DCM is then added dropwise to the reaction mixture and the mixture is stirred at room temperature for 1.5 h. After addition of water and DCM to the reaction mixture, the phases were separated and the aqueous phase was extracted with DCM. The combined organic phases were washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, filtered, and evaporated in vacuo.

Yield: 0.550g (62% of theory)

Purity: 70 percent of

ESI-MS：m/z＝275/277(Cl)(M+H)⁺

Rt (hplc): 1.54 minutes (method B)

Intermediate 11

5-amino-1, 3-dihydrospiro [ indene-2, 3 ' -pyrrolo [2, 3-b ] pyridin ] -2 ' (1 ' H) -one

This compound was synthesized as described in WO 2006/029153.

ESI-MS：m/z＝252(M+H)⁺

Rf (dc) ═ 0.4 (10% methanol/chloroform)

Intermediate 12:

(6-chloro-pyrimidin-4-yl) - (2, 3-difluoro-phenyl) -methanone

Step 1: 6-chloro-pyrimidine-4-carbothioic acid S-phenyl ester

1.58mL (15.4mmol) of thiophenol (thiophenol) and 2.75mL (16.08mmol) of DIPEA were added to 3.00g (16.1mmol) of 6-chloropyrimidine-4-carbonyl chloride in 100mL of DCM at 0 ℃ and stirred at 0 ℃ for 1 hour and at room temperature for 1 hour. The reaction mixture was then diluted with DCM and washed with saturated sodium bicarbonate solution and water. The organic phase was dried over sodium sulfate, filtered through silica gel and washed with DCM. The filtrate was then evaporated.

Yield: 3.80g (99% of theory)

MS：m/z＝250/252(Cl)(M+)

Rt (hplc): 2.95 minutes (method F)

Step 2: (6-chloro-pyrimidin-4-yl) - (2, 3-difluoro-phenyl) -methanone

Argon was piped through 0.50g (2.0mmol) of S-phenyl 6-chloro-pyrimidine-4-carbothioate, 0.38g (2.4mmol) of 2, 3-difluorophenylboronic acid and 0.46g (2.4mmol) of copper thiophene-2-carboxylate in 25mL of THF for 3 minutes, and then 46mg (0.05mmol) of Pd2dba3 and 35. mu.L (0.20mmol) of triethyl phosphite were added. The reaction mixture was stirred at room temperature for a further 48 hours, the precipitate formed was filtered off and the filtrate was evaporated. The residue was purified by flash chromatography.

Yield: 0.47g (83% of theory)

Purity: 90 percent of

ESI-MS：m/z＝255/257(Cl)(M+H)⁺

Rt (hplc): 4.23 minutes (method C)

Preparation of the Final Compounds

Example 1:

4-methyl-6- (6- (2 ' -oxo-2 ', 3 ' -dihydro-1 ' H-spiro [ piperidine-4, 4 ' -quinazolin-1-yl) pyrimidine-4-carbonyl) benzo [ d ] oxazol-2 (3H) -one

144mg (0.500mmol) of 6- (6-chloropyrimidine-4-carbonyl) -4-methyl-3H-benzooxazol-2-one, 108mg (0.500mmol) of 1 'H-spiro [ piperidine-4, 4' -quinazolin ] -2 '(3' H) -one and 0.174mL (1.00mmol) of DIPEA were mixed in 5.0mL of DMF and stirred at room temperature overnight. The reaction mixture was purified by preparative HPLC, the fractions containing the product were combined and the organic solvent was removed in vacuo. The aqueous phase was neutralized by addition of 4N NaOH aqueous solution. The precipitated product as a solid was filtered off, washed with water and dried.

Yield: 130mg (55% of theory)

ESI-MS：m/z＝471(M+H)⁺

Rt (hplc) 2.55 min (method C)

Example 2:

4-methyl-6- (6- (2 '-oxo-1, 1', 2 ', 3-tetrahydrospiro [ indene-2, 3' -pyrrolo [2, 3-b ] pyridin ] -5-ylamino) pyrimidine-4-carbonyl) benzo [ d ] oxazol-2 (3H) -one

144mg (0.500mmol) of 6- (6-chloropyrimidine-4-carbonyl) -4-methyl-3H-benzoxazol-2-one, 126mg (0.500mmol) of 5-amino-1, 3-dihydrospiro [ indene-2, 3 ' -pyrrolo [2, 3-b ] pyridine ] -2 ' (1 ' H) -one and 16.1mg (0.100mmol) of benzenesulfonic acid are mixed in 5.0mL of 2-pentanol and refluxed for 4 hours. The reaction mixture was evaporated, the residue triturated with PE, filtered off with suction and washed with PE. The residue was purified by preparative HPLC, the fractions containing the product were combined and the organic solvent was removed in vacuo. The aqueous phase was neutralized by addition of 1N NaOH in water. The precipitated product as a solid was filtered off, washed with water and dried.

Yield: 85mg (34% of theory)

ESI-MS：m/z＝505(M+H)⁺

Rt (hplc) 2.88 min (method C)

Example 3

3, 4-dimethyl-6- (6- (2 ' -oxo-2 ', 3 ' -dihydro-1 ' H-spiro [ piperidine-4, 4 ' -quinazolin-1-yl) pyrimidine-4-carbonyl) benzo [ d ] oxazol-2 (3H) -one

87.0mg (0.400mmol) of 1 'H-spiro [ piperidine-4, 4' -quinazolin ] -2 '(3' H) -one, 122mg (0.400mmol) of 6- (6-chloropyrimidine-4-carbonyl) -3, 4-dimethyl-3H-benzoxazol-2-one and 0.140mL (0.800mmol) of DIPEA were mixed in 3.0mL of DMF and stirred at room temperature for 48H. The reaction mixture was diluted with MeOH, and the precipitate was filtered off with suction, washed with ether, and dried.

Yield: 184mg (95% of theory)

ESI-MS：m/z＝485(M+H)⁺

Rt (hplc): 1.14 minutes (method A)

Example 4

3, 4-dimethyl-6- (6- (2 '-oxo-1, 1', 2 ', 3-tetrahydrospiro [ indene-2, 3' -pyrrolo [2, 3-b ] pyridin ] -5-ylamino) pyrimidine-4-carbonyl) benzo [ d ] oxazol-2 (3H) -one

16.0mg (0.100mmol) of benzenesulfonic acid were added to 126mg (0.500mmol) of 5-amino-1, 3-dihydrospiro [ indene-2, 3 ' -pyrrolo [2, 3-b ] pyridin ] -2 ' (1 ' H) -one and 152mg (0.500mmol) of 6- (6-chloro-pyrimidine-4-carbonyl) -3, 4-dimethyl-3H-benzoxazol-2-one in 5.0mL of 2-pentanol and boiled for 4 hours. The reaction mixture was evaporated and purified by preparative HPLC. The product containing fractions were combined, the organic solvent was removed in vacuo, and the residual aqueous phase was neutralized with 1m naoh aqueous solution. The precipitated product as a solid is filtered off with suction, washed with water and dried under vacuum.

Yield: 110mg (42% of theory)

ESI-MS：m/z＝519(M+H)⁺

Rt (hplc) 1.3 min (method B)

Example 5

1 '- (6- (3, 4-dimethyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carbonyl) pyrimidin-4-yl) spiro [ benzo [ d ] [1, 3] oxazine-4, 4' -piperidin ] -2(1H) -one

102mg (0.400mmol) of spiro [ benzo [ d ] [1, 3] oxazine-4, 4' -piperidin ] -2(1H) -one hydrochloride, 122mg (0.400mmol) of 6- (6-chloropyrimidine-4-carbonyl) -4-methyl-3H-benzoxazol-2-one and 0.210mL (1.20mmol) of DIPEA were mixed in 3.0mL of DMF and stirred for 48 hours. The mixture was purified by preparative HPLC-MS. The product containing fractions were combined, the organic solvent was removed in vacuo and the residual aqueous phase was neutralized with 4M aqueous NaOH. The precipitated product as a solid was filtered off with suction, washed with water and dried in CAD.

Yield: 90mg (46% of theory)

ESI-MS：m/z＝486(M+H)⁺

Rt (hplc): 1.25 minutes (method B)

Example 6

1- (6- (3, 4-dimethyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carbonyl) pyrimidin-4-yl) spiro [ piperidine-4, 4 ' -pyrido [2.3-d ] [1, 3] oxazin-2 ' (1 ' H) -one

55mg (0.21mmol) of spiro [ piperidine-4, 4 ' -pyrido [2.3-d ] [1, 3] oxazine ] -2 ' (1 ' H) -one hydrochloride, 65mg (0.21mmol) of 6- (6-chloropyrimidine-4-carbonyl) -3, 4-dimethyl-3H-benzoxazol-2-one and 0.15mL (0.84mmol) of DIPEA were mixed in 1.8mL of DMF and stirred at room temperature overnight. The reaction mixture was then purified by preparative HPLC-MS. The product containing fractions were combined and freeze dried.

Yield: 73.0mg (70% of theory)

ESI-MS：m/z＝487(M+H)⁺

Rt (hplc): 2.60 minutes (method C)

Example 7

1- (6- (3, 4-dimethyl-2-oxo-2, 3-dihydrobenzo [ d ] oxazole-6-carbonyl) -2-methylpyrimidin-4-yl) spiro [ piperidine-4, 4 ' -pyrido [2, 3-d ] [1, 3] oxazin-2 ' (1 ' H) -one

77mg (0.30mmol) of spiro [ piperidine-4, 4 ' -pyrido [2, 3-d ] [1, 3] oxazine ] -2 ' (1 ' H) -one hydrochloride, 88mg (0.28mmol) of 6- (6-chloro-2-methyl-pyrimidine-4-carbonyl) -3, 4-dimethyl-3H-benzoxazol-2-one and 0.17mL (1.0mmol) of DIPEA were mixed in 2mL of DMF and stirred at room temperature overnight. The reaction mixture was then purified by preparative HPLC-MS. The product containing fractions were combined and the organic solvent was evaporated. The residue was neutralized with 4N aqueous sodium hydroxide solution. The precipitate formed is filtered off with suction, washed with water and dried under vacuum.

Yield: 53mg (35% of theory)

ESI-MS：m/z＝501(M+H)⁺

Rt (hplc): 1.07 minutes (method B)

Example 8

5- (6- (7-methyl-2, 3-dihydrobenzofuran-5-carbonyl) pyrimidin-4-ylamino) -1, 3-dihydrospiro [ indene-2, 3 ' -pyrrolo [2, 3-b ] pyridine ] -2 ' (1 ' H) -one

A spatula head of benzenesulfonic acid was added to 70mg (0.28mmol) of 5-amino-1, 3-dihydrospiro [ indene-2, 3 ' -pyrrolo [2, 3-b ] pyridin ] -2 ' (1 ' H) -one and 0.10g (0.26mmol) of (6-chloro-pyrimidin-4-yl) - (7-methyl-2, 3-dihydro-benzofuran-5-yl) -methanone in 2mL of 1-pentanol and the mixture was stirred at 85 ℃ for 1 hour. The reaction mixture was evaporated, dissolved in DMF, acidified with a few drops of hydrochloric acid and purified by preparative HPLC. The product containing fractions were combined and freeze dried.

Yield: 60mg (48% of theory)

ESI-MS：m/z＝490(M+H)⁺

Rt (hplc): 1.39 minutes (method B)

Example 9

5- (6- (2, 3-difluorobenzoyl) pyrimidin-4-ylamino) -1, 3-dihydrospiro [ indene-2, 3 ' -pyrrolo [2, 3-b ] pyridin ] -2 ' (1 ' H) -one

70mg (0.28mmol) of 5-amino-1, 3-dihydrospiro [ indene-2, 3 ' -pyrrolo [2, 3-b ] pyridin ] -2 ' (1 ' H) -one, 80mg (0.28mmol) of (6-chloro-pyrimidin-4-yl) - (2, 3-difluoro-phenyl) -methanone and 60. mu.L of DIPEA were stirred in 600. mu.L of dimethyl sulfoxide for 1H at 80 ℃. After cooling, the reaction mixture was mixed with about 10mL of ice water. The liquid was decanted off and the residue was dissolved in DCM and MeOH. After drying over sodium sulfate, the mixture was filtered and the solvent was evaporated. The residue is triturated with diethyl ether, filtered off with suction and dried.

Yield: 82mg (60% of theory)

ESI-MS：m/z＝470(M+H)⁺

Rt (hplc): 3.97 min (method C)

The following examples describe the preparation of pharmaceutical preparations containing any desired compounds of the general formula I as active substances:

example I

Capsule containing 1mg of powder for inhalation of active ingredient

Consists of the following components:

1 capsule of powder for inhalation comprising:

active ingredient 1.0mg

Lactose 20.0mg

Hard gelatin capsules50.0mg

71.0mg

The preparation method comprises the following steps:

the active ingredient is ground to the desired particle size for the inhalation substance. The milled active ingredient was mixed homogeneously with lactose. The mixture was transferred to a hard gelatin capsule.

Example II

Containing 1mg of active ingredient forInhalable solutions of

Composition of

The spraying comprises the following components in one time:

active ingredient 1.0mg

Benzalkonium chloride 0.002mg

Disodium edetate 0.0075mg

Adding pure water to 15.0 μ l

The preparation method comprises the following steps:

dissolving active ingredient and benzalkonium chloride in water, and transferring toIn the cartridge.

Example III

Inhalable solutions for nebulisers containing 1mg of active ingredient

Comprises the following components:

1 vial contains:

0.1g of active ingredient

Sodium chloride 0.18g

Benzalkonium chloride 0.002g

Adding pure water to 20.0ml

The preparation method comprises the following steps:

the active ingredient, sodium chloride and benzalkonium chloride were dissolved in water.

Example IV

Propellant gas operated metered dose aerosol containing 1mg of active ingredient

Consists of the following components:

the spraying comprises the following components in one time:

active ingredient 1.0mg

Lecithin 0.1%

Adding propellant gas to 50.0 μ l

The preparation method comprises the following steps:

the micronized active ingredient is homogeneously suspended in a mixture of lecithin and propellant gas. The suspension was transferred to a pressurized vessel with a dosing valve.

Example V

Nasal spray containing 1mg of active ingredient

Consists of the following components:

active ingredient 1.0mg

Sodium chloride 0.9mg

Benzalkonium chloride 0.025mg

Ethylenediaminetetraacetic acid disodium 0.05mg

Adding pure water to 0.1ml

The preparation method comprises the following steps:

the active ingredients and excipients are dissolved in water and transferred to a suitable container.

Example VI

Injectable solution containing 5mg of active substance per 5ml

Consists of the following components:

active substance 5mg

Glucose 250mg

Human serum albumin 10mg

Polyethylene glycol tetrahydrofuran methyl ether 250mg

Adding water for injection to 5ml

Preparation:

dissolving polyethylene glycol tetrahydrofuran methyl ether and glucose in water for injection (WfI); adding human serum albumin; heating to dissolve the active ingredients; make up to the specified volume with WfI; transferred to an ampoule under nitrogen.

Example VII

Injectable solution containing 100mg of active substance per 20ml

Consists of the following components:

active substance 100mg

KH potassium dihydrogen phosphate₂PO₄ 12mg

Disodium hydrogen phosphate Na ═ Na₂HPO₄*2H₂O 2mg

Sodium chloride 180mg

Human serum albumin 50mg

Polysorbate 8020 mg

Adding water for injection to 20ml

Preparation:

dissolving polysorbate 80, sodium chloride, potassium dihydrogen phosphate and disodium hydrogen phosphate in water for injection (WfI); adding human serum albumin; heating to dissolve the active ingredients; make up to the specified volume with WfI; transfer to ampoule.

Example VIII

Freeze-dried powder (Lyophilisate) containing 10mg of active substance

Consists of the following components:

active substance 10mg

Mannitol 300mg

Human serum albumin 20mg

Adding water for injection to 2ml

Preparation:

dissolving mannitol in water for injection (WfI); adding human serum albumin; heating to dissolve the active ingredients; make up to the specified volume with WfI; transferring into a vial; and (5) freeze drying.

Solvent for lyophilized powder:

polysorbate 80 ═ tween 8020 mg

Mannitol 200mg

Adding water for injection to 10ml

Preparation:

dissolving polysorbate 80 and mannitol in water for injection (WfI); transfer to ampoule.

Example IX

Tablet containing 20mg of active substance

Composition of

Active substance 20mg

Lactose 120mg

Corn starch 40mg

Magnesium stearate 2mg

Povidone K25 (Povidone K25) 18mg

Preparation:

mixing active substance, lactose and corn starch uniformly; granulating with polyvidone water solution; mixing with magnesium stearate; pressing in a sheet making machine; the tablet weight was 200 mg.

Example X

Capsule containing 20m active substance

Consists of the following components:

active substance 20mg

Corn starch 80mg

Highly dispersed silicate 5mg

Magnesium stearate 2.5mg

Preparation:

uniformly mixing the active substance, the corn starch and the silicate; mixing with magnesium stearate; the mixture was filled into hard gelatin capsules No. 3 in a capsule filling machine.

Example XI

Suppository containing 50mg of active substance

Consists of the following components:

active substance 50mg

Adding stearin (solid tallow (Adeps solidus)) in an amount of 1700mg

Preparation:

melting the hard fat at about 38 ℃; uniformly dispersing the ground active material in the molten stearin; after cooling to about 35 ℃, it is injected into a cooled mold.

Example XII

Injectable solution containing 10mg of active substance per 1ml

Consists of the following components:

active substance 10mg

Mannitol 50mg

Human serum albumin 10mg

Adding water for injection to 1ml

Preparation:

dissolving mannitol in water for injection (WfI); adding human serum albumin; heating to dissolve the active ingredients; make up to the specified volume with WfI; transferred to an ampoule under nitrogen.

Claims

1. Compounds of the general formula I, their tautomers, their diastereomers, their enantiomers, their hydrates, their mixtures and their salts and hydrates of the salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases

Wherein

R¹Represents formula IIa or IIbGroup of IIb

And is

R²Represents H or C_1-3-alkyl, or

R¹And R²Together with the nitrogen atom to which it is bonded, represent a group of the general formula IIIa or IIIb.

G represents C-R^1.1Or the number of N is greater than the number of N,

t represents N-R^1.2Or an oxygen-containing gas,

R^1.1independently of each other represent

(a)H，

R^1.2independently of each other represent

H or

C_1-3-an alkyl group,

R^1.3to represent

(a)H，

F、-CN、C_1-3-alkyl, -CO₂-R^1.3.1Or

C_1-3-an alkyl group, wherein each methylene group may be substituted by up to 2 fluorine atoms and each methyl group may be substituted by up to 3 fluorine atoms,

R^1.3.1to represent

(a)H，

(b)C_1-6An alkyl group, a carboxyl group,

R³represents a quilt group R^3.1、R^3.2And R^3.3Substituted 6-or 10-membered aryl or

R^3.1to represent

(a)H，

(e)-C(O)-R^3.1.2，

(f)-S(O)₂-R^3.1.3，

R^3.1.1to represent

(a)H，

C_3-6Cycloalkyl radical, C_5-6A cycloalkenyl group, a cycloalkyl group,

(R^3.1.1.1)₂N，

at the nitrogen atom by a group R^3.1.1.1Substituted and by one or two radicals R at carbon atoms^3.1.1.2A substituted saturated, monounsaturated or diunsaturated 5-or 6-membered heterocyclic group, or

At carbon atom by a group R^3.1.1.2(ii) a substituted heteroaryl group, wherein,

R^3.1.1.1independently of each other represent

(a)H、C_1-4Alkyl radical, C_3-6A cycloalkyl group,

(b) a heterocyclic group,

(c) aryl-C_0-3-alkylene orheteroaryl-C_0-3-an alkylene group,

R^3.1.1.2independently of each other represent

(b) Phenyl or phenyl-CH₂，

R^3.1.1.2.1Representation H, C_1-6An alkyl group, a benzyl group,

R^3.1.2represents-O-C_1-3-alkyl, -OH, -NR^3.1.2.1R^3.1.2.2，

R^3.1.2.1Representation H, C_1-3-an alkyl group,

R^3.1.2.2representation H, C_1-3-an alkyl group,

R^3.1.3represents-O-C_1-3-alkyl, -NR^3.1.3.1R^3.1.3.2，

R^3.1.3.1Representation H, C_1-3-an alkyl group,

R^3.1.3.2representation H, C_1-3-an alkyl group,

R^3.2to represent

(a)H，

(e)-C(O)-R^3.2.1，

(f)-S(O)₂-R^3.2.2，

R^3.2.1represents-O-C_1-3-alkyl, -OH, -NR^3.2.1.1R^3.2.1.2，

R^3.2.1.1Representation H, C_1-3-an alkyl group,

R^3.2.1.2representation H, C_1-3-an alkyl group,

R^3.2.2represents-NR^3.2.2.1R^3.2.2.2，

R^3.2.2.1Representation H, C_1-3-an alkyl group,

R^3.2.2.2representation H, C_1-3-an alkyl group,

R^3.3to represent

(a)H，

(d)C_1-3-alkyl or C_1-3-alkyl-O-groups in which each methylene group is substituted by up to 2 fluorinesSubstituted with up to 3 fluorine atoms per methyl group,

(e)-C(O)-R^3.3.1，

(f)-S(O)₂-R^3.3.2，

R^3.3.1represents-O-C_1-3-alkyl, -OH, -NR^3.3.1.1R^3.2.1.2，

R^3.3.1.1Representation H, C_1-3-an alkyl group,

R^3.3.1.2representation H, C_1-3-an alkyl group,

R^3.3.2represents-O-C_1-3-alkyl, -NR^3.3.2.1R^3.3.2.2，

R^3.3.2.1Representation H, C_1-3-an alkyl group,

R^3.3.2.2representation H, C_1-3-an alkyl group,

R^3.3.3independently of each other represent

(a)C_1-4-alkyl or

(b)C_3-6A cycloalkyl group,

R^3.3.4independently of each other represent

(a)C_1-4-alkyl or

(b)C_3-6A cycloalkyl group,

(c) halogen, CN, -O-C_1-3-alkyl, -NH₂，

u represents N, N-oxide or C-R⁴，

V represents N, N-oxide or C-R⁵，

X represents N, N-oxide or CR⁶，

Y represents N or C-R⁷，

R⁴to represent

(a)H，

R^4.1represents H, OH or-O-CH₃，

R^4.2Represents H or C_1-3-an alkyl group,

R^4.3represents H or C_1-3-alkyl, or

R⁵to represent

(a)H，

(e) aryl-C_0-3-an alkylene-O-group,

R^5.1represents H, OH or-O-CH₃，

R^5.2Represents H or C_1-6An alkyl group, a carboxyl group,

R^5.3representation H, C_1-6Alkyl or-SO₂-C_1-3-alkyl, or

R⁶to represent

(a)H，

(e)C_1-3-alkyl or C_1-3-alkyl-O-groups in which each methylene group is substituted by up to 2 fluorine atoms and each methyl group is substituted by up to 3 fluorine atomsThe substitution is carried out by the following steps,

R^6.1represents H, OH or-O-CH₃，

R^6.2Represents H or C_1-3-an alkyl group,

R^6.3represents H or C_1-3-alkyl, or

R⁷Represents H, halogen or C_1-3-an alkyl group.

2. A compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

u, V, X, Y, R therein²And R³As defined in claim 1, and

R¹represents a group selected from:

R^1.1to represent

(a)H，

R^1.2to represent

(a) H or

(b)CH₃。

3. A compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

u, V, X, Y, R therein²And R³As defined in claim 1, and

and is

R^1.1To represent

(a)H，

Halogen, C_1-3-alkyl, -OH, -CN, -O-C_1-3-alkyl, -C (O) -O-C_1-3Alkyl radical, C_2-4-alkenyl, C_2-4-alkynyl, C_1-3-alkyl-S, -NH₂，

C_1-3-alkyl or C_1-3-alkyl-O-groups wherein each methylene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms.

4. A compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

wherein U, V, X, Y and R³As defined in claim 1, and

R¹represents a group selected from:

and is

R^1.1To represent

(a)F、CH₃、-OH、-O-CH₃Or

(b)CF₃。

5. A compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

u, V, X, Y, R therein²And R³As defined in claim 1, and

R^1.1to represent

(a)F、CH₃、-OH、-O-CH₃Or CF₃。

6. A compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

u, V, X, Y, R therein²And R³As defined in claim 1, and

R¹represents a group selected from:

7. a compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

wherein U, V, X, Y and R³As defined in claim 1, and

8. a compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

u, V, X, Y, R therein¹And R²As defined in claim 1, 2, 4 or 6, and

R³a group of the formula IV

A independently of one another represents C-H, C-F or N,

R^3.1to represent

(a)H，

Halogen, -NH₂、C_1-4-alkyl-NH, (C)_1-4-alkyl groups)₂N、C_1-3alkyl-C (O) -NH, C_1-3alkyl-S (O)₂-NH、-CN、-OH 、-O-C(O)-NH-C_1-3-an alkyl group,

C_1-4-alkyl, R^3.1.1-C_1-3Alkylene radical, C_2-4-alkenyl, C_2-4-alkynyl, C_1-3-alkyl-O, C_1-3-an alkyl-S group,

C_1-3-alkyl or C_1-3-an alkyl-O-group wherein each methylene group is substituted by up to 2 fluorine atoms and each methyl group is substituted by up to 3 fluorine atoms,

-C(O)-R^3.1.2，

-S(O)₂-R^3.1.3，

R^3.1.1to represent

(a)H，

C_3-6Cycloalkyl radical, C_5-6A cycloalkenyl group, a cycloalkyl group,

(R^3.1.1.1)₂N，

R^3.1.1.1independently of each other represent

H、C_1-4Alkyl radical, C_3-6A cycloalkyl group,

a heterocyclic group,

aryl-C_0-3Alkylene or heteroaryl-C_0-3-an alkylene group,

R^3.1.1.2independently of each other represent

H、F、C_1-3-alkyl, -CN, -OH, -O-C_1-3Alkyl, -CO (O) R^3.1.1.2.1、H₂N、(C_1-4-alkyl) -NH, (C)_1-4-alkyl groups)₂N，

Phenyl or phenyl-CH₂，

C_1-3-alkyl or-O-C_1-3-alkyl, wherein each methylene group is substituted by up to 2 fluorine atoms and each methyl group is substituted by up to 3 fluorine atoms, or

R^3.1.1.2.1Representation H, C_1-6An alkyl group, a benzyl group,

R^3.1.2represents-O-C_1-3-alkyl, -OH, -NR^3.1.2.1R^3.1.2.2，

R^3.1.2.1Representation H, C_1-3-an alkyl group,

R^3.1.2.2representation H, C_1-3-an alkyl group,

R^3.1.3represents-NR^3.1.3.1R^3.1.3.2，

R^3.1.3.1Representation H, C_1-3-an alkyl group,

R^3.1.3.2representation H, C_1-3-an alkyl group,

R^3.2to represent

(a)H，

Halogen, -NH₂、C_1-4-alkyl-NH, (C)_1-4-alkyl groups)₂N、C_1-3alkyl-C (O) -NH, C_1-3alkyl-S (O)₂-NH、-CN、-OH、-O-C(O)-NH-C_1-3-an alkyl group,

C_1-4alkyl radical, C_2-4-alkenyl, C_2-4-alkynyl, C_1-3-alkyl-O, C_1-3-an alkyl-S group,

-C(O)-R^3.2.1，

-S(O)₂-R^3.2.2，

R^3.2.1represents-O-C_1-3-alkyl, -OH, -NR^3.2.1.1R^3.2.1.2，

R^3.2.1.1Representation H, C_1-3-an alkyl group,

R^3.2.1.2representation H, C_1-3-an alkyl group,

R^3.2.2represents-NR^3.2.2.1R^3.2.2.2，

R^3.2.2.1Representation H, C_1-3-an alkyl group,

R^3.2.2.2representation H, C_1-3-an alkyl group,

R^3.3to represent

(a)H，

-C(O)-R^3.3.1，

-S(O)₂-R^3.3.2，

R^3.3.1represents-O-C_1-3-alkyl, -OH, -NR^3.3.1.1R^3.3.1.2，

R^3.3.1.1Representation H, C_1-3-an alkyl group,

R^3.3.1.2representation H, C_1-3-an alkyl group,

R^3.3.2represents-O-C_1-3-alkyl, -NR^3.3.2.1R^3.3.2.2，

R^3.3.2.1Representation H, C_1-3-an alkyl group,

R^3.3.2.2representation H, C_1-3-alkyl, or

R^3.3.3independently of each other represent

C_1-4-alkyl, or

C_3-6A cycloalkyl group,

R^3.3.4independently of each other represent

C_1-4Alkyl radical, C_3-6A cycloalkyl group,

halogen, CN, C_1-3-alkyl-O-, -NH₂，

9. A compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

u, V, X, Y, R therein¹And R²As defined in claim 1, 2, 4 or 6, and

R³a group of the formula IV

A independently of one another represents C-H, C-F or N,

R^3.1to represent

(a)H，

Halogen, -NH₂、C_1-4-alkyl-NH, (C)_1-4-alkyl groups)₂N、C_1-3-alkyl-C (O) -NH, -CN, -OH, -O-C (O) -NH-C_1-3-an alkyl group,

R^3.2to represent

(a)H，

(b) Halogen element、-NH₂、C_1-4-alkyl-NH, (C)_1-4-alkyl groups)₂N、C_1-3-alkyl-C (O) -NH, -CN, -OH, -O-C (O) -NH-C_1-3-an alkyl group,

R^3.3to represent

H，

R^3.3.3independently of each other represent

C_1-4-alkyl or

C_3-6A cycloalkyl group,

R^3.3.4independently of each other represent

C_1-4Alkyl radical, C_3-6A cycloalkyl group,

halogen, CN, C_1-3-alkyl-O-, -NH₂，

10. A compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

u, V, X, Y, R therein¹And R²As defined in claim 1, 2, 4 or 6, and

R³a group of the formula IVa

R^3.1To represent

(a)H，

F、C1、Br、-NH₂、C_1-3-alkyl-NH, (C)_1-3-alkyl groups)₂N、C_1-3-alkyl-C (O) -NH, -CN, -OH,

R^3.2to represent

(a)H，

F、Cl、Br、H₂N、(C_1-4-alkyl) -NH, (C)_1-4-alkyl groups)₂N、(C_1-3-alkyl) -C (O) -NH, -OH,

C_1-4-an alkyl group,

R^3.3to represent

(a)H，

(c)C_1-4-an alkyl group,

R^3.3.3independently of each other represent

C_1-4-alkyl or

C_3-6A cycloalkyl group,

R^3.3.4independently of each other represent

C_1-4Alkyl radical, C_3-6A cycloalkyl group,

halogen, CN, C_1-3-alkyl-O-, -NH₂，

C_1-3-alkyl or C_1-3-an alkyl-O-group wherein each methylene group is substituted by up to 2 fluorine atoms and each methyl group is substituted by up to 3 fluorine atoms, and

R^3.4represents H or F.

11. A compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

u, V, X, Y, R therein¹And R²As defined in claim 1, 2, 4 or 6, and

R³represents a group selected from:

12. a compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

u, V, X, Y, R therein¹And R²As defined in claim 1, 2, 3, 4, 5, 6 or 7, and

R³a group of the formula IVb

R^3.1To represent

(a)H，

F、Cl、Br、-NH₂、C_1-3-alkyl-NH, (C)_1-3-alkyl groups)₂N、C_1-3-alkyl-C (O) -NH, -CN, -OH,

R^3.3.3independently of each other represent

C_1-4-alkyl or

C_3-6Cycloalkyl radicals, and

R^3.3.4independently of each other represent

C_1-4Alkyl radical, C_3-6A cycloalkyl group,

halogen, -CN, -O-C_1-3-alkyl, -NH₂，

13. A compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

u, V, X, Y, R therein¹And R²As defined in claim 1, 2, 3, 4, 5, 6 or 7, and

R³a group of the formula IVb

R^3.1To represent

(a)H，

R^3.3.3independently of each other represent

(a)C_1-4-alkyl or

(b)C_3-6Cycloalkyl radicals, and

R^3.3.4independently of each other represent

(a)C_1-4Alkyl radical, C_3-6A cycloalkyl group,

(b) halogen, -CN, -O-C_1-3-alkyl, -NH₂，

(c)C_1-3-alkyl or C_1-3-alkyl-O-groups wherein each methylene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms.

14. A compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

u, V, X, Y, R therein¹And R²As defined in claim 1, 2, 3, 4, 5, 6 or 7, and

R³a group of the formula IVc

T denotes O, S, CH₂NH or N-R^3.3.3，

R^3.1To represent

(a)H，

R^3.3.3independently of each other represent

(a)C_1-4-alkyl or

(b)C_3-6A cycloalkyl group.

15. A compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

u, V, X, Y, R therein¹And R²As claimed in claim 1, 2, 3, 4, 5, 6 or 7Is defined, and

R³represents a group selected from:

16. a compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

y, R therein¹、R²And R³As defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, and

U-V-X represents a group selected from:

R⁴to represent

(a)H，

R^4.1represents H, OH or-O-CH₃，

R^4.2Represents H or C_1-3-an alkyl group,

R^4.3represents H or C_1-3-alkyl, or

R⁵to represent

(a)H，

(e) aryl-C_0-3-an alkylene-O-group,

R^5.1represents H, OH or-O-CH₃，

R^5.2Represents H or C_1-6An alkyl group, a carboxyl group,

R^5.3representation H, C_1-6Alkyl or-SO₂-C_1-3-an alkyl group,

R⁶to represent

(a)H，

R^6.1represents H, OH or-O-CH₃，

R^6.2Represents H or C_1-3-an alkyl group,

R^6.3represents H or C_1-3-alkyl, or

R^6.2And R^6.3Together with the nitrogen atom to which they are bound represent a 3-to 6-membered heterocyclic group.

17. A compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

ring (C)Represents a group selected from:

18. a compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

wherein

R¹Represents a group selected from:

R²the expression "H" is used to indicate the formula,

R³represents a group selected from:

and is

Ring (C)Represents a group selected from:

19. a compound of the general formula I according to claim 1, the tautomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

wherein

R³represents a group selected from:

and a ringRepresents a group selected from:

20. a compound of the general formula I according to claim 1, the enantiomers, diastereomers, hydrates, mixtures thereof and salts thereof and the hydrates of the salts, especially the physiologically acceptable salts thereof with inorganic or organic acids or bases,

wherein the compound of formula I is selected from:

21. a physiologically acceptable salt of a compound according to any one of claims 1 to 20 with an inorganic or organic acid or base.

22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 20 or a physiologically acceptable salt according to claim 21, optionally together with one or more inert carriers and/or diluents.

23. Use of a compound according to any one of claims 1 to 21 or a physiologically acceptable salt thereof for the preparation of a pharmaceutical composition for the acute and prophylactic treatment of headache, in particular migraine or cluster headache.

24. The use of a compound according to any one of claims 1 to 21, or a physiologically acceptable salt thereof, for the preparation of a pharmaceutical composition, said pharmaceutical composition is used for the treatment of non-insulin dependent diabetes mellitus (NIDDM), complex regional pain syndrome (CRPS1), cardiovascular disease, morphine tolerance, diarrhea caused by clostridial toxins, skin disease, especially heat and radiation induced damage including sunburn, inflammatory disease, such as inflammatory diseases of the joints (arthritis), neuroinflammation of the oral mucosa, inflammatory lung diseases, allergic rhinitis, asthma, diseases which are accompanied by excessive vasodilation and thus a decrease in vascular blood flow, such as shock and sepsis, for relieving pain, or for prophylactic or acute therapeutic treatment of symptoms of menopausal hot flashes due to vasodilation and increased blood flow in estrogen-deficient women and hormone-treated prostate cancer patients and castrated men.

25. A process for the preparation of a pharmaceutical composition according to claim 22, characterized in that a compound according to any one of claims 1 to 21 or a physiologically acceptable salt thereof is incorporated by non-chemical means into one or more inert carriers and/or diluents.