TW201038571A - New compounds - Google Patents

Abstract

The present invention relates to new CGRP-antagonists of general formula I, wherein U, V, X, Y, R1, R2 and R3 are defined as stated hereinafter, the tautomers, the isomers, the diastereomers, the enantiomers, the hydrates, the mixtures thereof and the salts thereof and the hydrates of the salts, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing these compounds, their use and processes for preparing them.

Description

201038571 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a novel CGRP-antagonist of the formula

(I) wherein 11, ¥, 乂, 丫, 尺 1, 1, and 113 are defined as follows; tautomers, isomers, diastereomers, enantiomers, Hydrates, mixtures and salts thereof and hydrates of such salts, in particular, physiologically acceptable salts thereof with inorganic or organic acids or bases, pharmaceutical compositions containing such compounds, uses thereof and methods for their preparation . SUMMARY OF THE INVENTION In a first embodiment, in the above formula j, R1 represents a group of the formula Ila or lib.

R2 represents an alkyl group, or R1 and R2 together with a nitrogen atom + _ bonded thereto represent a general formula or a group of (10)

139377.doc 201038571 G represents C-R1·1 or N, T represents N-R12 or 〇, R stands independently of each other (4)Η, ❹ (8) dentate, C丨.3 alkyl, -oh, -CN,-0- C丨_3 alkyl, ·<:(〇)-〇-C]-3 alkyl, C2.4 alkenyl, _C2_4 alkynyl, Cw alkyl-S, cyclopropyl, -NH2, -COOH, -NH-CXCO-O-Cw alkyl, -NH-QCO-Cw alkyl, ((0匚1.3院基或(^]_3娱乐1基-〇- group, wherein each methylene group is at most 2 Each fluorine atom is substituted and each methyl group is substituted with up to 3 fluorine atoms, and R1·2 independently represents (4) Η or (b) C1 _3 alkyl group, and R1'3 represents 〇(a) Η , (b) F, - CN, Cw alkyl, -C02-:rU.i or (C) Ci-3 alkyl, wherein each methylene group may be substituted with up to 2 fluorine atoms and each methyl group may have up to 3 fluorine atoms Substituted, * ό 1 · 3 · 1 ± -* K represents not (a) Η, (b) CU6 alkyl, R3 6 or 1 aryl substituted by R3·, RU&R3.3 Or 6-membered aryl substituted by a group attached to a carbon atom, RU, R3·2, and R3·3, 139377.doc 201038571 aryl, R31 represents (a) Η, (b) halogen, -ΝΗ2, CN4 alkyl- ΝΗ, (Cw alkyl) 2Ν, Cw alkyl-C(0)-NH, Cw alkyl-S(02)-NH, -CN, -OH, -OC(0)-NH-C 丨·3 alkyl, (c) Cw alkane Base, R^-Cu alkylene, C2_4 alkenyl, (: 2_4 alkynyl, Cw alkyl-o, Cw alkyl-S(0)m, cyclopropyl, (d) Cw alkyl or C!- a 3-alkyl-hydrazine- group in which each methylene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms, (e) -C(0)-R31·2, (f -s(o)2-r31·3, R3 11 represents (a) Η, (b) C3.6 cycloalkyl, c5_6 cycloalkenyl, (c) (R3·1·1·1)^ > (d) a saturated, monounsaturated or diunsaturated 5 or 6 member substituted at the nitrogen atom via a group R3".ii and substituted at the carbon atom with one or two groups R3·1.*.2 a heterocyclic group, or (e) a heteroaryl group substituted at the carbon atom via a group R3·1·1.2, R3.1·1·1 independently of each other (4)H, Cl.4, and c3.6 ring Alkyl, (b)heterocyclyl, 139377.doc 201038571 (C) aryl-Co, 3 alkyl or heteroaryl < 〇3 alkyl, R3·1·1·2 are represented independently of each other a) Η, F, Ch alkyl, -CN, -OH, -O-Cw alkyl, -CCXCOR3.1·1·2·1, h2n, (Cl_4 alkyl)_ΝΗ, (Ci 4 alkyl 2N, (b) phenyl or phenyl-CH2, (c) Cu alkyl or -oc!.3 alkyl, wherein each methylene is substituted with up to 2 IL atoms and each thiol is up to 3 Substituted by a fluorine atom, or R3·1·1·2·1 represents H, C!-6 alkyl, benzyl, 3 12 R · · represents - O-Cu, -OH, -isrR3·1.2·1 !^3·1·2.2, R3.1.2·1 represents Η, (:丨-3 alkyl, R3·1·2.2 represents Η, C 卜3 alkyl, 丨 and Rm·2 together may form a selected from nitrogen Heterocyclic butyl, pyrrolidinyl, σ-bottomyl, oxazinyl and morphinyl rings, R3.13 represents -O-Cw alkyl, -NR3·1·3.^3.1.3.2, R3· 1.3·1 represents Η, C 卜 3 alkyl, R3.1·3.2 represents Η, C 卜 3 alkyl, R3.l.3.l and R3.l·3.2 together may also form a selected from azetidinyl , pyrrolidinyl, brittle base, brigade base and ruthenyl ring, R3·2 represents (4) Η, (b) halogen, -NH2, Cm alkyl-oxime, (Cw alkyl) 2n, Cw alkyl- C(0)-NH, Ci-3 alkyl-S(〇2)-NH '-CN,·ΟΗ,-0-C^CO-NH-Cu alkyl, (c) Cm alkyl, C2-4 Alkenyl, C2-4 alkynyl, Cl_3 alkyl 〇, Cw 139377.doc 201038571 alkyl-S(0)m, cyclopropyl, (d) a C..3 alkyl or C.sub.3 alkyl-indole group wherein each methylene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms, (e) -C (0)-R3·21, (f) -S(0)2-R3.2·2, r3.2.1 represents -Q-Cu, _〇H, 2.1.2, R3·2·1·1 Represents H, Cu alkyl, R3.2.1·2 represents H, Cw alkyl, and R3·2·1·1 together with R3.2.1.2 may also be selected from azetidinyl, pyrrolidinyl, and盐基,派17秦基和莫琳基之环, R3·2.2 represents -NR3·2'2,1!^3.2,2,2, R3·2'2'1 represents Η, Cw alkyl, R3· 2'2'2 represents an anthracene or a Cw alkyl group, and together with Ru'2'2, a ring selected from the group consisting of azetidinyl, pyrrolidinyl, brittle base, 'bottom base and base group , R3·3 represents (a) Η, (b) halogen, ΝΗ 2, Cw alkyl-hydrazine, (Cw alkyl) 2 Ν, C _ 3 alkyl-C(0)-NH, Cw alkyl-S ( 02) -NH, -CN, -OH, -OC^CO-NH-Cu alkyl, (c) Cm alkyl, C2.4 dilute, C2-4 alkynyl, Ci-3 alkyl-hydrazine, Cu Alkyl-s(o)m, cyclopropyl, (d) C!-3 alkyl or C,.3 alkyl-O- group, wherein each methylene group is passed to 139377.doc -8- 20103857 1 more than 2 fluorine atoms are substituted for each generation, and the methyl group is taken up to 3 fluorine atoms to take (4)-C(0)-R3·3·, (1)-S(0)"R3丄' Μ.] R3·3·1 Represents -OC丨_3 alkyl, _〇h, _Nr3.3.丨·1r3 3 i 2,

R

R represents Η, C 。.3 alkyl, represents Η, c].3 alkyl, U 3.3.1.1 ^ u 3.3.1.2 L - Ο ❹ together with R can also be formed from «. . a ring of a pyrrolidinyl group, a pyridyl group, a piperazinyl group and a morpholinyl group, R3·3·2 represents -OC 丨·3 alkyl group, _NR3.3'2.1r3.3 2 2, 2·1 represents Η , Ci_3 alkyl R3·3·2·2 represents H, c丨·3 alkyl R3

1 and R

R 3.3.2· 22 may also form a ring selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, or R3·2 and R3.3 together with a carbon ruthenium attached thereto I am overwhelmed by the formation of a monounsaturated 5-membered heterocyclic group or a monounsaturated or diunsaturated 6-membered 7-mussel heterozygous group or 5 to 6-membered heteroaryl, of which, month J The escaping may contain a few groups, a thiol group or an aryl imino group adjacent to a nitrogen atom, and the cleavage may additionally be carried out at one or two of the nitrogen atoms via the group r3 3 3 Substituted, and optionally substituted at one or two carbon atoms - or two groups R3 · 3 · 4, r3 · 3 · 3 independently of each other 139377.doc 201038571 (a) Cw alkyl, Or (b) C3_6 cycloalkyl, R3 '3·4 independently of each other means (a) Cw alkyl, or (b) (: 3.6 cycloalkyl, (c) halogen, CN, -O-Cw alkyl, -NH2, (d) a Cu alkyl or Cu alkyl-hydrazine- group in which each methylene group is substituted with up to 2 fluorine atoms and each - mercapto group is substituted with up to 3 gas atoms, U represents N, N-oxide or C-R4, V N, N-oxide or C-R5, X represents N, N-oxide or CR6, Y represents N or C-R7, and up to three of the previously mentioned groups U, V, X or Y Also denotes a nitrogen atom, R4 represents (a) Η, (b) C!-6 alkyl or CN3 alkyl-O- group, which are respectively substituted by a group R4·1, (c) R4, 2R4'3N, rUrUN-Cw alkyl, (d) halogen, -CN, -OH, -COOH, Cw alkyl-hydrazine, Cw alkyl-hydrazine-C.3 extended alkyl, C3-6 cycloalkyl, C3.6 Cycloalkyl group _Ci_4 alkylene, Ch alkyl-(:(0)-0-(^-3alkylene, (e) C].3 alkyl or C 1-3 alkyl-hydrazine-group 5 wherein each of the fluorene groups is 139377.doc -10- 201038571 more than two fluorine atoms are substituted and each methyl group is substituted with up to 3 fluorine atoms, and R4·1 represents Η, OH or -〇-CH3, R4· 2 represents Η4〇ν3 alkyl, R4·3 represents an alkyl group, or R and R 1% together with a nitrogen atom bonded thereto represent a 3- to 6-membered heterocyclic group, ❹

Q R5 represents (a) Η, (b) a Cw alkyl group or a Cl.3 alkyl 〇 〇 group, which is substituted by the group rS1#, (C) -NRS.2R5·3, NR5.2r5_3_c "3 Alkyl, (4) halogen, -CN, -OH, Cw alkyl-0_Ci3 alkyl, c3 6 cycloalkyl, 〇3.6 cycloalkyl-Cl-4 alkyl" Gy alkyl _c(〇)_〇_ Cl-3 extended alkyl, (e) aryl-C0_3 alkyl-hydrazine- group (1) Cw alkyl or Cw alkyl-hydrazine- group, wherein each methylene group is substituted with up to 2 atoms and each - methyl is substituted with up to 3 fluorine atoms, R5·1 represents Η, OH or -〇-CH3, RS·2 represents Η or CN6 alkyl, R represents H, C!_6 alkyl or -SC^-Cu The group, or R5·2 and R5·3 together with the nitrogen atom to which it is bonded, together with the nitrogen atom of 3 to 6 are heterocyclic 139377.doc 201038571 R6 means (a) Η, (b) C _ _ alkyl or a Cw alkyl-O- group via a group R6.^, (c) R6.2R6'3N, R6_2R6.3N-CN3 alkyl, (d) halogen, -CN, -OH, -COOH , Cl.3 alkyl-hydrazine, Ci 3 alkyl-O-Cw alkylene, c3-6 cycloalkyl, c3-6 cycloalkyl-Ci 4 alkyl, Ci_3 alkyl extended alkyl, (e) Ci-3 Base or C!_3 alkyl-〇-group, each of which Up to 2 fluorine atoms are substituted and each methyl group is substituted with up to 3 fluorine atoms, R6·1 represents Η, OH or -〇-CH3, R6·2 represents Η or Ci_3 alkyl, and R6·3 represents HSCw alkyl, Or R6·2 and R6·3 together with the nitrogen atom to which they are bonded represent a heterocyclic group of 3 to 6 members, and R represents a tautomer or a diastereomer of an anthracene, a halogen or a Cw alkyl group. And salts thereof and hydrates of such salts, or physiologically acceptable salts, enantiomers, hydrates, and in particular, specifically and inorganic or organic The examples comprise a compound of the above formula I, wherein ', v, x, y, r2 and r3 are as defined above in the first embodiment, and R1 represents a group selected from the group consisting of: 139377.doc • 12-201038571

R1'1 represents. (a) Η , (b) 素素, Cw alkyl, -〇H, -CN, -O-Cw alkyl, -C(O)-O-Cw alkyl, c24 alkenyl, C2_4 alkynyl, Cw alkyl-s, ❹-NH2, (C) Cw alkyl or Cw alkyl_0- group, wherein each fluorenylene group is substituted with up to 2 fluorine atoms and each methyl group is at most 3 fluorine atoms are substituted, and R12 represents (a) Η, or (b) CH3, tautomers, diastereomers, enantiomers, hydrates, mixed chelates thereof and salts thereof Hydrates of such salts, in particular, with inorganic or organic acids or physiologically acceptable salts thereof. • A third embodiment of the invention comprises a compound of the above formula I, wherein U, V, X, Y and R3 are as defined above in the first embodiment, and

Ri and W together with the nitrogen atom to which they are bonded represent a group selected from the following:

139377.doc •13- 201038571

RK1 represents (4) Η, (b) i, Cu, -OH, -CN, -O-Cu, -C(O)-O-Cw alkyl, C2-4 alkenyl, C2-4 alkynyl , Cw alkyl-S, -NH2, (c) C; [_3 alkyl or C!-3 alkyl-O- group, wherein each fluorenylene group is substituted with up to 2 fluorine atoms and each thiol group Substituted with up to 3 fluorine atoms, its tautomers, diastereomers, enantiomers, hydrates, mixtures and salts thereof, and hydrates of such salts, in particular with inorganic or organic A physiologically acceptable salt of an acid or a base. A fourth embodiment of the present invention comprises a compound of the above formula, wherein U, V, X, Y, R2 and R3 are as defined above in the first embodiment and R1 represents a group selected from the group consisting of :

R1'1 indicates

(4) F, CH3, -OH, -O-CH 339377.doc -14- 201038571 (b) cf3, its tautomers, diastereomers, enantiomers, hydrates, mixtures and their salts And hydrates of such salts, in particular with inorganic or organic salts or physiologically acceptable salts thereof. A fifth embodiment of the invention comprises a compound of the above formula I, wherein U ' V ' X, 丫 and han 3 are as defined above in the first embodiment, and - R1 and R2 together with the nitrogen bonded thereto The atoms together represent a group selected from the following: Ο

O R1·1 represents (a) F, CH3 '-oh, -〇-CH3 or CF3, * tautomers, diastereomers, enantiomers, hydrates, mixed substances and A salt thereof and a hydrate of the salt, in particular, a physiologically acceptable salt thereof with an inorganic or organic acid or base. A sixth embodiment of the invention comprises a compound of the above formula I, wherein v X, γ, R 2 and R 3 are as defined above in the first embodiment, and R represents a group selected from the group consisting of: 139377 .doc -15· 201038571

a hydrate of a tautomer, a diastereomer, an enantiomer, a hydrate, a mixture thereof, a salt thereof, and a salt such as hydrazine, in particular, a physiologically acceptable inorganic or organic acid or base Accept the salt. A seventh embodiment of the present invention comprises a compound of the above formula, wherein U, V, X, Y and R3 are as defined above in the first embodiment, and

R1 and R2 together with the nitrogen atom to which they are bonded represent a group selected from the group consisting of: A

〇

HN

丹立变兵J, 傅傅_~...HIE, leeches, their salts and hydrates of these salts, in particular they are physiologically acceptable with inorganic or acid or alkali salt. An eighth embodiment of the present invention comprises the compound of the above formula I, wherein U, V, X, Y, ri & r2 are as hereinbefore described in the first, ^ -, four or 139377.doc -16 - (IV) , 201038571 is defined in the six embodiments, and R3 represents a group of formula IV

A stands for CH, CF or N independently of each other, 'R3·1 denotes 〇(a)H' (b) self-prime, -NH2, Cl-4 炫*基·NH, (C _4 alkyl) 2N, Ci -3 alkyl-C(0)-NH, c-3 alkyl-S(0)2-NH, -CN, -OH, -0-CCCO-NH-Cm alkyl, (OCw alkyl, R3· 1.1-.alkyl, C2-4 alkenyl, c2_4 alkynyl, Cu alkyl-hydrazine, C1_3 alkyl-s ' (d) CK3 alkyl or Cw alkyl-fluorene-group, each of which The fluorenyl group is substituted with up to 2 fluorine atoms and each fluorenyl group is deuterated by up to 3 fluorine atoms, (4)-C(0)-R31.2, (f) -S(0)2-r3.13, R3 ·1·1 indicates (4)Η, (b) C3.6 cycloalkyl, C5.6 cycloalkenyl, (c) (R31·1·1)^ - (4) at the nitrogen source + via the group R3·". a saturated, monounsaturated or diunsaturated 1 substituted at the carbonogen + via one or two groups R3·1·1·2 139377.doc 17 201038571 5 or 6 membered heterocyclic group, or e) a heteroaryl group substituted at the carbon atom via a group r3.ii.2, R3.1.1·1 independently of each other means (a) H, Cb4 alkyl, [3.6 cycloalkyl, (b) (c) aryl-CG-3 alkyl or heteroaryl _C()_3 alkyl, R3.1.1·2 independently of each other (a) Η, F Cw alkyl, -CN, -OH, -O-Cw alkyl, -C0(0)R311.21, H2N, (Cu alkyl)-NH, (Cm alkyl)2N, (b) phenyl or benzene Base —(:Η2, (c) Cu alkyl or 〇〇_cN3 alkyl, wherein each methylene group is substituted with up to 2 fluorine atoms and each fluorenyl group is substituted with up to 3 fluorine atoms, or R3·1 ·1·2·1 represents Η, Cm alkyl, phenyl fluorenyl, R3.1.2 represents -0-C丨_3 alkyl, -OH, -NR3·1.2·丨R3·1·2·2, R3.丨·2” represents Η, Ci-3 alkyl, R3”·2.2 represents Η, CN3 alkyl, and R3·1·3 represents —NR3*1·3·1!^.1·3·2, R3·1.3 .1 represents Η, Cw alkyl, R3.1.3·2 represents Η, Cw alkyl, R3·2 represents (a) Η, (b) halogen, -ΝΗ2, Cw alkyl-ΝΗ, (Cw alkyl) 2Ν ,Ci.3 alkyl-C(0)-NH, Cb3 alkyl-S(0)2-NH, -CN, -〇H, -Ο- 139377.doc -18- 201038571 CCCO-NH-Cu Alkyl, (c) Cw alkyl, C2.4 alkenyl, c2-4 alkynyl, Cl_3 alkyl 〇, r ^ 1-3 alkyl-s, (d) Ci. 3 alkyl or Ci_3 alkyl a group wherein each methylene group is substituted with two fluorine atoms and each methyl group is substituted with up to three fluorine atoms, (e) -C(0)-R3·21, (f) -s(o )2-r3. 2·2, R3.2·1 represents -O-Cw alkyl,_0H, _NR3.2.1.1R3.2.1.2, R3·2.1.1 represents H 'Cw alkyl, R3.2.i.2 represents H , Cw alkyl, R3·2·2 represents -NR3·2,2,1!^·2,2,:, R3·2'2'1 represents H, C丨_3 alkyl, R3'2'2 '2 represents H, Cu alkyl, R3·3 represents (a) H, (b) halogen, -NH2, Cy alkyl-NH, (Cw alkyl) 2n 'C] 3 alkyl-C(0)- NH, C丨_3 alkyl-S(0)2-NH, -CN, -〇H, -〇_ QCO-NH-Cw alkyl, (c) Cm alkyl, C2-4 alkenyl, c2_4 alkyne a group, Cw alkyl-〇, Ci 3 alkyl-S, (d) C _3 alkyl or Cw alkyl-〇- group, wherein each fluorenylene group is substituted with up to 2 fluorine atoms and each hydrazine Substituted by up to 3 fluorine atoms, 139377.doc -19· 201038571 (e) -C(0)-R3·31, (f) -S(0)2-R3·3 2, R Table _〇- C i·3 炫, -OH, -NR3·3.丨.iR3·3·1.2, R3·3.1.1 represents H, C 3 alkyl, R3·3·1·2 represents Η, Cw alkyl , R3·3·2 represents -O-Cw alkyl, -NR3.3.2.1R3.3.2.2, R3·3.2·1 represents H group, R3·3·2·2 represents H, Cu alkyl, or R : 2 and R3·3 together with the carbon atoms connected to them form a single and 5 members a soil group having an early unsaturated or diunsaturated 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the previously mentioned heterocyclic ring may contain (tetra), sulfur (tetra) or cyanide adjacent to the nitrogen atom. The imino group, and optionally, in the case of one or two nitrogen atoms, substituted by the group R-3, and or two carbon atoms via one or two groups, respectively, may additionally be in a R3·3· 4 is substituted, R3·3·3 independently of each other represents (a) C!-4 炫, or (b) (: 3_6 cycloalkyl, R independently of each other represents (a) Ci-4 alkyl, c3.6 Cycloalkyl, (8), CH, Ci3 alkyl, 〇_, _ leg 2, methyl group to (C) C _3 alkyl or Ci·3 alkyl 〇 〇 group, each of which 139377 .doc 20- 201038571 A fluorine atom is substituted with two more fluorine atoms and each methyl group is substituted for up to 3 generations, its tautomers, diastereomers and salts thereof, and hydrates of such salts Or a physiologically acceptable salt, enantiomer, hydrate, or in particular, in combination with an inorganic or organic invention - the ninth embodiment comprises a compound of the above formula I, wherein

卩...乂...the coffee is as defined above in the fourth or sixth embodiment, and R3 represents a group of the formula IV

(IV), A independently of each other represents CH, CF or N, and R3·1 represents (a) Η, 〇 (b) halogen, -ΝΗ2, C〗 4-alkyl-hydrazine, (Cm alkyl) 2Ν, Cw Pyridyl-C(0)-NH, -CN, -OH, -O-qCO-NH-Cu alkyl, (C) C 1 ·4 alkyl, C 〖-4, C2-4 fast radical, C 1 _3 alkyl-oxime, C 1 _3 alkyl-s, (d) Ci_3 Hyun " or C1-3 alkyl-oxime-group, wherein each fluorenylene group is substituted with up to 2 fluorine atoms and each Monomethyl is substituted with up to 3 fluorine atoms, R3·2 represents (a) Η, 139377.doc -21 - 201038571 (b) Halogen, -NH2, Cm alkyl-NH, (Cw alkyl) 2N, Cu alkane -C(0)-NH, -CN, -OH, -OC^CO-NH-Ch alkyl, (c) Cw alkyl, c2.4 alkenyl, C2-4 alkynyl, Cw alkyl-o , CK3 alkyl-s, (d) C!·3 leucoyl or Cu alkyl-〇-group' wherein each methylene group is substituted with up to 2 fluorine atoms and each fluorenyl group is subjected to up to 3 fluorine atoms Substituted, denotes (a) Η, (b) halogen, -NH2, Cu alkyl-NH, (C"alkyl)2n, Cu alkane-〇-C(〇)-NH-C,-3 alkyl,

base-C(0)-NH, -CN, -OH, alkyl-s *

The adjacent carbonyl group, thiocarbonyl group, and the heterocyclic ring previously mentioned may contain a nitrogen atom or a cyanoimin group, and the cleavage may be additionally one or two or two groups, and the branching is visible. In addition, one or two helium atoms are substituted by a group or two carbon atoms via 139377.doc -22- 201038571 R3·3·4, and R3·3·3 independently of each other represents 0) Cw alkyl, or (b) C3.6 cycloalkyl, R3·3·4 independently of each other (a) Cw alkyl 'c3 6 cycloalkyl, (b) halogen, CN, Ci.3 alkyl..._dish 2, ( c) a Cw alkyl or Cl_3 alkyl 〇 基 group in which each fluorenylene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms, its tautomers, diastereoisomers Isomers 'enantiomers, hydrates, mixtures and salts thereof and hydrates of such salts, in particular with inorganic or organic acids or physiologically acceptable salts thereof. A tenth embodiment of the present invention comprises a compound of the above formula I, wherein U, V, X, Y, 丨 and ^ are as defined above in the first, second, fourth or sixth embodiment And R3 represents a group R3·1 of the formula IVa

Ar3.2 *^^33 , (IVa) R3·1 represents (a) Η, (b) F, Cl, Br, -ΝΗ2, Cw alkyl-ΝΗ, (Cw alkyl) 2Ν, Ci.3 alkyl -C(0)-NH, -CN, -OH, 139377.doc -23- 201038571 (c) Ci_4, C2-4, C2-4, Cl-3, C, Ci- 3 alkyl-s, (d) Cw alkyl or Cw alkyl-〇- group, wherein each fluorenylene group is substituted with up to 2 fluorine atoms and each fluorenyl group is substituted with up to 3 fluorine atoms, R3· 2 represents (4) Η, (b) F, cn, Br, H2N, (Cw alkyl)-NH, (Cm alkyl) 2 Ν, (Cu alkyl)-C(0)-NH, -〇Η, (c) a C 1 _4 base, (d) a C i _3 base or a C i _3 alkyl-〇- group in which each - fluorenylene group is substituted with up to 2 fluorine atoms and each thiol group is up to 3 fluorine ^Atomic substitution 'R3·3 indicates (4)Η, (b) F, cn, Br, H2N, (Cw alkyl)_NH, (Cl4 alkyl) 2ν, (Cu alkyl)-C(0)-NH, -OH , (c) C1.4 alkyl, (sentence!·3 leumino or C)-3 alkyl-oxime group, wherein each methylene group is substituted with up to 2 fluorine atoms and each methyl group Up to 3 fluorine atoms are substituted, R3·2 and R3.3 together with the carbon atom to which they are attached疋牧·<> 屌卞 屌卞 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成 形成Doc •24· 201038571 The previously mentioned heterocyclic ring may contain a few groups adjacent to a nitrogen atom, a thiol or a cyanoimin group, and optionally a group of one or two nitrogen atoms, respectively. R3·3.3 is substituted, and the knives may be additionally substituted at _ or two carbon atoms or two groups R3·3·4, and R3·3·3 are independently represented by each other.

(a) Cm alkyl, or (b) (: 3_6 cycloalkyl, R3·3·4 independently of each other (a) Cw alkyl, c3_6 cycloalkyl, (8) _, CN, Cl.3 alkyl _〇..._NH2, (ΟCw alkyl or Cl_3 alkyl group, wherein each methylene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to (10) i atoms, and R3·4 represents Η or F, Its tautomers, diastereomers, enantiomers, hydrates, mixtures and salts thereof and hydrates of such salts are more physiologically compatible with inorganic or organic acids or bases. Accepted salt. The tenth embodiment of the invention comprises a compound of the above formula k, wherein U, V, x, Y, Rl_ are as defined above in the first, second, fourth or sixth embodiment And R represents a group selected from the group consisting of: 139377.doc -25· 201038571

Its tautomers, diastereomers, enantiomers, hydrates, mixtures and salts thereof and hydrates thereof, in particular, physiologically compatible with inorganic or organic acids or bases Accept the salt. A twelfth embodiment of the present invention comprises a compound of the above formula I, wherein U, V, X, Υ, Ri and R2 in 139377.doc • 26-201038571 are as described above in the first, second, third, As defined in the fourth, fifth, sixth or seventh embodiment, and R3 represents a group of the formula IVb

, (IVb)

R3·1 represents (4) Η, (b) F, Cl, Br, -NH2, Cw alkyl-oxime, (C!.3 alkyl) 2Ν, Ci.3 alkyl-C(0)-NH, -CN, -OH, (C) Cw alkyl, c2.4 alkenyl, c2-4 alkynyl, d-3 alkyl-O, c].3 alkyl-s, (d) Cw alkyl or Cw alkyl_ a 〇-group in which each methylene group is substituted with up to 2 fluorine atoms and each fluorenyl group is substituted with up to 3 fluorine atoms, and R and R together with the carbon atom to which they are bonded form a monounsaturated 5-membered heterocyclic ring a group of monounsaturated or diunsaturated 6 (4) groups or 5 to 6 membered heteroaryl groups, wherein the previously mentioned heterocyclic ring contains a group adjacent to a nitrogen atom, a thiol group or a cyano group Amino groups, and ° each optionally in the or two nitrogen atoms via a group of 3 3 generations, and may each be additionally substituted at one or two bases by one or two groups, 139377.doc -27. 201038571 r3·3·3 independently of each other represents (a) a Cw alkyl group, or (b) a C3.6 cycloalkyl group, and R3·3·4 independently of each other represents (a) a Cl·4 alkyl group, C3.6 cycloalkyl, (b) halogen, -CN, _〇_Ci 3 alkyl, _NH2, (C) C1·3 or K!_3 alkyl-oxime-group, each of which base Up to 2 fluorine atoms are substituted and each thiol is substituted with up to 3 fluorine atoms, the tautomers 'diastereomers, enantiomers, hydrates, mixtures and salts thereof and the salts thereof Hydrates, in particular, with inorganic or organic acids or physiologically acceptable salts thereof. A thirteenth embodiment of the present invention comprises the compound of the above formula I, wherein U, V, X, Υ, R1 & R2 are as described above in the first, second, third, fourth, fifth 'sixth Or as defined in the seventh embodiment, and R3 represents a group of the formula IVb

, (IVb) R3·1 represents (4) Η, (b) F, C b Br, -NH2, C _3 alkyl_NH, (C丨_3 alkyl) 2 Ν Cw alkyl-C(0)-NH ' -CN, -OH, (C) Ci_4 炫, C2-4 dilute, C2-4 fast radical, Ci-3 alkyl-hydrazine, ^ 139377.doc -28 - 201038571 alkyl-s, (4)C,-3 a calcining group or a Cl.3 alkyl group, wherein each methylene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms, and R3·2 and R3, 3 together with a bond thereof a ring group or a 5-membered heteroaryl group, which starts from ... unsaturated 5

The previously mentioned heterocyclic ring contains a cyanoimido group adjacent to the atom of the carbon, and & vol. 4 may each be additionally substituted at the or two nitrogen atoms via the group r3 3 and taken as two The case is additionally substituted at 4 carbon atoms by ~$ two groups R3...4, R3·3·3 independently of each other representing (a) C1.4 alkyl, or (b) C3-6 cycloalkyl, And R3·3·4 independently of each other represent (a) Cw alkyl, c3 6 cycloalkyl, (8) halogen, -CN, -O-Cw alkyl, _Nh2, (c) Cu alkyl or Cl_3 alkyl 〇 a group wherein each methylene group is substituted with up to 2 fluorine atoms and each fluorenyl group is substituted with up to 3 fluorine atoms, and its tautomers, diastereomers, enantiomers, hydration And mixtures of the substances, mixtures and salts thereof, and hydrates of such salts, in particular with physiologically acceptable salts of inorganic or organic acids or bases. 139377.doc • 29- 201038571 A fourteenth embodiment of the invention comprises a compound of the above formula i, wherein U, V, X, Y, fourth, fifth, sixth or R3 represents a group of formula IVc Groups Y, R1 and R2 are as defined above in the first, second, third, sixth or seventh embodiment, and

, (IVc) T represents Ο, S, CH2, NH or N-R3·3.3, R3·1 represents (a) Η, (b) F, Cl, Br, _NH2, Cu sinter-NH, s, hN, Ci_3 Alkyl-C(0)-NH, -CN, -OH, (c) C 1_4 alkyl, C2-4 dilute, C2-4 alkynyl, C 1.3 alkyl-hydrazine, C 1 ·3 alkyl- S, (d) a Cw alkyl or Cw alkyl-fluorene group, wherein each fluorenylene group is substituted with up to 2 fluorine atoms and each fluorenyl group is substituted with up to 3 fluorine atoms, and R3·3·3 Independent of each other, (a) C1-4 cyclyl 5 or (b) (23_6 cycloalkyl, tautomers, diastereomers, enantiomers, hydrates, mixtures thereof and salts thereof) a hydrate of the salt, in particular a physiologically acceptable salt thereof with an inorganic or organic acid or base. A fifteenth embodiment of the invention comprises a compound of the above formula I, 139377.doc -30 - 201038571 wherein UV, χ, γ ' R 丨 and R 2 are as defined above in the first, second, third, fourth, fifth, sixth or seventh embodiment, and R 3 represents a Group of people:

Its tautomers, diastereomers, enantiomers, hydrates, mixed sigma and salts thereof, and hydrates of such salts, in particular their physiology with inorganic or organic acids or bases Acceptable salt. A sixteenth embodiment of the invention comprises a compound of the above formula I, wherein Υ, R, R2 and R3 are as described above in the first, second, third, fourth, fifth, sixth, seventh, Defined in the eighth, ninth, tenth, eleventh, eleventh, thirteenth, fourteenth or fifteenth embodiments, and U_V-X represents a group selected from the group consisting of:

N~N-(C-R6)=, _N=(C_R5)_N=, _n=(c_r5)_(c_r6)=, -(N_ telluride)=(C-RS)_(CR6)=, _( CR4) = N_N=, -(CR4)=N -(CR )==, -(C_r4)=N(oxide)-(c-r6)=, _(cr4)=(c-r5) 139377.doc -31· 201038571 -N=, -(CR4) = (C-R5)-(N-oxide)=, -(CR4) = (C-R5)-(cr6)=, and R4 represents (a) H (b) a Cu alkyl or Cw alkyl-O- group substituted by a group R4·1, (c) R4, 2R4, 3N, rUrWN-Cw alkyl, (d) halogen, -CN , -OH, -COOH, Cw alkyl-hydrazine, Cu alkyl-O-Ci.3 alkylene, (: 3-6 cycloalkyl, C3_6 cycloalkyl-Cw alkylene, Cw alkyl-CCCO-O -Cw alkylene, (e) Cw alkyl or Cw alkyl-0- group, wherein each fluorenylene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms, R4. 1 represents Η, OH or -0-CH3, R4·2 represents Η or Cu alkyl, R4·3 represents Η or Cu alkyl, or R4·2 and R4·3 together with the nitrogen atom bonded thereto represent 3 members To a 6-membered heterocyclic group, R5 represents (a) hydrazine, (b) a Cw alkyl group or a Cw alkyl-fluorene group, which are respectively substituted by a group R5·1, (c) -NR5.2R5.3 , NRUrW-Cu alkylene, (d) halogen, -CN, -OH, Cw alkyl-O-Cw alkylene, (: 3-6 ring 139377.doc 32- 201038571 alkyl, C3_6 cycloalkyl-Cw alkyl, Ci.3 alkyl-c(o)-o- Ci_3 alkylene, (e) aryl-C〇-3 alkyl-hydrazine- group, (f) Cw alkyl or C _3 alkyl-fluorene group, wherein each methylene group is at most 2 fluorine atoms are substituted and each methyl group is substituted with up to 3 fluorine atoms, R5·1 represents Η, ΟΗ or -〇-CH3, and R5·2 represents 11 or (:1.6 alkyl,

R5·3 represents H, Ci.6 alkyl or -SOrCu alkyl, and R6 represents (a) Η, (b) C!·6 alkyl or Cu alkyl-〇-group, respectively, via a group 6.1 Substituted, (c) R6, 2R6_3N, r6.2r6.3n-c丨·3 alkylene, (d) halogen, -CN, -OH, -COOH, Cw alkyl-〇, Cl-3 O-Cw stretching group, c3_6 cycloalkyl group, (: 3_6 cycloalkyl-Ci4 alkylene group, Cu alkyl-(:(0)-0-(^.3 alkylene group, (e) C!- a 3 alkyl group or a Ci. 3 alkyl group-Ο- group in which each of the methylene hydrazines is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms, and R6·1 represents Η, OH or - 0-CH3, R6·2 represents hydrazine or Cw alkyl, R6·3 represents HiCw alkyl, or 3 to 6 membered heterocyclic groups R6·2 and R6·3 together with the nitrogen atom bonded thereto 139377. Doc -33- 201038571, its tautomers, diastereomers, enantiomers, hydrates, mixtures and their salts and hydrates of such salts, in particular with inorganic or organic hydrazine The physiologically acceptable salt of the invention. The seventeenth embodiment of the present invention comprises Y, R1, R2 and r3 of the above formula I, as in the first and second , the fifth: 'the fifth, sixth, seventh, first, ninth, tenth, tenth fourth, second, thirteenth, fourteenth or fifteenth embodiment, the first Ten-S*.

Represents a group selected from the following:

139377.doc -34- 201038571

Its tautomers, diastereomers, enantiomers, hydrates, mixtures and salts thereof and hydrates thereof, in particular, physiologically compatible with inorganic or organic acids or bases Accept the salt. 139377.doc -35- 201038571 An eighteenth embodiment of the invention comprises a compound of the above formula i, wherein R1 represents a group selected from the group consisting of:

R2 means Η,

R3 represents a group selected from the following:

Ch3 〇

Ch3 139377.doc -36- 201038571

CH3

〇/CH3N people! And

Chu N^N 139377.doc -37- 201038571

Its tautomers, diastereomers, enantiomers, hydrates and salts thereof and hydrates of such salts, in particular with inorganic or diacids or physiologically Acceptable salt. The nineteenth embodiment of the present invention comprises the compound of the above formula I, wherein R1 and R2 together with the nitrogen atom to which they are bonded represent a group selected from the group consisting of:

139377.doc •38- 201038571

139377.doc -39- 201038571 n-vch^

Its tautomers, diastereomers, enantiomers, hydrates, mixtures and salts thereof and hydrates thereof, in particular, physiologically compatible with inorganic or organic acids or bases Accept the salt. The following compounds are mentioned as examples of particularly preferred compounds of the above formula I: Numbered structures (1) 丫, ds (3) ν〇ΝΛν^ ΗΝ^ό (4) 139377.doc -40- 201038571 No.-- - Structure (5) (6) ch3 (7) (8) (9) - one

Ο Its enantiomers, diastereomers, hydrates, mixtures and salts thereof, and hydrates of salts such as hai, which are physiologically acceptable with inorganic or organic acids. salt. Terms and Definitions Used The present specification of the present invention is explained in accordance with the conventions and rules of chemical bonds. The compounds included in the present invention are those which are also chemically stable. All substituents are independent of one another unless otherwise stated. If, for example, a plurality of Cw alkyl groups are present as a substituent in a group, in the case of 3 (^_4 alkyl substituents, they are independent of each other, and one may represent a methyl group, " Ethyl and one of which is represented by n-propyl. Within the scope of the present application, in the definition of possible substituents, such 139377.doc -41 - 201038571 ^ is also expressed in the form of a base structure. If present, then The asterisk (7) of the substituent structure is regarded as the point of attachment to the rest of the molecule. For example, the phenyl group is shown as follows: Further, the substituent atom following the point of attachment is regarded as being at the ! atom. The object of the present invention ' Also includes the compounds of the present invention (including salts thereof) in which - or a plurality of hydrogen atoms (for example, !, 2, 3, 4 or 5 hydrogens are replaced by hydrazine. "(C), which is a part of another group, means a branched chain having (1) carbon atoms and a bondless group. The "Ci-4 alkyl group" means 14 carbons. A branched chain of atoms and an unbranched alkyl group and the term "Cl-6 alkyl" means a branch having (1) carbon atoms Chains and unbranched alkyl groups. Examples include: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, t-butyl, pentyl, neopentyl or The n-hexyl group, abbreviations and the like may also be used in the above-mentioned groups as the case may be. Unless otherwise stated, the definition of propyl and butyl includes all possible isomeric forms of the group. Thus, for example, the propyl group includes N-propyl and isopropyl, butyl includes isobutyl, second butyl and tert-butyl, etc. 〃 The term "(:1-6 1-6 & base) (including those as part of other groups) CVW alkyl) means a branched chain having 1 to 6 carbon atoms and a branch-free extension group and the term "C"·3 alkylene group means a branched chain having from 丨 to 3 carbon atoms and no branching. An alkyl group. Examples include: anthracene, exoethyl, propyl, I39377.doc -42- 201038571 1_methylethyl, butyl butyl i-methyl propyl, i 丄Methyl-extended ethyl ' 1,2-dimethyl extended ethyl, pentyl, 1.1-dimethylpropyl, 2,2-methyl propyl, 1,2-dimethyl extended propyl , 丨, 3-dimethylpropyl or exfoliate Unless otherwise stated, the definition of a propyl group includes all possible isomeric forms of the group having the same carbon. 因此 Thus, for example, propyl also includes 1-methyl extended ethyl and butyl. Including 1-methylpropanyl, 1.1-.=methyl-extended ethyl, 1,2·dimethylexylethyl. The definition of 〇Co-alkylene represents a bond. The term "C2_6-alkenyl" ( The inclusion of C 2-6-alkenyl as part of another group means that it has a branched chain of 2 to 6 carbon atoms and an unbranched alkenyl group, and the meaning of C 2 · 4 alkenyl means 2 to The branched chain of 4 carbon atoms and the unbranched alkenyl group are made to contain at least one double bond. Alkenyl groups having 2 to * carbon atoms are preferred. Examples include: ethenyl/vinyl, acryl, butyryl, pentyl or hexyl. Unless otherwise stated, all possible isomeric forms of propenyl, butenyl, pentenyl and hexenyl are described. Thus, for example, the acrylyl group includes a 1-propyl group and a 2-propylene group, and the butylene group includes a dibutyl group, a 2-butanyl group, and a 3"-butenyl group, a methyl group-1-propylene group. Base, 1.methyl-2-propenyl, etc. C2-6 alkynyl (including "c2-6-alkynyl" as part of another group) means a branch having 2 to 6 carbon atoms The chain and the unbranched block group and the term "C2_4 block group" mean a branch bond having 2 to 4 carbon atoms and an unbranched block group, the restriction being that it contains at least one reference bond. Examples include: ethynyl, propyl, butynyl, pentynyl or hexyl. Unless otherwise stated, the definitions of propynyl, butynyl, pentynyl and hexynyl include all possible isomeric forms of the 139377.doc • 43- 201038571 group. Thus, for example, propynyl includes 1-propynyl and 2-propynyl, and butynyl includes indolyl, 2-butynyl and 3-butynyl' 1-methyl-1 - propynyl, benzyl-2-propynyl and the like.浯C3·6环炫基” (including those that are part of other groups)

Cw cycloalkyl) means a cyclic alkyl group having 3 to 6 carbon atoms and the term "C5<cycloalkyl" means a cyclic alkyl group having 5 to 6 carbon atoms. Examples include: fluorenylcyclobutyl, cyclopentyl or cyclohexyl. Unless otherwise stated, a cyclic alkyl group may be substituted with one or more groups selected from the group consisting of methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluoro, ethane, bromo and hydrazine. The term "CS-6 cycloalkenyl" (including those Cs-6 cycloalkenyl as part of another group) means a cyclic alkenyl group having 5 or 6 carbon atoms which contains an unsaturated bond. Examples include: cyclopentenyl or cyclohexyl. Unless otherwise stated, a cyclic alkenyl group may be substituted with one or more groups selected from the group consisting of decyl, ethyl, isopropyl, tert-butyl, hydroxy, a, gas, bromine and iodine. Unless otherwise stated in the definition, the term "heterocyclyl" or "heterocyclic group" means a stable 5-member, 6-member or 7-membered monocyclic heterocyclic system or 8 members, 9 members, members or U members. A bicyclic heterocyclic ring system which does not form an aromatic ring system in at least one ring and which may have a hetero atom selected from nitrogen, oxygen and sulfur in addition to a carbon atom. Both the nitrogen atom and the sulfur atom may be deuterated as appropriate and the nitrogen atom may be quaternized. The heterocycle may contain - or two pendant, sulfur-reactive or cyanoimido groups adjacent to the nitrogen atom. The heterocycle previously mentioned may be attached to the remainder of the molecule via a carbon or gas atom. Unless otherwise stated, the substituent may be substituted by one or more selected from the group consisting of 139377.doc -44- 201038571 (a) OH, N〇2, CN, OCF3, 〇CHF2, 〇CH2F, NH2 (b) halogen, preferably fluorine or gas, (<〇C!_6 alkyl) preferably C!_3 alkyl, especially preferably ethyl, methyl, isopropyl or tert-butyl, (d -SOrO-Cu alkyl, preferably 〇-methyl, (e) -O-Cw, 'preferably-〇-methyl or _〇_ethyl, (f) COOH, COO-Cu alkyl Preferably, c〇_〇_methyl or c〇〇_acetinyl' and the groups may be the same or different. The following compounds are mentioned by way of example, but the invention is not limited thereto: nitrogen heterocycle Butane, oxetane, thietane, dithiazine, tetrahydrofuran, dihydrofuran, dioxolane, imidazolium, imidazoline, imidazolidinone, dihydroimidazole Ketone, oxazoline, oxazolidine, oxazolidinone, pyrrolidone, dihydropyrazole, pyrrolidine, pyrroline, morpholine, tetrahydropyridine, dihydropyran, tetrahydropyran, dioxane , piperazine, piperidine, piperazinone, piperidine, piperazine, thiomorpholine S-oxide, thio-lanine dioxide, thio- phenazine, dihydrooxazine, morphine, linalion, all-oxazide dioxide, έ-caprolactam, oxygen nitrogen Oxalone (oxazepan〇ne), arsenazo, thiazepanone, perhydroazepine, dihydroquinazolinone, indoline, dihydroisoindole, benzoxazolone, Benzimidazolone - chromanone, tetrahydroquinoline, tetrahydrobenzoxanthine, tetrahydrobenzisoxazole, tetrahydrobenzothiophene, tetrahydrothienopyridine, tetraoxobenzofuran , tetraoxazolidine pyridine, tetrahydroisoxazole pyridine. According to the invention, the following heterocycles are preferred: 139377.doc •45- 201038571

Heart, atmosphere, death,

The term "aryl" (including those aryl as part of another group) means 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 139377.doc -46- 201038571 is phenyl. Unless otherwise stated, the aromatic group may be substituted with one or more groups selected from the group consisting of: NH2'

(4) OH, N02, CN, 〇CF3, 〇CHF2, 〇CH2F (b) Halogen 'preferably fluorine or chlorine, methyl, iso (c) Ci-6 alkyl group 'better Cu base group' especially preferably ethyl Propyl or tert-butyl, ❹ ❹ (d) -S〇2-0-Ci-3 alkyl, preferably _〇_methyl, (e) -O-Cw alkyl, preferably _〇_甲Base or _〇_ethyl, (f) COOH, CO-O-Cw alkyl group 'preferably c〇〇 methyl or (3) ethyl group, and the groups may be the same or different. _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ The bond: 5 member Ge 2: a hetero atom and another conjugated bismuth compound which is sufficient to form an aromatic system. Examples of the heterocyclic aromatic group are as follows (but the invention is not limited to furan, pyrrole, thiophene, pyrazole, Heterologous peaks, snails, oxazoles, thiazoles, isothiazides, sputum, sputum, sputum, tetrasodium, sulphur, sulphur, pyrimidine, pyrazine, pyridazine, triazine.丨丨5 g F歹〗 5 杂%% aromatic group is preferred: 139377.doc -47. 201038571 The following 6-membered heterocyclic aromatic group is preferably a 9-member or 10-membered bicyclic heteroaryl group according to the present invention. Cyclobicyclic heteroaryl ring): as follows (but the invention is not limited to such =, different ', sit, doxazine, benzopyrene, benzo. phenophene, benzimidazole, benzophenone Electric ... 嗟 嗟 、, benzotriter, benzoheptyl thiazole, quinoline, isoquinoline " octane, pyridazine, quinoxaline, j porin" ratio. Biting and licking... bite and licking... bite and bite Cloth, given voice °, ° votes Yin, choke throat, benzo wicked nitrile saliva, saliva Lin, Lin Han isobutyl, 'I H Han given voice ° triazine, benzo anger. Ride carbonitrile.

According to the present invention, the following bicyclic heteroaryl ring is preferred: *-〇> Ν <χ>, *~c〇, , <r> , , <〇, , <〇

139377.doc 48- 201038571

Unless otherwise stated, the previously mentioned heteroaryl groups may be substituted with one or more groups selected from the group consisting of: (a) OH, N〇2, CN, 〇CF3, OCHF2, 〇CH2F, NH2, (b) halogen, preferably fluorine or chlorine,

(c) Cw alkyl, preferably c]-3-alkyl, especially preferably ethyl, methyl, isopropyl or tert-butyl, (d) -SCVO-Cu alkyl, preferably _〇_methyl , (e) -O-Cw alkyl 'preferably _ 〇 _ methyl or _ 〇 _ ethyl, (f) COOH, CO-O-Cu alkyl, preferably C 〇 〇 曱 曱 or c 〇 _〇_ Ethyl, and the groups may be the same or different. The bicyclic heteroaryl ring may preferably be substituted in the phenyl group. The term "halogen" means a fluorine, chlorine, bromine or moth atom. The compound of formula I may have an acidic group (mainly a carboxyl group) and/or a basic group (such as an amine functional group). Therefore, the compound of the formula may exist in the form of an internal salt, and may exist in the form of a salt, especially one of the following: · A pharmaceutically acceptable inorganic acid (such as hydrobromic acid, phosphoric acid, nitric acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, ethidium) Acidic acid, benzoic acid, p-toluene acid), or organic acids (such as araic acid, succinic acid, 6 acid, fumaric acid, cis-succinic acid, citric acid, lactic acid 'tartaric acid' lemon Acidic; a pharmaceutically acceptable base such as an alkali metal or alkaline earth metal hydroxide (such as sodium hydroxide or potassium hydroxide) or 139377.doc -49- 201038571 acid salt, ammonia, zinc hydroxide or hydroxide Or an organic amine (such as diethylamine, diethylamine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine). The compounds of the present invention may exist in the form of racemates, with the proviso that they have only one pair of grassy elements, but may also be obtained in pure enantiomeric form (i.e., in (and) or (^) form). Compounds having a carbon-carbon double bond may exist in two or more forms. The following nitrogen-containing heteroaryl groups may exist in different tautomeric forms:

The compounds prepared in the mother's condition are not limited to one tautomeric form but include all tautomeric forms. However, the present application also includes individual diastereomeric enantiomeric pairs or mixtures thereof obtained under conditions in which more than one palmitic element is present in the compound of formula I, and the composition is as mentioned above. Individual optically active enantiomers of the racemate. The present invention relates to the compound, which is optionally in the form of a mixture of individual optical isomers, individual enantiomers or racemates, in the form of tautomers and in the form of a free base or pharmacologically The corresponding acid addition salt form of the acid received. The invention also includes so-called prodrugs of the compounds of formula I. The term prodrug is used to mean any molecule which releases an active ingredient of formula I in vivo after administration to a mammal. The prodrug itself may have very low pharmacological activity or may not have the pharmacological activity of 139377.doc 50-201038571, but after administration, the active ingredient of the formula i is released in the living body, τ > a 丄, limbs release And the active ingredient has the activity described. As is known to those skilled in the art, prodrugs of the general formula can be prepared by modifying suitable functional groups in the compound of formula 1 (H. Bundgaard (ed.) Design 〇f pr〇drugs (1986),

Elsevier). The invention also includes such metabolites derived from the compounds of formula I. As used herein, a metabolite means a compound formed from a compound in vivo after administration. Examples of metabolites include: Ο - a methyl group of a compound of formula I can be converted to the corresponding hydroxyindenyl group (_CH3_>_CH2OH); - an alkoxy group of a compound of formula I can be converted to the corresponding hydroxyl group (_〇R_> _ OH); - a second amine of the compound of formula I can be converted to the corresponding first amine (_NRiR2_ > -NHRi - NHR2); - a nitrogen atom of the compound of formula I can be converted to the corresponding nitrogen oxide (=N_) 〇->=N+-(〇·)-) 〇Preparation Process The present invention is also directed to a process for the preparation of a compound of formula I wherein the substituents have the meanings previously described. • Some methods for preparing the compounds of formula I of the present invention are illustrated in the following synthetic schemes and examples:

139377.doc -51 - , (1) 201038571 where 11, ^^, 丫, 丫, 111, 112 and ]^3 are as defined above. In some cases, the order in which the reaction schemes are carried out can be varied to simplify the reaction or to prevent undesirable by-products. The following examples are provided to make the invention easy to understand. The invention is intended to be illustrative of the invention and is not intended to limit the invention in any way. In some cases, the final product can be further derivatized, for example, by manipulation of a substituent. Such manipulations are generally known to those skilled in the art, such as oxidation, reduction, alkylation, deuteration, and hydrolysis, but are not necessarily limited to the above-described manipulations. 'Starting compounds are prepared by methods known in the art or as described herein. The corresponding functional groups in the compound can be protected by conventional protecting groups prior to carrying out the reaction. The protecting groups can be decomposed using appropriate methods in the art at appropriate stages of the reaction sequence (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 according to the procedures and specific examples provided or modified accordingly using known and/or available starting materials f, reagents and conventional synthetic methods. Modifications to such reactions known to those skilled in the art, but not described in detail herein, may also be practiced. The following methods for preparing the compounds of the general formula 1 of the present invention and precursors thereof are described as being particularly suitable: The starting compounds are either commercially available or as described in the literature, as known to those skilled in the art or as described herein. Method to prepare. Any corresponding functional group in the compound can be protected by conventional protecting groups prior to carrying out the reaction. These protecting groups can be decomposed using methods known in the art at appropriate stages in the reaction 139377.doc -52- 201038571 sequence. In the reactions described below, any reactive group such as a hydroxyl group, a carboxyl group, an amine group, an alkylamino group, a phosphonium group or an imine group may be protected by a conventional protecting group during the reaction, These conventional protective 'bases are decomposed after the reaction. • For example - a suitable protecting group for a hydroxy group may be methoxy, benzyloxy, trimethyl hydrazinyl, ethenyl, benzhydryl, tert-butyl, triphenyl fluorenyl, Benzoyl or tetrahydroindolyl, - a suitable protecting group for a carboxyl group may be a trimethylsulfonylalkyl group, a methyl 'ethyl group, a second butyl group, a benzyl group or a tetrahydroindolyl group. And a suitable protecting group for the guanamine group may be N-methoxymethyl (M0M), N-benzofluorenyl fluorenyl (BOM), N-(trimethyl decyl) ethoxy fluorenyl (SEM), N-tert-butyldimethylmethyl alkoxy fluorenyl, N-third Q butyl fluorenyl sulphide (TBDMS), N-triisopropyl fluorenyl (TIPS), N- Benzyl, N-4-decyloxybenzyl (pmb), N-triphenylsulfonyl (Trt), N-tert-butoxycarbonyl (B〇c), Ν·benzoquinoneoxycarbonyl (Cbz) or hydrazine-trimethyldecylethylsulfonyl (SES), - a suitable protecting group for an amine group, an alkylamino group or an imine group may be an ethyl fluorenyl group or a trifluoroethyl fluorenyl group. , phenyl fluorenyl, ethoxycarbonyl, tert-butoxycarbonyl, benzomethoxycarbonyl, alum, methoxyphenyl fluorenyl Or 2,4-dimethoxybenzyl and additional thiol groups for the amine group. Other protecting groups and their decomposition systems are described in T.w. Greene, P G.M. 139377.doc -53- 201038571

Wuts, "Protective Groups in 〇rganic Synthesis", Wiley, 2006. Subsequent to the case, for example, by 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 in an aqueous solvent such as water or Hydrolysis of propanol/water, tetrahydrofuran/water or dioxane/water, or by (for example) in the presence of tridecyl iodane at a temperature between 0C and loot: preferably (7) it and other The ether is cleaved at a temperature to decompose any protecting groups used. However, the 'benzyl, methoxybenzyl or benzyloxy group is, for example, hydrogen in the presence of a catalyst such as palladium/charcoal such as methanol, ethanol, ethyl acetate, dimethylformamide In dimethylformamide/acetone or glacial acetic acid, an acid such as hydrochloric acid is added as appropriate, at a temperature between ot: and 5 (rc, but preferably at ambient temperature and at a temperature of 7 bar, However, it is preferably decomposed by hydrogenolysis under a hydrogen pressure of from 5 to mbar. The methoxyphenyl fluorenyl group may also be in the presence of an oxidizing agent such as ammonium cerium (IV) nitrate such as dichloromethane, acetonitrile or acetonitrile/water. In the solvent, it is decomposed at a temperature between TC and 5 (rc, but preferably at ambient temperature. The methoxy group is suitable for the three desertifications (4) in a solvent such as a gas-fired gas at -35 ° C and Decomposition at a temperature between -25 ° C. The 2,4-dimethoxyphenylhydrazine group is preferably decomposed in trifluoroacetic acid in the presence of anisole. The second butyl or third butoxycarbonyl group is preferred. Decomposition by treatment with an acid such as trifluoroacetic acid or hydrochloric acid using a solvent such as dichloromethane, dioxane or ether as appropriate. 139377.doc -54- 2010 38571 The ugly group is preferably in the presence of a hydrazine or a first amine such as methylamine, ethylamine or n-butylamine in a solvent such as decyl alcohol, ethyl hydrazine, % isopropanol 'hydrazine/water or dioxane. Decomposes at a temperature between 2 and TC (TC). The methoxymethyl group can be cleaved in the presence of an acid such as dihydrogen. An acid such as trifluoroacetic acid can be used without a solvent. N-(dimethyl-stone) ethoxymethyl can be in TBAF^ Μ·dimeryl _ 0 3,4,5'6_ Decomposition in the presence of a tetrahedral 2 (1H)-° dense phase. Alternatively, the SEM protecting group may be decomposed with an acid such as nitrogen chloride in an organic solvent such as diche or ethanol. Preferably, in the presence of a solvent such as tetrazolium orthoquinone in a solvent such as morpholine (e.g., morpholine) at a temperature between i and ,1, preferably at ambient temperature and at Treated under inert gas with a catalytic amount of ruthenium (triphenylphosphine)-palladium (0) or by a solvent such as aqueous ethanol and optionally such as 1,4-diazabicyclo[2,2, 2] octane base exists in 2 〇 it Decomposition by treatment with a catalytic amount of chlorinated ginseng-(triphenylphosphine)-ruthenium (1) at a temperature between 70 ° C. The following method of preparing the compounds of the general formula I of the invention and their precursors proves to be particularly suitable The final compound of formula 1 (wherein U, V, X, Y, R1, 尺 2 and R3 are as defined above) can be obtained by formulating a compound of formula (1_1) with a formula having a leaving group LG (1-2) The electron-deficient compound is reacted to obtain _ group (preferably chloro and bromo), -S02CH3, -〇S〇2CH3, -〇S〇2C6H4-CH3 or -S-CH3 (-S- CH3 needs to be further reacted with an organic peroxide to be converted into an actual 139377.doc-55-201038571 leaving group) or the like can be used as the leaving group LG, but it is not limited to this list. The use of a chlorine group is especially preferred. Process 1:

(1-1) (1-2) (1-3) The reaction can be carried out by nucleophilic aromatic substitution in an inert solvent using an auxiliary base at a temperature ranging from 〇 C to the reflux temperature of the bath. The reaction is carried out, for example, in tetrahydrofuran, toluene, diphenylbenzene, dialkylformamide (especially preferably dimethylformamide), cyclodecylamine (especially preferably N-methyl-pyrrolidone), hydrazine. , 4_ Second noise, acetonitrile in a suitable inert solvent or in an inert solvent mixture. Suitable auxiliary bases include a second amine such as triethylamine or ethyldiisopropylamine, a metal hydroxide such as potassium carbonate or sodium carbonate, sodium hydride (NaH) or diisopropyl amination (LDA). The inert solvent used must be compatible with the base used. Preferably, the reaction is carried out in dimercaptomethylamine at a temperature between ambient temperature and solvent reflux temperature in the presence of a third amine assay. Alternatively, the structure of the formula (1 -3) shown in Scheme 1 (wherein u, V, χ, Υ, R1, R2 and R3 are as defined above) can be synthesized by a reaction of a transition metal catalysis. The compound of the formula (丨-丨) can be reacted with a compound of the formula (1-2) having a leaving group LG in an inert solvent in the presence of a catalyst and an auxiliary base. Additionally, suitable ligands can be used for the catalyst. Gas-based, bromo, hard, trifluoroacetate, trifluorosulfonate, acid, sulfonate and toluene, but this list is not limited. Diphenylbenzene, tetrahydrofuran, dimethylformamide, 139377.doc -56- 201038571 Dimethoxyethane, toluene, benzene, 1,4-dioxane, acetonitrile or a solvent mixture can be used as the inert solvent. A preferred solvent is xylene. Suitable bases are especially amine bases such as triethylamine or diisopropylethylamine, or inorganic bases such as carbonic acid planer, cesium acetate, potassium carbonate, sodium carbonate or potassium phosphate. Under normal pressure, the preferred reaction temperature is from RT to solvent reflux temperature. Typical catalysts are, for example, transition metal catalysts such as stilbene (diphenylmethyleneacetone)-dipalladium (0), fluorene-(triphenylphosphine)-palladium (0), palladium (II) acetate, Pd (PPh3). a palladium catalyst of the type 2Cl2 'Pd(CH3CN)2Cl2, Pd(dppf)Cl2 or palladium(II) chloride. Typical ligands are, for example, triphenylphosphine, triphenylarsenic, BINAP, XPhos, XantPhos or 2-(di-t-butylphosphino)biphenyl. Compounds of formula (2-4) can be prepared as shown in Scheme 2 (wherein U, V, X, Y, R1, R2 and R3 are as defined above). Process 2:

Hal*R3H3 Halogen-metal exchange ❹

υ-ν'χR1.nW (2-2) R1· u"v'x (2-4) M = metal, such as Li, MgHal, B(OH)2 (2-3)

Hal = halogen, such as ChBr T = -COOH, -COOAIk, -CONR2 -CN, -COCI, -C(0)-0-C(0)-j^, the reaction starts from the compound of the formula (2-1), Wherein Hal represents a halogen atom, preferably chlorine, bromine or moth. The Grignard or the catalyzed compound of the formula (2-2) can be converted from the corresponding dentate compound of the formula (2-1) by so-called halogen-metal exchange or by inserting a metal into the halogen. - Prepared by carbon bonding. The corresponding lithiated compound of the formula (2-2) can be synthesized, for example, from an organolithium compound such as n-butyllithium, a second butyllithium or a tert-butyllithium, to I39377.doc -57- 201038571 Come to the halogen-metal parent exchange. Corresponding magnesium compounds (Grenner compounds) may also be obtained by using, for example, isopropyl magnesium bromide or brominated second butyl magnesium or isopropyl magnesium chloride or vaporized second butyl magnesium or diisopropyl magnesium or The corresponding Grignard reagent of the second butyl magnesium is obtained in conjunction with a salt such as gasified lithium which accelerates the metallization process or a dentate-metal exchange in the presence of the salt. The corresponding metal-transferred organomagnesium compound can also be synthesized in situ from the corresponding precursor (see, for example, Angew).

Chem. 2004, 116, 3396-3399 and Angew. Chem. 2006, 118, 165-169 and references contained therein). In addition, an acid-type complex (_ate complex) of an organomagnesium compound may be used, for example, from vaporized butyl or butylmagnesium bromide or isopropylmagnesium chloride or isopropylmagnesium bromide. Produced in combination with a butyl clock (see Angew. Chem. 2000, 112, 2594-2596 and Tetrahedron Lett. 2001, 42, 4841-4844 and references contained therein). The halogen-metal exchange is preferably in 丨〇〇. Between 〇 and 4 ( (especially the best is -80 ° C to 1 (temperature range of TC) in the preferred alkyl ether (especially the best ether), cyclic ether (especially the best 1,4-two. Exfoliating or tetrahydrofuran), sulfonate, hexane or an inert solvent or a mixture thereof. It may be used, for example, with a metal such as trimethyl sulphur, zinc sulphate or bromide, indium sulphide or indium bromide. The salt transfers the magnesium or organolithium compound metal thus obtained to synthesize an alternative organometallic compound of the formula (2-2) which is also suitable for the reaction. Or the 'organometallic compound (2-2) may also Prepared by inserting a metal into a carbon-dentate bond. For this conversion, lithium or magnesium is a suitable elemental metal. The insertion reaction is preferably between -80 ° C and 100 t: (especially the best one is _ 7〇cC to 139377.doc 58- 201038571 4 ° ° C temperature range) in the preferred alkyl ether (especially the best ether), cyclic ether (especially the best 1,4-dioxane or tetrahydrofuran) ' f benzene It is carried out in an inert solvent of hexane or a solvent mixture thereof. In the case where no spontaneous reaction occurs, it may be necessary to use, for example, 1,2-two. Ethane, iodine, trimethyl decane chloride, ethyl hydrazine, hydrogenated hydrogen or supersonic to activate the metal. The reaction of the organometallic compound of the formula (2_2) with the compound (2-3) is preferably _1 〇 (rc to 1 〇〇〇c temperature range • is carried out within the range, and a temperature range of -80 ° C to 50 t is particularly preferred. In ❹ such as preferred alkyl ether (especially the best ether, dimethoxy The reaction is carried out in the ethyl ether), the cyclic ether (especially the best 1,4-dioxane or tetrahydrofuran), the aromatic hydrocarbon (especially the best toluene or benzene), the inert solvent of hexane or a solvent mixture thereof. It is carried out in air, but it is preferably carried out in a protective gas atmosphere such as argon or nitrogen. It is proved to be advantageous to temporarily protect the functional group in the compound (2_3). Lithium substitution of the formula (2-2) or The magnesium-substituted compound can be reacted in a desired manner with a compound of the formula (2-3) having a carboxyl group or a derivative thereof such as an ester, a nitrile, a Q carboxylic acid vapor or a guanamine such as glucosamine. The reaction is often *can be used without any additional transition metal catalyst or with another such as bismuth, indium or The metal undergoes a metal transfer reaction. However, in some cases, the two modifications have also proved to be advantageous. Aromatic shed acid, ester derived therefrom, dialkyl aryl borax or The triflate aryl ester can be reacted with an acid gas or a carboxylic acid in a transition metal such as palladium as a catalyst to obtain the corresponding ketone (V. Polackova ' St. Toma, I. Augustinova, Iveta; Tetrahedron; 2006; 62 ; 50 ; 11675-11678 and references cited therein and R. Kakino ' H. Narahashi, I. Shimizu, A. -59- 139377.doc 201038571

Yamamoto, Bull. Chem. Soc. Jpn., 2002, 75, 1333-1345). The corresponding boron-substituted compound, such as boric acid, dialkyl aryl borane or borate, can be synthesized from the metallated material by reaction with a boron electrophile such as a boronic acid ester or a derivative thereof. It is also possible to synthesize a boron-substituted compound from a trans- or pseudo-halogenated precursor molecule using a transition metal catalyst (preferably) and a deletion or a butterfly compound (Tetrahedron Lett. 2003, 4895-4898 and References cited therein). Metallization and/or coupling reactions can also be carried out in a microreactor and/or in a micromixer. The addition reaction can be carried out without any additional addition, or in the case of a non-reactive reactant, an accelerator such as BF3*OEt2 can be added (see M. Schlosser, Organometallics in Synthesis, John Wiley & Sons). , Chichester/New York/ Brisbane/ Toronto/Singapore, 1994) ° The compound of formula (2-1) is commercially available or can be obtained by organic chemistry or as described in the expert literature. To synthesize (see, for example, J. March, Advanced Organic Reactions, Reactions Mechanism, and Structure, Fourth Edition, John Wiley & Sons, Chichester/New York/Brisbane/Toronto/Singapore > 1992 and its bow | Literature). The use of transition metals and organometallic compounds for synthesis is described in detail in the monograph (see, for example, L. Brandsma, SF Vasilevsky, HD Verkruijsse, Application of Transition Metals Catalysts in Organic Synthesis, Springer-Verlag, Berlin/Heidelberg, 1999). M. Schlosser, Organometallics in Synthesis, John Wiley & Sons, 139377.doc -60- 201038571

Chichester/New York/ Brisbane/ Toronto/Singapore, 1994; P.J. Stang, F. Diederich, Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1997 and references contained therein). A method of synthesizing a compound of the formula (3-4) wherein U, V, X, Y and R3 are as defined above is illustrated in Scheme 3. Process 3:

HahR3H3 (3-1)

U, V, X (3-3)

Hal = Cl, Br, 1,0S02QF3, OSOsP-Tol Halogen-metal exchange organometallic compound (3-2) ΜΗ^3Η3 T * -COOH, -COOAIk, -CONR2 •CN, -COCI, -c(o>- Oc(o)·burning base

R3H3 〇(3-4) Μ = metal, such as U, MgHal, B(OH)2 starting from an i-based compound of the formula (3-1) (especially preferably chloride, bromide and iodide) The corresponding lithium or magnesium can be synthesized by, for example, exchanging a metal with butyl lithium, isopropylmagnesium hydride or diisopropylmagnesium or by inserting an elemental metal into a ii-carbon bond. Substituted compound. The corresponding boron-substituted compound, such as boric acid, dialkyl aryl borane or borate, can be synthesized from the metallated material by reaction with a boron electrophile such as a boronic acid ester or a derivative thereof. A boron-substituted compound can also be synthesized from a halogenated or pseudohalogenated precursor molecule using a transition metal catalyst (preferably palladium) and a boron or boron lanthanum compound (Tetrahedron Lett. 2003, 4895-139377.doc • 61 · 201038571 4898 and references cited therein). A lithium-substituted or magnesium-substituted compound of the formula (3-2) may be added to a compound of the formula (3-3) or a derivative thereof (such as an ester, a nitrile, a carboxylic acid vapor or a guanamine) containing a slow group. (such as vines). These reactions can often be carried out without any additional transition metal catalyst or metal transfer reaction with another metal such as ruthenium, indium or zinc. However, the two modifications mentioned in some cases have also proven to be advantageous. An aromatic boronic acid, an ester derived therefrom, a dialkyl aryl borane or an aryl trifluoroborate can be reacted with an acid chloride or a carboxylic acid in the presence of a transition metal such as palladium as a catalyst to obtain a corresponding ketone ( V. Polackova, St. Toma > I. Augustinova >Iveta;Tetrahedron;2006;62;50; 11675-11678 and references cited therein and R. Kakino, H. Narahashi, I. Shimizu, A. Yamamoto , Bull. Chem. Soc. Jpn., 2002, 75, 1333-1345). The compound of the formula (4-3) can be prepared as shown in Scheme 4 (wherein U, V, X, Y and R3 are as defined above). Process 4:

(4-1) Hal = halogen

The compound of the formula (4-1) having a leaving group LG and an acid halide group may be combined with the aromatic compound of the formula (4-2) in Friedel-Crafts or The reaction is changed in its form. The Friedel-Crafts reaction is carried out in the presence of a catalytic or stoichiometric catalyst. Specific 139377.doc -62- 201038571 The appropriate catalyst is A1C13, FeCl3, iodine, iron, ZnCl2, sulfuric acid or trifluoromethanesulfonic acid. Instead of acid halides, the corresponding carboxylic acid, anhydride, ester or nitrile can also be used. The reaction is preferably carried out in a halogenated hydrocarbon. Dichloromethane and hydrazine, 2 _ broth are especially preferred. The Friedel-Crafts reaction is carried out at a temperature ranging from -30 ° C to 120 ° C, preferably from 30 ° C to 10 ° C. However, it is also possible to carry out the reaction without a solvent. The reaction can also be carried out in the microwave. The compound of the formula (5-3) can be prepared as shown in Scheme 5 (wherein u, v, X, Y, R1, R2 and R3 are as defined above). Process 5:

Similar to the method of T. Ishiyama et al. (J. 〇rg. chem., 1998, 63 ' 4726), it is possible to (preferably) have a formula having a leaving group LG in a temperature range from ambient temperature to solvent reflux temperature. (5-1) a compound and a boron-substituted compound (such as boric acid (R=H), boric acid ester (R=alkyl), dialkyl arylborane) in an inert solvent and carbon monoxide in the presence of a catalyst Respond in the atmosphere. Preferably, under high carbon monoxide pressure, 8 (rc to U (high reaction temperature of rc is used. In addition, a suitable ligand may be used for the catalyst. An alkali metal iodide such as sodium hydride or potassium molybdate may be added as Additives: bromo-mothyl, trifluoroacetate, trifluorosulfonate, decanesulfonate and tosylate groups can be used as the leaving group LG, although this list is not limiting The inert solvent used may be xylene, tetrahydrofuran, dimercaptomethyl hydrazine 139377.doc -63- 201038571 amine, monomethoxyethane, benzene, benzene, stupid _, 14-two 3 evil hospital , acetonitrile or solvent mixture. The preferred solvent is phenyl hydrazine ether. Suitable base is inorganic base 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 pressure of carbon monoxide can be i bar Typical catalysts are, for example, palladium catalysts such as stilbene (diphenylmethyleneacetone)-diibar (0), ruthenium-(triphenylphosphine)-palladium (ruthenium), palladium acetate _ ( π),

Pd(PPh3)2Cl2, Pd(CH3CN)2Cl2, Pd(dppf)Cl2 or gasification handle (η). Typical ligands are, for example, triphenylphosphine, tricyclohexylphosphine, tri-tert-butylphosphine, diphenylarsenic, 2,2'-bis(diphenylphosphino)-1,1,-binaphthyl (3 to gossip), two second butylphosphino 2', 4', 6'-triisopropylbiphenyl (xph〇s), 4,5-bis-diphenylphosphanyl (diphenylphosphanyl) -9,9-Dimethyl-9H-dibenzoxanthene (XantPhos) or 2-(di-t-butylphosphino)biphenyl, 1, hydrazine, bis(diphenylphosphino)ferrocene (Dppf), 1,2-bis(diphenylphosphino)ethane (dppe), 1}3_bis(diphenylphosphino)propane (dppp), and 1,4-bis(diphenylphosphino) Butane (dppb). It is particularly preferable to use Pd(PPh3)2Cl2 as a catalyst, potassium carbonate as a base, 1 bar of carbon monoxide, potassium iodide as an additive, and benzoquinone as a solvent. The corresponding boron-substituted compound is commercially available or can be synthesized from a metallated compound by reaction with a boron electrophile such as a boronic acid ester or a derivative thereof. In addition, a substituted compound can be prepared, for example, from a correspondingly functionalized or pseudo-imided precursor molecule in a transition metal catalyzed reaction (Tetrahedron Lett. 2003, 4895). -4898 and references cited therein). A method of synthesizing a compound of the formula (6-3) wherein U, V, X, Y and 139377.doc-64·201038571 R3 are as defined above is shown in Scheme 6. Process 6:

(6-1) (6-2) (6-3) The method of A. Miyashita et al. (Heterocycles, 1997, Vol. 45, No. 11, 2159-2173) The compound of the formula (6- 0 1) of lg is reacted with an aromatic aldehyde in an inert solvent in the presence of a catalyst and a compound to obtain a compound of the formula (6-3). The fluorine group, the chlorine group 'bromo group, the thiol group, the trifluoromethanesulfonate group, the methanesulfonate group and the tosylate group can be used as the leaving group LG, but this list is not limitative. Particularly preferred are gas radicals and bromine groups. A cyclic ether (preferably tetrahydrofuran) and a dialkylguanamine (preferably dimercaptoamine) can be used as the inert solvent. A suitable catalyst is a azole rust salt such as 1,3-dimercaptoimidazole rust or iodized i,3-dimercaptobenzimidazole. A suitable base is a metal halide. Sodium hydride is especially preferred. The reaction is carried out at a temperature ranging from RT to solvent reflux 〇 temperature. High temperatures are preferred.

It is also possible to replace the azole rust salt with sodium phthalic acid sulfinate at a high temperature and to perform a gold test. The reaction is carried out in an inert solvent in the presence of cyanide (preferably potassium cyanide) (A)

Miyashita et al. 'Heterocycles' 1998, Vol. 47, No. 1, 407-414). Compounds of the formula (7-4) can be prepared analogously to A. Miyashita et al. (Heterocycles, 1997, Vol. 45, No. 11, 2159-2173) and the literature cited therein, as shown in Scheme 7. U, V, X, 丫 and 尺 3 are as defined above). 139377.doc -65- 201038571 Process 7:

(7-1) (7-2) (7-3) N (7-4) A compound of the formula (7-1) having a leaving group LG and a 2-arylacetonitrile or a 2-heteroarylacetonitrile The reaction is carried out in an inert solvent in the presence of a base to obtain a compound of the formula (7-3). The fluorine group, the gas group, the bromine group, the iodine group, the trifluoromethanesulfonate group, the methanesulfonate group and the tosylate group can be used as the leaving group LG, but this list is not limitative. Particularly preferred are chlorine groups and bromine groups. The inert solvent may be dialkylformammine (preferably dimethylformamide). Metal hydrides are suitable as bases. Sodium hydride is especially preferred. The reaction is carried out at a temperature ranging from RT to the reflux temperature of the solvent. It is preferred to carry out the reaction at a high temperature. The compound of the formula (7-4) is synthesized by oxidative deacylation of a compound of the formula (7-3). Oxidative decyanolysis is carried out in an inert solvent (through which oxygen is passed through the inert solvent) in the presence of the test. The ring (preferably tetrahydrofuran) can be used as an inert solvent. A suitable base is a metal hydride. Sodium hydride is especially preferred. The reaction is carried out at a temperature ranging from -20 ° C to the reflux temperature of the solvent. The reaction is preferably carried out at RT. The novel compounds of formula I of the present invention may contain one or more pairs of palms. If, for example, there are two pairs of palm centers, the compound may exist as two diastereomeric pairs of enantiomers. The invention includes individual isomers as well as mixtures thereof. Diastereomers may be based on their different physicochemical properties, for example, by fractional crystallization from a suitable solvent, by high pressure liquid or column chromatography, using palmar or (preferably) non-palphasity. The stationary phase is separated. 139377.doc • 66- 201038571 The racemates encompassed by Formula I can be isolated, for example, by HPLC on a suitable palmitic stationary phase (e.g., for palmitic AGP, Chiralpak AD). Racemates containing an exemplary or acidic functional group may also be separated via a diastereomeric optically active salt, such as by (1) or (_) tartaric acid, (1) or (_) _ diethyl hydrazine. Tartaric acid, (+) or (-)-monomethyl tartrate or optically active acid of (+) or (-)-camphorsulfonic acid or, for example, (R)-(+)-l-phenylethylamine, (S)- An optically active base reaction of (-)-l-phenethylamine _ or strychnine is produced.之外 According to a conventional method for separating isomers, one of the racemates of the formula I is reacted with one of the above-mentioned optically active acids or assays in an equimolar amount in a solvent and utilized The solubility is such that the resulting crystalline, diastereomeric optical/tongue salt is separated. This reaction can be carried out in any type of solvent with the proviso that the solvent has a very different solubility for the salts. Preferably, methanol, ethanol or a mixture thereof (for example, a volume ratio of 5 Å: 5 Å) is used. Each of the optically active salts is then dissolved in water, carefully using a base such as sodium carbonate or saponin or a suitable acid such as dilute hydrochloric acid or methane sulfonic acid, and hydrazine is obtained in this manner ( Corresponding free compounds in the form of +) or (-). Mixtures of the individual (R) or (S) enantiomers or of the two optically active • # enantiomers encompassed by Formula 1 may also be prepared by using a suitable reaction group in the (R) or (S) configuration. The fractions were obtained by performing the synthesis described above. The novel compounds of formula I and their physiologically acceptable salts have important pharmacological properties based on their selective CGRP-antagonistic properties. The present invention is further directed to pharmaceutical compositions containing such compounds, their use, and their preparation. The novel compounds and physiologically acceptable salts thereof mentioned herein have 139377.doc -67 - 201038571 CGRP-antagonistic properties and exhibit good affinity in CGRP receptor binding studies. These compounds show CGRP-antagonistic properties in the pharmacological test system described below. The following experiments were performed to demonstrate the affinity of the above-mentioned compounds for human CGRP-receptors and their antagonistic properties. A. SK-N-MC cells (representing human CGRP receptors) binding studies SK-N- MC cells were cultured in "Dulbecco's modified Eagle medium". The medium is removed from the overgrown culture. The cells were washed twice with PBS buffer (Gibco 041-04190®), and the cells were detached by adding PBS buffer mixed with 0.02% EDTA, and separated by centrifugation. Resuspended in 20 ml of "Balanced Salt Solution" [BSS (in mM): NaCl 120, KC1 5.4, NaHC03 16.2, MgS04 0.8, NaHP04 1.0, CaCl2 1.8, D-glucose 5.5, HEPES 30, pH 7.40] The cells were centrifuged twice at 10 〇 xg and resuspended in BSS. After measuring the number of cells, the cells were homogenized using Ultra-Turrax and centrifuged at 3000 x g for 10 minutes. Discard the supernatant and place the pellet in Tris buffer (10 mM Tris, 50 mM NaCl, 5 mM MgCh, 1 mM EDTA, pH 7.40) enriched with 1% bovine serum albumin and 0.1% subtilin. It was centrifuged again and resuspended (1 ml per 1,000,000 cells). The homogenized product was frozen at -80 °C. Membrane formulations were stable under these conditions for more than 6 weeks. After thawing, the homogenized product was diluted 1:10 with assay buffer (50 mM Tris, 150 mM NaCn, 5 mM MgCl2, 1 mM EDTA, pH 7.40) and homogenized with Ultra-Turrax for 30 seconds. The 230 μΐ homogenized product of 139377.doc -68- 201038571 was incubated with 50 pM 125I-E-tyrosinamide-calcitonin-gene-related peptide (Amersham) at ambient temperature for 1 80 minutes and increased by 250 μM. The concentration of the test substance in the total volume. The cultivation was terminated by rapid filtration using a cell harvester with a GF/B glass fiber filter treated with polyethrenimide (0.1%). Protein binding radioactivity was measured using a gamma counter. The non-specific binding system is defined as the binding radioactivity after the presence of 1 μΜ human CGRP-ot during culture. • Analyze the concentration binding curve using a computer-assisted nonlinear curve fit. The compounds described above exhibit a Ki value of $5 〇 μΜ in the test described. B. CGRP antagonism in SK-N-MC cells SK was treated with 250 μM culture buffer (Hanks' HEPES, 1 mM 3-isobutyl-1-mercaptopurine, 1% BSA, pH 7.4) -N-MC cells (1 million cells) were washed twice and pre-incubated at 37 C for 15 minutes. After adding CGRP (10 μ μΐ) as an agonist or adding 3 to 4 different concentrations of the substance at an increased concentration (10 11 Μ to 6·6 M), the mixture was further cultured for 15 minutes. Q The intracellular cAMP was then extracted by adding 20 μM of 1 M HC1 and centrifuging (2〇〇〇xg, 4 (:, 15 minutes). The supernatant was frozen in liquid nitrogen and stored at -20 °C. The cAMP content of the sample was determined by radioimmunoassay (Messrs. Amersham) and the pa2 value of the antagonistic substance was determined graphically. In the in vitro test model, 'the compound of the present invention is in the sputum. C(}Rp_antagonistic properties are exhibited in the dose range between Μ·!2 Μ and ΙΟ·4 。. To show that the compound of formula I exhibits good to excellent under different structural elements 139377.doc •69· 201038571 The test procedure obtains the CGRP-antagonistic activity selected from the structural elements. The table below provides the values obtained according to the above. It should be noted that the compounds are not specific to them and are not intended to emphasize specific compounds: Example Kj [nM] - m 6 ~~~— 13⁄4 27 --- ------- The compounds of the present invention and their physiologically acceptable salts are suitable for headaches (especially Acute and prophylactic sputum or cluster headache and tension headache The compound of the present invention also has a positive effect on the following diseases: non-sleeping* ("-" cardiovascular disease, L-type diarrhea, morphine tolerance; " sporozoite (-) toxin Abdominal filling; skin diseases, especially skin damage caused by heat and light radiation, including sunburn, bryorrhea, pruritus, (four) two and severe pain; inflammatory diseases, such as inflammatory joint diseases (osteoarthritis, wind) Rheumatoid arthritis, neurogenic arthritis), invasive soft tissue rheumatism (muscle fiber pain), neurogenic oral cavity: disease: inflammatory lung disease, allergic rhinitis, asthma, c〇pD; : The expansion of blood and the resulting reduction in blood supply to tissues, such as: gram and sepsis; chronic pain, such as diabetic neuropathy, chemotherapy-induced neuropathy, HIV-induced neuropathy, post-herpetic neuropathy Tissue traumatic neuropathy, trigeminal neuralgia, temporomandibular dysfunction, CRPS (complex regional pain syndrome), f pain; and visceral diseases such as intestinal irritable syndrome (IBS) and inflammation Intestinal syndrome. In addition, the present invention has a systemic pain alleviating effect. Estrogen deficiency in women and hormone-treated patients with prostate cancer and men with castration are caused by vasodilation and increased blood flow. The symptoms of menopause and hot flashes are advantageously affected by the CGRP antagonists of the present application having prophylactic and acute therapeutic capabilities, which differ from hormone replacement therapy in that there are no side effects. When administered intravenously or subcutaneously The dose required to achieve the corresponding effect is suitably 0.0001 mg to 3 mg per kg body weight, preferably 1 mg 〇 to 1 mg per kg body weight, and when administered orally, nasally or by inhalation, the corresponding The agent 1 required for the action is suitably from 1 mg to 10 mg per kg body weight, preferably from 1 mg to 1 mg per kg body weight, in each case, from i to 3 times per day. Treatment with right CGRP antagonists and/or CGRP release inhibitors as a supplement to conventional hormone replacement therapy suggests reducing the dose specified above. In this case, the dose may be from the lower limit mentioned above. 5 up to 1/1 of the specified upper limit. The invention further relates to the use of a compound of the invention as a valuable adjuvant for the preparation and purification (by affinity chromatography) of an antibody, and which is, for example, by deuteration of a suitable precursor (eg It is used in RIA and ELISA assays by hydrazine-catalyzed hydrogenation or by replacing the halogen atom with hydrazine, and it is used as a diagnostic or analytical adjuvant in neurotransmitter studies. The active substance combinations that can be used in combination include, for example, antiemetics, prokinetic agents, neuroleptics, antidepressants, neurokinin antagonists, anticonvulsants, histamine-H1-receptor antagonism Agent, blocker, α· agonist and α-antagonist, ergot alkaloid, palliative analgesic, non-steroidal 139377.doc -71 - 201038571 Alcohol anti-inflammatory agent' corticosteroid, calcium antagonist, 5_HTib /id_Activator or other anti-migraine agent, which may be formulated with one or more inert conventional carriers and/or diluents such as plain or coated lozenges, capsules, powders, suspensions,疋 dose aerosol or suppository, such carriers and/or diluents such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water / Ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethyl cellulose or a fatty substance such as stearin or a suitable mixture thereof. Thus, other active substances that can be used in the combinations mentioned above include, for example, non-steroidal anti-inflammatory drugs, acecl〇fenac, acemeucin, acetaminophen-acetamide Phenol (paracetamol), azathioprine, difenfenic acid, diflunisal, fenbufen, fenoprofen, fiurbipr〇fen, ibuprofen More than uprofen), called indomethacin (ind〇metacin), self-identification (ket)p(7)(four), leflunomide (leflUn〇mide), lornoxicam (1〇rn〇xicam), fentanic acid (mefenamic acid), naproxen (Qing (10) (8), piroxicam, sulfasalazine, zoic acid (z〇mepirac) or its peony can be used as salt and beauty侬西康(爪—(10)); and other selective COX2-inhibitors, such as rofecoxib (r〇fee〇xib), valdecoxib' parecoxib (parec〇xib), etoricoxib (et 〇ric〇x (9) and celecoxib (eelee〇xib); and substances that inhibit the early or late stages of prostaglandin synthesis or such as EP2_receptor Prostaglandin receptor antagonists of amp; and Ip•receptor scavengers. It is also possible to use ergotamine, dihydroergotamine, antiemetic $(metQdep_ide), 139377.doc -72- 201038571 domperidone , diphenhydramine, cyclizine, promethazine, chlorpromazine, vigabatrin, timolol, isomei, isometheptene, pizotifen ), botox, gabapentin 'pregabalin, duloxetine, topiramate, riboflavin, montelukast, lisinopril ( lisinopHl), micardis, prochloroperazine, dexamethasone, flunarizine, dextropropoxyphene, methicillin , metoprolol, propranolol, nadolol, atenolol, clonidine, 0 indomin, pain Carbamazepine, phenytoin, valproate Valproate), amitryptiline, imipramine, venlafaxine, lidocaine or diltiazem and other 5-HT1B/1D-agonists, such as Almotriptan, avitriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, suma Sumatriptan and zolmitriptan. In addition, CGRP antagonists and vanilloid receptor antagonists, such as VR-1 antagonists; glutamate receptor antagonists, such as MGlu5 receptor antagonists, mGlul receptor antagonists, iGlu5 receptors, may be added. Antagonists, AMPA receptor antagonists; sputum receptor blockers, such as P2X3 antagonists; NO-synthase inhibitors, such as INOS inhibitors; calcium channel blockade 139377.doc -73- 201038571 Agents such as PQ type Blockers, N-type blockers; unloading ion channel openers, such as KCNQ channel openers; nanochannel blockers, such as channel blockers; NMDA receptor antagonists; acid-sensitive ion channel antagonists, such as ASIC3 antagonist; bradykinin receptor antagonists, such as receptor antagonists; cannabinoid receptor agonists, such as CB2 agonists, cm agonists, 7 somatostatin receptor agonists, such as Sst2 Receptor agonist. The dose of such active substances is suitably from 1/5 of the usually recommended minimum dose to the usual recommended dose of ιη', i.e., 2 〇 to _ 舒 舒 舒 舒 舒 舒 舒 舒 舒 舒 舒 舒 舒 舒 舒 舒 舒 舒 舒 舒 舒. Formulations Compounds prepared according to the present invention may be administered by intravenous, subcutaneous, intramuscular, intra-articular, intrarectal, intranasal routes, by inhalation, topical, transdermal: orally or as appropriate for treatment Other active substances of migraine are administered in combination, while aerosol formulations are especially suitable for inhalation. The combination can be applied simultaneously or sequentially. Suitable forms for administration are, for example, tablets, capsules, solutions, sugar-table emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective compound should be in the range of from 〇丨% to 9% by weight, preferably from 0.5% to 50% by weight of the total composition, that is, sufficient to achieve the dosage range specified below. the amount. The preparation may be administered orally in the form of a powder, a solution or a suspension in a tablet, a powder, a capsule such as a hard gelatin capsule. When administered by inhalation, the biomass combination can be administered in the form of a powder, aqueous or aqueous _ethanol solution or using a propellant gas formulation. 139377.doc ^74- 201038571 Accordingly, preferably, the pharmaceutical formulation is characterized by the level of one or more compounds of formula I of the above preferred embodiments. Oral administration of a compound is particularly preferred, and it is especially preferred to administer one or two times a day. Suitable lozenges can be obtained, for example, by mixing the active materials with known excipients such as, for example, inert diluents such as, for example, succinic acid, squaric acid or lactose; disintegrating agents; , such as corn house powder or alginic acid; binders such as powder or gelatin; lubricants such as magnesium or magnesium talc; and / or delayed release agents, such as slow methyl cellulose, cellulose acetate Or polyacetate vinegar. Tablets may also contain several layers. The coated tablet can thus be prepared by coating a core coating similar to that of a tablet with a material generally used for tableting, such as those typically used for the coating of a keying agent, for example. A ketone (c〇llid〇ne) or insect, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or to prevent incompatibility, the core can also consist of multiple layers. Similarly, the drag coating layer can be composed of multiple layers of hydrazine to achieve delayed release, possibly using the excipients mentioned above. (4) < Sugar containing the active substance of the present invention or a combination thereof (IV) additionally containing a sweet taste SJ such as saccharin, oligo$ Μ / 1 cyclamate, glycerin or sugar; and enhancer: for example, vanilla extract or willow Aspirate the extract. It can also be used as a suspending agent or a thickener (such as 竣methylcellulose nano), a wet turbid agent (a condensation product of diacetate and epoxy bromide) or a preservative (such as :::::":,---')*) The substance λ is mixed with an inert carrier such as lactose or sorbitol and 139377.doc -75- 201038571 is packaged in gelatin capsules for preparation. (10) as prepared by mixing with a neutral lipid or polyethylene glycol or a derivative thereof provided for this purpose. 】"If available excipients include, for example, water; pharmaceutically acceptable Agents such as rocky soil (eg oil cranes), vegetable oils (eg peanuts or chrysanthemum: oil), monofunctional or polyfunctional alcohols (eg ethanol or glycerol); loading - obstacle powders (eg kaolin, clay, talc, white) Ridge), powder (9) such as highly dispersed sulphuric acid and salt), sugar (such as sugar, sugar and glucose), emulsifier (such as lignin, waste sulfite liquid, vitamins, powder and polyethylidene) Thinner ketones and lubricants (eg stearic acid:, talc, stearic acid and sodium lauryl sulfate). 'for oral administration In addition to the carriers mentioned above, the tablets may of course contain additives such as sodium citrate, calcium carbonate and dicalcium phosphate and various additives such as starch (preferably horsebell starch), gelatin and the like. : External lubricants such as magnesium stearate, sodium lauryl sulfate and talc can be used in the bonding process at the same time. In the case of aqueous suspensions, the active substance can be used in addition to the excipients mentioned above. Various flavor enhancements are also preferred by inhalation administration of the compound, especially; and - or twice. For this purpose, the compound must be made in a form that can be adapted for inhalation. Inhalable formulations include inhalable powders, propellant-containing dosed aerosols or propellant-free inhalable solutions, optionally in admixture with conventional physiologically acceptable excipients. . In the context of the present invention, the term "inhalable solution containing no propellant" also includes concentrates or sterile ready-to-use inhalable solutions. Formulations which can be used in accordance with the present invention are described in more detail in a subsection 139377.doc-76-201038571. [Embodiment] Experimental portion In general, IR, i-NMR and/or mass spectrum of the prepared compound were obtained. Unless otherwise stated, the Rf value was determined using a prefabricated TLC silicone board 60 F254 (E. Merck, Darmstadt, item number: 1.05714) which was not subjected to expansion tank saturation. The given ratio of dissolving agent is the unit of volume for a particular solvent. The given volume unit of NH3 is for a concentrated solution of NH3 in water. Unless otherwise stated, the acid, base and salt solutions used to treat the reaction solution are aqueous systems of the specified concentration. Millipore made silicone (MATREXtm, 35 μπι-70 μιη) for chromatographic purification. The HPLC data provided is measured under the parameters listed below and using the column mentioned. Column used: (column temperature: 30 ° C; injection volume: 5 μιη; detected at 254 nm) S1 Zorbax tube column (Agilent Technologies), SB (StableBond) C 18 ; 3.5 μιη ; 4.6x75 mm S2 Zorbax column (Agilent Technologies), SB (StableBond) C18; 1.8 μιη; 3.〇x30 mm S3 Zorbax column (Agilent Technologies), SB (Stable Bond) C18; 5 μιη; 4.6x75 mm S4 Xbridge(Waters)C18 3.0x30 mm, 2·5 μιη S5 Sunfire C18(Waters) ; 3.5 μιη ; 4.6x75 mm S6 Symmetry Cl8(Waters) i 4.6x75 mm 5 3.5 μιη 139377.doc -77· 201038571 Solvent: Solvent A: Water (containing 0.1% citric acid); solvent B: acetonitrile (containing 0.1% formic acid); solvent C: water (containing 0.1% ammonia); solvent D: acetonitrile (containing 0.1% ammonia), the percentage is based on the total volume. Gradient: Gradient time [min] %A %B G1 (1.6 mL/min) 0.00 95 5 0.10 95 5 1.75 5 95 1.90 5 95 1.95 95 5 2.00 95 5 Gradient time [mini %A %B G2 (1.6 mL/min ) 0.00 95 5 4.50 10 90 5.00 10 90 5.50 95 5 Gradient time [mini %A %B G3 (1.6 mL/min) 0.00 95 5 4.00 50 50 4.50 10 90 5.00 10 90 5.50 95 5 Gradient time [mini %A % B G4 (1.6 mL/min) 0.00 95 5 1.00 10 90 2.50 50 50 2.75 95 5 139377.doc -78- 201038571 Gradient time [mini %A %B G5 (1.6 mL/min) 0.00 95 5 2.00 10 90 5.00 10 90 5.50 95 5 Gradient time [mini %C %D G6 (1.4 mL/min) 0.00 95 5 1.80 10 90 2.00 10 90 2.20 95 5 Gradient time [min] %C %D G7 (1.6 mL/min) 0.00 95 5 2.00 50 50 2.25 10 90 2.50 10 90 2.75 95 5 Method: Column gradient method A SI G1 Method B S2 G1 Method C SI G2 Method D SI G3 Method E S2 G4 Method F SI G5 Method G S4 G6 Method H S2 G7 Method I S5 G3 Method K S5 G2 Method L S6 G3 Method M S6 G8

In preparative HPLC purification, the same gradient as that obtained for analytical HPLC data 139377.doc -79-201038571 is typically used. The product was collected under quality control and the fractions containing the product were combined and dried in a cold bundle. In the absence of any further information about the configuration, it is unclear whether a pure enantiomer is involved or whether partial or even complete racemization has occurred. Use the following abbreviations in the test description:

AcOH acetic acid BINAP 2,2'-bis(diphenylphosphino)-, fluorene-binaphthalene BOC tert-butoxycarbonyl CDI 1,1'-carbonyldiimidazole eye cyclohexane DCM dichloromethane DIPE diiso Propyl ether DIPEA Diisopropylethylamine DMF dimethyl decylamine of th. Theoretical value of d-water demineralized water El Electron impact ionization (in MS) ESI Electrospray ionization (in MS) EtOAc Ethyl acetate EtOH Ethanol el. Eluent HC1 Hydrochloric acid HCOOH Formic acid 139377.doc -80- 201038571

HPLC Southern liquid chromatography HPLC-MS HPLC coupled with mass spectrometry HV high vacuum i.vac. under vacuum (in vacuum) cone. concentrated MeOH sterol MS mass spectrometry MW molecular weight [g/mol] NaOH sodium hydroxide NH4〇 H Ammonium hydroxide (aqueous ammonia solution, 30%) NMP 7V-methyl-2-pyrrolidine Pd2dba3 bis(diphenylarbenium acetonide) palladium-(0) PE petroleum mystery Rf retention index (in TLC) RT ambient temperature Rt Retention time (in HPLC) TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran DC drying cabinet CAD circulating air dryer starting compound preparation intermediate 1 6-apyrimidine-4-methyl fluorene 139377.doc -81 - 201038571

Step 1: 6-hydroxypyrimidine-4-decanoic acid

63.5 g (287 mmol) of sodium oxalate acetate and 3 〇 2 § (287 mmol) of cerium acetate were added to 24.1 g (0.597 m〇〇Na〇H) in 3·6 l of water. The mixture was stirred overnight. Then activated charcoal was added and the mixture was refluxed for 1 h. It was filtered hot and evaporated and then acidified with EtOAc EtOAc. Purification is used in the next step. Yield: 83.0 g Step 2: 6 - Gas screams -4- 曱醯

50 g (0.352 mol) of 6-hydroxypyrimidine-4-carboxylic acid was taken and 500 mL of phosphorus oxychloride was added thereto. Next, 150 g (0.72 〇 m〇1) of a pentachloride dish was added in portions with stirring. The reaction mixture was refluxed for 5 h. The oxychlorinated disk was evaporated and the residue was purified by vacuum distillation through a column. Yield: 52 (83% of theory) EI-MS: m/z = 176/178/180 (M) + (2 Cl) Intermediate 2 Methyl-3H-Benzene Chews -2-_ I39377.doc -82 - 201038571

25.0 g (200 mmol) of 2-amino-m-cresol and 70.4 mL (400 mmol) of DIPEA were placed in 1.0 L DCM and cooled to 0 °C. Add 38.0 g (227 mmol) of 1. Γ-jiji two flavors dropwise to 30 minutes. Sitting on the solution. • The mixture was stirred at 〇 ° C for 30 min and then stirred at RT overnight. After evaporating the reaction mixture to half its volume in vacuo, the aqueous phase was washed with water (2×250 <RTI ID=0.0>> The organic phase was evaporated in vacuo. The residual crude product was triturated with a mixture of diethyl ether and EtOAc. The solid solid was filtered, washed with PE and dried in vacuo. Yield: 25·0 g (86% of theory) ESI-MS : m/z = 150 (M+H) +

Rt (HPLC) = 2.67 min (method C) intermediate 3 ο 6-(6-apyrimidine-4-carbonyl)-4-methyl-3-indole-benzoxazol-2-one

2.34 g (13.2 mmol) of 6-chloro-ammonium-4-decanoic acid chloride, 8.00 g (60.0 mmol) of trichlorochloride I. and 1.79 g (12.0 mmol) of 4-mercapto-3H-benzoin. The sit-2-ketone was heated to 130 ° C for 1.5 h. After cooling to RT, the mixture was combined with ice water and then extracted with ethyl acetate. EtOAc EtOAc EtOAc. The crude product which remained as a solid was triturated with diethyl ether, suction filtered and dried in air. Yield: 2.00 g (52% of theory) ESI-MS: m/z = 290 / 292 (M+H) + (Cl)

Rt (HPLC) = 3.17 min (Method C) Intermediate 4 6-(6-Apyrimidine-4-carbonyl)-3,4-dimercapto-3H-benzoxazol-2-one

Add 0.3 5 g (8.0 mmol) of sodium hydride (55% in suspension in mineral oil) to 2.2 g (7.6 mmol) of 6-(6-gas σ密0定-4- wear in 10 mL DMF In the group 4-methyl-3-indole-benzoxazol-2-one. The reaction mixture was stirred at RT for 30 min. Then 0.95 mL (1 5.0 mmol) was added and the mixture was stirred at RT for 1 h. The reaction mixture was combined 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 was triturated with ether, suction filtered and dried. Yield: 1·6 g (69% of theory) ESI-MS : m/z = 304 / 306 (M+H) +

Rt (HPLC): 3.5 5 min (Method C) Intermediate 5 ΓΗ-spiro [piperidine-4,f-quinazoline]-2'(3'H)-one 139377.doc -84- 201038571

This compound and its precursor were synthesized as described in WO2003/1 04236. ESI-MS : m/z=218 (M+H)+

Rf: 0.08 (silicone, DCM/cyc/MeOH/NH4OH=70/15/15/2) Intermediate 6 spiro [benzo[d][l,3]oxazine-4,4'-piperidine]-2 (1H)-ketohydrochloride

This compound and its precursors were synthesized as described in US 6,43 6,962. ESI-MS : m/z=219 (M+H)+

Rf: 0.14 (silicone, DCM/cyc/MeOH/NH4OH=70/15/15/2) Intermediate 7 snail [piperidine-4,4,-pyrido[2,3-d][l,3] Azine]-2,(1'H)-one hydrochloride

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

A solution of 32.7 g (0.150 mol) of BOC anhydride in 100 mL of 139377.doc -85-201038571 THF was added dropwise to 17.4 g (0.135 mol) of 6-chloropyridin-2-ylamine at RT under nitrogen atmosphere. 300 mL (0.300 mol) of a solution of sodium bis(trimethyldecane)amine (1 M in THF) in 200 mL of THF. The reaction mixture was stirred overnight at rt and evaporated in vacuo. The residue was stirred between EtOAc and 1N aqueous brine. The organic phase was separated and the aqueous 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 and dried. Yield: 29·2 g (95% of theory) ESI-MS : m/z = 228 (M+)

Rt(HPLC): 1.70 min(^-^B) Step 2: 7'-Chloro-2'-sideoxy-oxime, 2'-dihydrospiro[piperidine-4,4'-pyrido[2, 3〇1][1,3]oxazine]-1-carboxylic acid benzyl ester

26.0 mL (173 mmol) of Ν, Ν, Ν, Ν-tetradecyl-ethylenediamine in 180 mL of THF was cooled to -20 ° C with 70.0 mL (175 mmol) of 2.5 Μ butyl under nitrogen atmosphere. Lithium solution combination. After stirring for 30 minutes, the reaction mixture was cooled to -78 ° C, and at this temperature, 17.8 g (78.0 mmol) of (6-chloro-pyridin-2-yl)-amine hydrazine in 120 mL of THF was slowly added dropwise. Third butyl acid ester. The reaction mixture was stirred at -78 <0>C for 2.511 and then with a solution of <RTIgt;</RTI> A combination of ketones. After 1 hour at -78 °C, the mixture was heated to RT and then stirred at 40 °C for 18 h. Borrow 139377.doc •86- 201038571 The reaction mixture was decomposed by dropwise addition of 150 mL of saturated sodium bicarbonate solution. It was then extracted with DCM. The combined organic phases are washed with water, dried and treated. The residue was triturated with a pad of EtOAc (EtOAc) (EtOAc). Yield: 16.4 g (54% of theory) ESI-MS: m/z = 388 (M+H)+

Rt (HPLC): 1.57!11丨11 (Method 8) Step 3: Spiro [piperidine-4,4,-pyrido[2,3-d][l,3]oxazine]-2, (1Ή) -ketohydrochloride 0

16.4 g (42.0 mmol) of 7'-chloro-21-sideoxy-oxime, 2'-dihydrospiro[pyridinyl-4,4,- in 5 mL of EtOH under hydrogen atmosphere at RT. Pyridine [2,3d][l,3]oxazine]-1-carboxylic acid benzyl ester and 2.00 g palladium/charcoal (Pd/c 1 〇./0) were hydrogenated for 6 h. Next, ΐ·〇 g palladium/charcoal (pd/C 10%) was added and the reaction mixture was further hydrogenated at RT for 3 h under a hydrogen atmosphere. After filtering the reaction mixture, the solvent was removed in vacuo. The residue was wet-milled with EtOH, and the formed precipitate was suction filtered, washed with EtOH and dried. Yield: 5.40 g (50% of theory) ESI-MS : m/z = 220 (M+H)+

Rt (HPLC): 0.90 min (Method C) Intermediate 8 6-(6-Gas-2-methyl-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazole-2-one 139377. Doc -87- 0 201038571 Step 1:

2.00 g (13.0 mm 〇1) of 6 hydroxy-2-pyridylpyrimidine_4·carboxylic acid was refluxed with 119 mL (130 mmol) of oxygen for 2 h. After cooling, 2.70 g (13.0 mmol) of vaporized phosphorus (v) was added and the mixture was boiled for 2 h. The reaction mixture was cooled to RT and evaporated to dryness in vacuo. And co-evaporated with benzene for 2 times. The residue was wet milled several times with DCM and excess DCM was decanted. The combined DCM phase was evaporated and the residue was further reacted as a crude product. Yield: 2.48 g (quantitative) Step 2: 6-(6-Gas-2-methyl-pyrimidin-4-ylcarbonyl)-4-methyl-3H-benzoxanthion-2-one.

2.48 g (13.0 mmol) of 6-gas-2-methyl-mouth -4- 曱醯, 1_94 g (13.0 mmol) of 4-mercapto-3H-benzoxazol-2-one And 6.93 g (52.0 mmol) of aluminum trioxide was heated to 125 ° C for 1_5 h. The mixture was combined with ice water and the resulting precipitate was suction filtered and washed with water. The sulphate was then dissolved in MeOH/DCM and filtered through a pad of Celite. Evaporation of the liquid and 139377.doc •88- 201038571 The residue was purified by flash chromatography. The fractions containing the product were combined, evaporated and wet-ground with diethyl ether. The precipitate was suction filtered, washed with diethyl ether and dried. ~ Yield: 0.600 g (15% of theory) ESI-MS : m/z=304 (M+H)+

Rt (HPLC): The method called melon (1) Intermediate 9 6_(6-Gas-2-methyl-pyrimidine-4-carbonyl)-3,4-dimethyl_3H_benzoxazole_2辋

Add 59 mg (1.4 mmol) of sodium hydride (5 5% in suspension in mineral oil) to 0.37 g (1.2 mmol) of 6-(6-chloro-2-methyl- in 5.0 mL of DMF at RT. ° ° -4-amino)-4-mercapto-3H-benzene and humming. Sit-2-one I. The reaction mixture was stirred at RT for 30 min. Then 〇.1〇 mL (1.60 mm〇1) moths were added and the mixture was stirred for i h at RT. Then 〇1〇 mL (1.46 mmol) of moth methane was added and the mixture was stirred overnight under the ruler. The reaction mixture was diluted with ice water and the resulting precipitate was filtered with suction. The residue was washed with water and dried in vacuo. Yield: 0.3 7 g (96% of theory) ESI-MS · m/z = 318 (M+H)+

Rt (HPLC): 1.53 min (method B) Intermediate 10 139377.doc -89- 201038571 (6-gas-mouthate-4-yl)-(7-menthyl-2,3-dihydro-benzo-β夫味-5-基)-甲嗣

Step 1: 7-mercapto-2,3-dihydro-benzopyrene. South-3-ol ΟΗ ch3 0.945 g (7.35 mmol) of trimethylsulphoxonium chloride was placed in 20 mL of THF under nitrogen atmosphere and batchwise with 0.300 g (7.50 mmol) of sodium hydride (55%, suspension in mineral oil) combination. The reaction mixture was refluxed for 2 h. Next, 1 · 〇〇 g (7.35 mmol) of 2-hydroxy-3-methylbenzaldehyde in 2 mL of THF was added dropwise to the reaction mixture and refluxed overnight. PE was then added and the suspension obtained was filtered. The mash was evaporated in vacuo and purified by flash chromatography. The fractions containing the product were combined and evaporated. Yield: 0.615 g (56% of theory) ESI-MS : m/z = 133 (Μ-Η20+Η) +

Rt (HPLC): 1.09 min (method b) Step 2: 7-Methyl-2,3-dihydro-benzofuran ch3 Under nitrogen atmosphere, make 5 mL of acetic acid in 〇·61() g(4 G6 mm〇1)7-甲139377.doc -90- 201038571 The base-2,3-dihydro-benzofuran-3-ol was refluxed with 770 μί (8.16 mmol) of acetic anhydride for 2 h. After cooling to RT, 60 mg of palladium/charcoal (Pd/C 10%) was added and the mixture was hydrogenated under a hydrogen atmosphere (3 bar) for 3.5 h. The catalyst was filtered off and the solvent was evaporated. Yield: 0.350 g (64% of theory) MS: m/z = 134 (M+) Step 3 _ (6 - gas-. mp. -4-yl)-(7 - fluorenyl-2, 3- Rat-benzoquinone-fol-5-yl)-fluorenone

0.396 g (2.24 mmol) of 6-chloropyrimidine-4-carboxylic acid chloride and 0.328 g (2.46 mmol) of trichlorochloride I in 10 mL of DCM were mixed for 20 min at RT. Then 0.300 g (2.24 mmol) of 7-methyl-2,3-dihydro-benzofuran in DCM was added dropwise to the reaction mixture and the mixture was stirred at RT for 1.5 h. After adding 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 aq. aq. Yield: 0.550 g (62% of theory) ' Purity: 70% ESI-MS : m/z = 275/277 (Cl) (M+H)+

Rt (HPLC): 1.54 min(^T^B) Intermediate 11 5-amino-1,3-dihydrospiro[茚-2,3'-pyrrolo[2,3-13]pyridine]-2, (1,11)_ketone 139377.doc -91 - 201038571 ο

Ηη2 This compound was synthesized as described in WO2006/029153. ESI-MS: m/z = 252 (M+H)+

Rf (DC) = 0.4 (10% methanol/chloroform) Intermediate 12: (6-Gas-pyrimidin-4-yl)-(2,3-difluoro-phenyl)-methanone

Step 1: 6-Gas-pyrimidine-4-thiocarbonate S-phenyl ester

N^N

c|AAislD 1.58 mL (15.4 mmol) of thiophenol and 2.75 mL (16.08 mmol) of DIPEA were added at 〇C to 3.00 g (16.1 mmol) 6-^ in 100 mL DCM. ^. Determine _4_曱醯 in the chlorine and in the 〇. I gave it down and gave it for 1 h at rt. The reaction mixture was then diluted with DCM and washed with aq. sodium hydrogen sulfate and water. The organic phase was dried over sodium sulfate, passed through a tear, and then filtered and washed with DCM. The filtrate was then evaporated. Yield: 3.80 g (99% of theory) MS: m/z = 250/252 (Cl) (M+)

Rt (HPLC): 2.95 min (Method F) Step 2: (6-chloro-pyrimidin-4-yl)-(2,3-difluoro-phenyl)-methylhydrazine 139377.doc -92· 201038571

Argon was piped through 0.50 g (2.0 mmol) of 6-chloro-pyrimidine-4-thiocarbonate S-phenyl ester, 0.38 g (2.4 mmol) of 2,3-difluorophenylboronic acid in 25 mL of THF. 0.46 g (2.4 mmol) of thiophene-2-phosphonate for 3 minutes followed by the addition of 46 mg (0.05 mmol) of Pd2dba3 and 35 pL (0-20 mmol) of triethyl phosphite. The reaction mixture was stirred for a further 48 h at RT, then the formed precipitate was filtered and evaporated. The residue was purified by flash chromatography. Yield: 0.47 g (83% of theory) Purity: 90% ESI-MS: m/z = 255/257 (Cl) (M+H)+

Rt (HPLC): 4.23 min (Method C) Preparation of the final compound Example 1 : 〇4-methyl-6-(6-(2'- oxo-2',3'-dihydro-indole-spiro[ Piperidine-4,4'-quinazolin]-1-ylpyrimidine-4-carbonyl)benzo[d]oxazole-2(3H)-one

Will be 144 mg (0.500 mmol) of 6-(6-chloroindole -4-amino)-4-methyl-3H-benzo- oxa ketone, 108 mg (0-500 snail [° bottom] °定139377.doc -93- 201038571 0 坐琳]·2'(3Ή)·ketone and 0_174 mL (1.00 mmol) DIPEA were combined in 5.0 mL DMF and stirred overnight at RT. The reaction mixture was prepared by preparative hPLc Purification 'Combines the fractions containing the product and removes the organic solvent in vacuo. The aqueous phase is neutralized by the addition of 4 N aqueous NaOH. The solid product of the precipitate is filtered, washed, washed with water and dried. :130 mg (55% of theory) ESI-MS : m/z=471 (M+H)+

Rt (HPLC) = 2.5 5 min (Method C) Example 2: 4-Methyl-6-(6-(2'- pendantoxy-1,1',2,,3_tetrahydrospiro) ,3,_pyrrolo[2,3-b]pyridine]-5-ylamino)pyrimidine-4-carbonyl)benzo[d]oxazole-2(3H)-one

144 mg (0.500 mmol) of 6-(6-chloropyrimidin-4-carbonyl)-4-methyl-3H-benzoxazol-2-one, 126 mg (0.500 mmol) 5-amino-1,3 -Dihydrospiro[茚-2,3'-pyrrolo[2,3-b]pyridine]-2,(1Ή)-one and 16.1 mg (0.100 mmol) benzenesulfonic acid combined in 5.0 mL of 2-pentanol And reflux for 4 h. The reaction mixture was evaporated, and the residue was triturated with PE, suction filtered 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 the addition of a 1 N aqueous NaOH solution. The precipitated solid product was filtered off, washed with water and dried. 139 377. doc s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s

Rt (HPLC) = 2.88 min (Method C) Example 3 3,4-Dimethyl-6-(6-(2'- oxo-2',3'-dihydro-l'H-spiro[piper Pyridin-4,4'-quinazoline]-1-yl)pyrimidine-4-carbonyl)benzo[d]oxazole-2(3H)-one

0 ch3 will be 87.0 mg (0.400 mmol) 1 Ή-snail [spotted-4,4'-啥.坐琳]-2,(3Ή)-ketone, 122 mg (0.400 mmol) of 6-(6-chloropyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.140 mL (0.800 mmol) of DIPEA was combined in 3.0 mL DMF and stirred at RT for 48 h. The reaction mixture was diluted with MeOH. Yield: 184 mg (95% of theory) 〇 ESI-MS : m/z = 485 (M+H) +

Rt (HPLC): 1.14 min (>r^A) Example 4 3,4-Dimethyl-6-(6-(2'-sideoxy-1, fluorene, 2',3-tetrahydrospiro[茚-2,3'-pyrrolo[2,3-b]"bipyridine]-5-ylamino)pyrimidine-4-carbonyl)benzo[d]oxazole-2(3H)-one

139377.doc •95· 201038571 Add 16.0 mg (〇.100 mmol) of benzenesulfonic acid to 126 mg (0.500 mmol) of 5-amino-i,3-dihydrospiro in 5 〇mL 2 of pentanol. 2,3'_pyrrolo[2'3-b]. The mixture was bucked with -2'(1Ή)-ketone and 152 mg (0.500 ° of 4-carbonyl)-3,4-dimercapto-3H-benzoxazol-2-one and boiled for 4 h. The reaction mixture was evaporated and purified by preparative HPLC. The mixture containing the product was combined to remove the organic solvent in vacuo and neutralize the residual aqueous phase with 1 M aqueous NaOH. The precipitated solid product was suction filtered, washed with water and dried in vacuo. Yield: 110 mg (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-oxooxy-2.3-dihydrobenzo[d]pyrene-6-rebel) Acridin-4-yl) snail [benzoxan] [l,3]oxazine_4,4,-piperidine]-2(1Η)-鲷

102 mg (0.400 mmol) spiro[benzo[d][l,3]oxazine-4,4,-piperidine]-2(1H)-one hydrochloride, 122 mg (0.400 mm 〇l) 6 -(6-Chloropyrimidin-4-yl)-4-mercapto-3H-benzoxanthene and 0.210 mL (l.20 mm〇i) DIPEA were combined in 3.0 mL DMF and scrambled for 48 h. The mixture was purified by preparative HPLC-MS. The fractions containing the product were combined, the organic solvent was removed in the air and the residual aqueous phase was neutralized with 4 M aqueous NaOH. The precipitated solid product was suction filtered, washed with water and dried in CAD 139377.doc:96·201038571. Yield: 90 mg (46% of theory) ESI-MS: m/z = 486 (M+H)+

Rt (HPLC): 1 · 25 min (method B) Example 6 1-(6-(3,4-dimethyl-2-oxo-2.3-diazobenzo[d] chew--6- Pyrimidine-4-yl) snail [piperidine-4,4,-pyrido[2.3-d][l,3]oxazine-2'(indolene)-one

55 mg (0.21 mmol) of snail [β bottom bite - 4, 4'-° ratio. And [2_3-d][l,3]°Call]-2'(1Ή)-acid I hydrochloride, 65 mg(0.21 1111]1〇1)6-(6-chloro°Bite-4 -Methyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.84 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at RT. The reaction mixture was then purified by preparative HPLC-MS. The oxime fractions containing the product were combined and lyophilized. Yield: 73_0mg (70% of theory) ESI-MS : m/z = 487 (M+H)+

Rt (HPLC): 2.60 min (Method C) Example 7 1-(6-(3,4-Dimethyl-2-oxo-2,3-dihydrobenzo[d]oxazole-6-carbonyl )- 2-methylpyrimidin-4-yl) snail [piperidine-4,4'-pyrido[2,3-d][l,3]oxazine-2,(ΓΗ)-one 139377.doc - 97- 201038571

77 mg (0-30 mmol) spirulina sigma -4,4'-° ratio σ and [2,3-d][l,3]Doxazine]-2'(1Ή)-one hydrochloride 88 mg (0.28 mmol) 6-(6-Gas-2-mercapto-pyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.17 mL (1.0 mmol DIPEA was combined in 2 mL DMF and stirred overnight at RT. The reaction mixture was then purified by preparative HPLC-MS. The fractions containing the product are combined and the organic solvent is evaporated. The residue was neutralized with a 4 N aqueous sodium hydroxide solution. The precipitate thus formed was suction filtered, washed with water and dried in a vacuum. Yield: 53 mg (35% of theory) ESI-MS: m/z = 501 (M+H)+

Rt (HPLC): 1.07 min (Method B) Example 8 5-(6-(7-methyl-2.3-dihydrobenzofuran-5-carbonyl)pyrimidin-4-ylamino)) 1,3-di Hydronose-2,3,-pyrrolo[2,3-b]pyridine 1-2, (ΓΗ)-_

The benzenesulfonic acid at the tip of the spatula was added to 7 〇mg (0.28 mmol) of 5-amino-1,3-dihydrospiro in 2 mL of pentanol [茚-2,3'-0 ratios each [ 2,3-b]n-pyridyl]-2'(1Ή)-one and 0.10 g (0.26 mmol) (6-gas-pyrimidin-4-yl)·(7-甲139377.doc -98- 201038571 base- 2,3-Dihydro-benzofuran-5-yl)-fluorenone and the mixture was stirred at 85 ° C for 1 h. The reaction mixture was evaporated, dissolved in EtOAc EtOAc (EtOAc)EtOAc. The fractions containing the product were combined and dried in a cold bed. Yield: 60 mg (48% of theory) ESI-MS: m/z = 490 (M+H)+

Rt (HPLC): 1.39 min (Method B) Example 9 5-(6-(2,3-Difluorobenzimidyl)pyrimidin-4-ylamino)-1,3-dihydrospiro[茚-2 ,3,-pyrroloindole 2,3-b]pyridine]-2,(ΓΗ)-ketone

70 mg (0.28 mmol) of 5-amino-1,3-dihydrospiro[茚-2,3,-pyrrolo[2,3-b]pyridine]-2 in 600 pL of diterpene. (1Ή)-ketone, 80 mg (0.28 〇mmol) (6-chloro-pyrimidin-4-yl)-(2·3-difluoro-phenyl)-methanone and 60 μί DIPEA at 80. . Stir for 1 h. After cooling, the reaction mixture was combined with about 10 mL of ice water. The liquid was decanted and the residue was dissolved in DCM and MeOH. After drying over sodium sulfate, the mixture was filtered and evaporated. The residue was triturated with ether, taken and dried. Yield: 82 mg (60% of theory) ESI-MS: m/z = 470 (M+H)+

Rt (HPLC): 3.97 min (Method C) The following example describes the preparation of a pharmaceutical formulation containing any desired compound of formula I as active substance 139377.doc-99-201038571:

EXAMPLE I Capsules for powder inhalation containing 1 mg of active ingredient: 1 capsule for powder inhalation Contains: Active ingredient 1.0 mg Lactose 20.0 mg Hard gelatin capsule 50.0 mg 71.0 mg Method of preparation: Grinding active ingredient into inhaled substance The required particle size. The ground active ingredient is uniformly mixed with the lactose. Transfer the mixture to hard gelatin capsules 〇

Example II Inhalable solution for Respimat@ containing 1 mg of active ingredient per spray Containing: Active ingredient 1.0 mg Gasified ammonium ammonium 0.002 mg Ethylene diamine tetraacetate 0.0075 mg Adding pure water to 15.0 μΐ Preparation Method: The active ingredient and the gasified benzoquinone ammonium were dissolved in water and transferred to a Respimat 8 cartridge. 139377.doc -100- 201038571

Example III Inhalable solution for nebulizer containing 1 mg of active ingredient Ingredients: 1 bottle contains: Active ingredient 〇-1 g Sodium chloride 0.18 g Benzammonium chloride 0.002 g Add pure water to 20.0 ml ❹

Preparation:

The active ingredient, sodium carbonate and benzalkonium chloride are dissolved in water. Example IV A propellant gas operated dosing aerosol composition containing 1 mg of active ingredient: Each spray dose contains: Active ingredient 1.0 mg Lecithin 0.1% Propellant gas added to 50.0 μΐ Preparation method: Micron size The active ingredient is uniformly suspended in a mixture of lecithin and a propellant gas. Transfer the suspension to a pressurized container with a metering valve 〇

Example V Composition of a nasal spray containing 1 mg of active ingredient: 139377.doc -101 - 201038571 Active ingredient 1.0 mg Sodium gasification 0.9 mg Ammonium Benzalkonium chloride 0.025 mg Disodium edetate 0.05 mg Add pure water to 0.1 ml Preparation method:

The active ingredient and excipients are dissolved in water and transferred to a suitable container. Example VI Injectable solution containing 5 mg of active substance per 5 m丨 Composition: 5 mg 250 mg Active substance Glucose Human serum albumin 10 mg Polyethylene glycol tetrahydrofuranyl ether 250 mg Add water for injection to 5 ml Preparation: Ethylene glycol tetrahydrofuranyl ether and glucose are dissolved in water for injection (Wfl); human serum albumin is added; the active ingredient is heated and dissolved, and the volume is made up to a specified volume by Wfl; and transferred to an ampoule under nitrogen.

Example VII Injectable solution containing 100 „^ active substance per 20 ml Composition: Active substance 100 mg Potassium dihydrogen phosphate = KH2P04 12 mg 139377.doc -102- 201038571 Hydrogen sulphate sulphate = Na2HP04*2H2 〇 2 mg gas 180180 mg Human serum albumin 50 mg Polysorbate 80 20 mg Add water for injection to 20 ml 制备 Preparation: ♦ Sorbitol 80, sodium chloride 'potassium dihydrogen phosphate and disodium hydrogen phosphate dissolved in water for injection (Wfl); adding human serum albumin; adding the active ingredient, ',, public solution' with WfI to the specified volume " transfer to ampoule. Example VIII contains 10 mg of active substance to dry powder (Ly〇 phUisate) Composition:

The active substance mannitol human albumin is added with water for injection to prepare: 1 0 mg 300 mg 20 mg 2 ml π-mouth glycoside solution in water for injection (wfI); adding human serum tongue-forming portion plus detoxification. to vial H East dry rw ^ volume; solvent for lyophilized powder: polysorbate 80 = Tween 80 mannitol added water for injection to 20 mg 200 mg 10 ml 139377.doc 201038571 Preparation: Polysorbate 80 and Mannitol is dissolved in water for injection (wfI); transferred to ampoules. Example IX Lozenges containing 20 mg of active substance Active ingredient 20 mg Lactose 120 mg Corn starch 40 mg Magnesium stearate 2 mg Povidone K 25 (Povidone K 25) 1 8 mg Preparation: Active substance, lactose and corn The starch was uniformly mixed; granulated with aqueous povidone; mixed with stearic acid; compressed in a bond: machine; the weight of the spinner was 200 mg.

Example X contains 2 〇m active substance of ray·capsule composition: active substance 20 mg corn starch 80 mg highly dispersed Shishi stone 5 mg magnesium stearate 2.5 mg Preparation: The active substance, corn starch and vermiculite are uniformly mixed; Mixed with magnesium stearate 139377.doc • 104- 201038571; the mixture is filled into a hard gelatin capsule No. 3 in a capsule filling machine. Example XI suppository containing 50 mg of active substance: Active substance added stearin (solid animal fat) (Adeps solidus)) sufficient to prepare: 50 mg 1700 mg

Put the hard fat at about 38. (: melt down; uniformly disperse the ground active substance in molten hard fat; after cooling to about 3 5, it is injected into the mold. Example 4) into the cooled mold contains 10 mg of active substance per 1 m Injectable solution composition: 活性 Active substance mannitol human serum albumin is added with water for injection to prepare: 10 mg 50 mg 10 mg 1 ml The mannitol is dissolved in the injection white; the active ingredient is heated and dissolved in the gas and transferred to the ampoule. In water (Wfl); add human serum white egg, make up to the specified volume with Wfl; in 気139377.doc -105·

Claims (1)

201038571 VII. Patent application scope: 1. A compound of formula I R2 represents a hydrazine or a CN3 alkyl group, or R1 and R2 together with a nitrogen atom bonded thereto represent a group of the formula Ilia or 111b. G represents C-R1·1 or N, and T represents N-R1·2 or Ο, and R1·1 independently represents (a) Η, (b) halogen, Ch alkyl, -OH, -CN, -O- Cu alkyl, -C(0)-0-Ci-3 alkyl, C2-4 dilute, _C2-4 block, Ci_3 calcination 139377.doc 201038571 base-S, cyclopropyl, _nh2, -cooh, _NH_c (〇) 〇_Ci-3 alkyl, -NH-C(0)-Ci_3 alkyl, (C) C!.3 alkyl or Cl.3 alkyl-〇- group, wherein each methylene group After two fluorine atoms are substituted and each methyl group is substituted with up to three fluorine atoms, R1·2 independently represents Η or C!-3 alkyl, and R1·3 represents (4) Η, F, -CN, and , -COyRHi or Cw alkyl, wherein each fluorenylene group may be substituted with up to 2 fluorine atoms and each fluorenyl group may be substituted with up to 3 fluorine atoms, and R1·3·1 represents (a) Η, (b) Cb6 alkyl, R3 substituted by a group R3·1, R3·2 and R3.3, 6 member or i aryl, or substituted with a carbon atom-bonded groups R3.1, R3·2 and R3·3 6-membered heteroaryl, 'R3.1 main record not (a) Η, (b) ι|, -ΝΗ2, Cl.4 alkyl-ΝΗ, (Cl.4 alkyl) 2Ν, Ck alkyl - C(0)-NH, Cu 炫-S ( 〇2)_nh, -CN, -OH, -O-CCC^-NH-Cu alkyl, 139377.doc 201038571 (c) Cw-based 'R'U-Cw stretching group, C2_4 thin group, c2_4 alkynyl group , Cb3 alkyl-hydrazine, Ch3 alkyl-s(0)m, cyclopropyl, (d) C^3 leucine or Cu alkyl-oxime-group, wherein each methylene group has up to 2 fluorines Atom substituted and each methyl group substituted with up to 3 fluorine atoms, (e) -(:(0)-113.1.2, (f) -S(〇)2-R3·13, R3.1,1 (a) Η, C3-6%·alkyl, C5-6 ring, (R311*1)2N > substituted at the nitrogen atom via the group R3·1·1·1 and at the carbon atom _ Or a saturated, monounsaturated or diunsaturated 5- or 6-membered heterocyclic group substituted by two groups R3·1·1·2, or substituted at the carbon atom via a group R3·1·1·2 a heteroaryl group, R3·1.1.1, independently of each other, represents (a) Η, (^_4 alkyl, C3_6 cycloalkyl, (b) heterocyclic, (c) aryl-C〇-3 alkyl or Heteroaryl-CQ-3alkylene, R3.1·1·2 independently of each other (a) Η, F, Cu alkyl, -CN, -OH, -0-Ci_3 alkyl, -CO(〇 R31 丄2·ι, h2n, (Cw alkyl)·ΝΗ, (C1-4 alkyl) 2N, (b) stupid or phenyl _ch2, 139377.doc 201038571 each fluorene up to 3 The gas atom is taken as (C) Cj_3 alkyl or _〇_c] 3 alkyl group, wherein 2 fluorine atoms are substituted and each methyl group is ' or C, Cw alkyl, phenyl fluorenyl, 3 12 R · represents -〇_C] 3 alkyl, _〇H, _Nr3.12 ,, 2 , R312 2 R _ · · represents Η, Cw alkyl, R3.1·2·2 represents Η, Cw alkyl, R Μ.2.1 and R3”.2.2 — A ring selected from the group consisting of aza. ^ w 11 heteropoly butyl, piperidinyl, piperazinyl and morpholinyl is formed to "represent -^^丨-alkyl, ...!^.1·3^.! . . > R3·1·3.1 indicates Η, C 卜 3 alkyl, °tb rotidine R3.1·3.2 indicates Η, Ch alkylcyclobutyl, ° 洛洛 bite Rm^R3.1.3.2 A ring selected from the group consisting of a pyridyl group, a piperidinyl group, a piperazinyl group, and a morpholinyl group can be formed, and R3'2 represents (a) fluorene, (b) a lignin, a hydrazine, a C"alkyl group ΝΗ, (Ci 4 Alkyl-C(0)-NH, Cl.3 alkyl _s(〇2)_NH, _CN, - -OH, -0-C(0)-NH-C丨_3 Alkyl, (c) Cm alkyl, C2-4 alkenyl, c2_4 alkynyl, Ci 3 alkyl 〇, Cu alkyl-S(0)m, cyclopropyl, (d) Ci·3 alkyl or C!·3 院基-〇_ group, wherein each fluorenylene group is substituted with up to 2 fluorine atoms and each fluorenyl group is substituted with up to 3 fluorine atoms, 139377.doc -4- 201038571 (e) -( :(9)-only 3.2.1, (f) -S(0)2-R3·2.2, R3·2·1 represents -O-Cw alkyl, -〇H, -NRWi.iw,1, RJ.2.1. 2, R represents H, Ci_3 alkyl, R3·2·1·2 represents H, Cw alkyl, 0 to 0 each 0 is 0 to 唆 R3·2·1·1 and R 3·2.1.2 Together, a ring selected from the group consisting of anthracenyl, benzylidene, α-azinyl and hydrazin can also be formed, and R3·2·2 represents -NR3·2'2'1!^3 ·2,2,2, Ο R3·2, 2'1 represents Η, Cu alkyl, R3·2, 2, 2 represents Η, C, -3 alkyl, R3·2'2'1 and R3·2, 2'2 together Forming a ring selected from the group consisting of azetidinyl, azulidine, azoxazinyl and morphinyl, R3·3 represents (a) fluorene, (b) halogen, -NH2, CN4 alkyl-hydrazine, (Cb4 Alkyl) 2n, C]-3 alkyl-C(0)-NH, Cb3 alkyl _s(〇2)_NH, -CN, -OH, -O-qCO-NH-Cu alkyl, (c) Ci.4 alkyl, C2_4 alkenyl, c2-4 alkynyl, Cb3 alkyl-O, Ci-3alkyl-S(0)m, cyclopropyl, alkyl or Cu-group-〇- group, Wherein each methylene group is substituted with up to 2 fluorine atoms and each fluorenyl group is substituted with up to 3 fluorine atoms, (e) -C(0)-R3·31, (f) -S(0)2-R3 ··············· H, c 3 alkyl, R s · 1 '1 and R 3 · 3 · 1.2 can also form a ring selected from the group, piperidinyl 'piperazinyl and morpholinyl: 〃 % butyl, pyrrolidine R represents -〇-C!-3 alkyl, _NR3.3.2.1r3 3 2 2 R3·3·2·1 represents Η, C丨·3 alkyl, R3·3·2·2 Η, (:丨_3 alkyl, R3·3.2·1 and R3·3·2·2- may also form a ring selected from the group consisting of azetidinium, piperidinyl, piperazinyl and morpholinyl % A t-rodentyl R3·2 and R3·3 together with the carbon atom M u ^ ^ attached thereto form a soap-saturated 5 member', a clothing group or a monounsaturated or a diunsaturated, a heteroaryl group. The "hetero" or a 5- to 6-membered carbonyl group or a thiocarbonyl group may have a heterocyclic ring or a cyanoimine group, and the cleavage may additionally be at - or two nitrogen atoms. Substituted by the group r3 3 3 and the cleavage may be additionally substituted at one or two carbon atoms via one or two groups R3·3·4, R3·3'3 independently of each other (a) C1 _4 An alkyl group or (b) a C3.6 cycloalkyl group, R3 3·4 independently of each other represents (a) ci·4 alkyl or 139377.doc 201038571 u (b) C3-6 cycloalkyl, (c) halogen, CN, _〇.Ci 3 alkyl, _NH 2 , (d) Cw alkyl or Ci_3 alkyl 〇 基 group, wherein each fluorenylene group is substituted with up to 2 fluorine atoms and each methyl group is up to 3 Substituted by a fluorine atom, indicating N, N-oxide or C_R4, V represents N, N- The compound or c_Rs, X Ο Υ represents N, N-oxide or cr6, and wherein at most three of the previously mentioned groups U, V, X or Y represent a nitrogen atom, and R4 represents (a) Η, (b) a C..6 alkyl or Cu alkyl-hydrazine group, which is substituted by a group of only 4.1, ❹ (c) R4_2R4, 3N, R4_2R4.3N_Cl_3 alkyl, (d) halogen, -CN , -OH, -COOH, Ch alkyl-hydrazine, CN3 alkyl group - 0-C!·3 stretching base, (: 3_6 cycloalkyl, C3.6 cycloalkyl-Cm alkyl, (: 丨_ 3 alkyl-CCCO-O-Cw alkylene, (e) Ci·3 alkyl or Ci-3)·0-group' wherein each fluorenylene group is substituted with up to 2 fluorine atoms and each hydrazine Substituents substituted with up to 3 fluorine atoms, R4·1 represents Η, OH or -0-CH3, R4·2 represents Η or Cw alkyl, 139377.doc 201038571 R4·3 represents HSCw alkyl, or 3 to 6 The heterocyclic rings R4·2 and R4·3 together with the nitrogen atom to which they are bonded are a group of a group, and R represents (a) Η, a group other than a group (b), a C 2 alkyl group or a Cl. 3 alkyl group. - group, the dragon is sub-substituted (C) -NR5.2R5·3, NRs.2R5.3-Ci-3 alkylene, (d) halogen, -CN, -OH, Cl_3 alkyl_alumina U' Ci-3 Alkyl, C3 6 cycloalkyl, C3_6 cycloalkyl-C stretching methyl, C]-3 alkyl-(:(0)-0-(:,.3 alkyl, (e) aryl a -C〇-3 extended alkyl-oxime-group, (f) a Ci-3 alkyl or a Cu-alkyl-anthracene group, 1 + - a tantalum-anthracene group substituted with up to 2 fluorine atoms and Each of its Y groups is substituted with up to 3 fluorine atoms, R5·1 represents Η, ΟΗ or -0-CH3, R5'2 represents Η or Cw alkyl, and R5·3 represents H, C -6 alkyl or -SCVCy alkyl, or Rs.2 and R5.3 together with the nitrogen atom to which they are bonded, together with a 6- to 6-membered heterocyclic group, R6 represents (a) Η, (b) Cl_6 alkyl or Cl a -3 alkyl-oxime group, which is substituted by a group Rei, respectively, 139377.doc 201038571 (c) R6, 2R6.3N, rUrUN-Cw alkyl, (d) halogen, -CN, -〇H, -COOH, Cu alkyl 〇, Γ ^ 1-3 alkyl-O-Ci · 3 alkylene, C 3 · 6 cycloalkyl, Cs_6 ring-based - Ci. 4 stretching, C] -3 a base-C(0)-0-Ci-3 extended alkyl group, (e) a Cw alkyl group or a Cw alkyl-fluorene group, wherein each methylene group is substituted with up to 2 fluorine atoms and each methyl group Substituted by up to 3 fluorine atoms, Ο R6·1 represents Η, OH or -〇-CH3, R6·2 represents Η or Ci_3 alkyl, R6·3 represents Η4 (^_3 alkyl, or R and R6·3 together with the pelt bond: ± j The pore atoms of ^, /, 埏, , , together represent a 3- to 6-membered heterocyclic group, and R represents H, halogen or Cu alkyl, and its tautomer, diastereomer 'enantiomer' a hydrate of a structure, a hydrate, a heart and a salt thereof, and a salt such as g, in particular, a physiologically acceptable salt thereof with an inorganic or organic acid or a base. Where U, ν, χ, Y, r^r3 are as defined in claim 1, and the R table is not selected from the following groups: R1'1 represents 139377.doc 201038571 (a) Η - (b) Element, Cm alkyl, _〇H, _CN, _〇_Ci_3 炫, alkyl, C24 alkenyl c24 alkynyl, 3 alkyl -S, -NH2, (4) a CV3 alkyl or a Cl-3 group, wherein each -methylene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms, and R1·2 represents (a) Η or (b) CH3, a structure, a hydrate, and an inorganic or a tautomer thereof, a diastereomer, an enantiomeric mixture and a salt thereof, and a hydrate of the salt, A physiologically acceptable salt of a particular organic acid or base. 3. A compound of formula I according to claim 1 which is as defined in claim 1 and wherein R1 and R2 together with a nitrogen atom group bonded thereto: wherein U, V, X, γ, 尺2 and r3 Indicates 139377.doc selected from the following η r N, °rN-o HN R1 201038571 R1'1 means (a) Η, ruthenium, ci-3 alkyl, -OH, -CN, -O-Cu succinyl, -C(O)-O-Ci-3 alkyl, c2.4 olefin a group, c2_4 alkynyl, c"alkyl-S, -NH2, Cl.3 alkyl or C1-3 alkyl-O- group, wherein each methylene group is substituted with up to 2 acute atoms and each The radicals of up to three fluorine atoms are taken from the 'potent', tautomer, diastereomer, enantiomer, hydrate, the orthoquinone and the salt thereof, and the hydrate of the salt, In particular it is a physiologically acceptable salt with an inorganic or organic acid or base. 4. A compound of the formula 叫1, wherein υν, X, 丫 and r3 are as defined in claim 1, and R1 represents a group selected from the group consisting of: R1·1 represents (a) F, CH3, -0H, .~(^ or (b) CF3, tautomers, diastereomers, enantiomers, hydrates, mixtures thereof and salts thereof And a hydrate of the salt, in particular a physiologically acceptable salt thereof with an inorganic or organic acid or base. 139377.00C • 11 - 201038571 5. A compound of the formula 请求1, wherein υ, ν , χ, γ, Han 2, and Han 3 are as defined in claim 1, and R1 and R2 together with the nitrogen atom to which they are bonded represent a group selected from the following: (4) F, CH3, -oh, 〇_CH3 or Cf3, tautomers, diastereomers, enantiomers, hydrates, mixtures thereof and salts thereof, and hydrates of such salts, ^ Its physiologically acceptable salt with an inorganic or organic acid or base. 6. The compound of formula 1 according to claim 1, wherein U, V, X, Y, R2 and R3 are as defined in claim 1, and R1 represents a group selected from the group consisting of: a tautomer, a diastereomer, an enantiomer, a hydrate 139377.doc -12- 201038571 a mixture thereof and a salt thereof and a hydrate of the salt, in particular with an inorganic or organic acid or A physiologically acceptable salt is tested. A compound of formula I according to claim 1, wherein U, V, X, Y and R3 are as defined in claim 1, and R and R2 together with the nitrogen atom to which they are bonded represent a group selected from the group consisting of : ❹ It: isomers, diastereomers, enantiomers, hydrates, hydrazine mixtures and salts thereof, and hydrates of such salts, in particular their physiology with inorganic or organic acids or bases Acceptable salt. 8. The compound of formula I according to claim 1, wherein ϋ, V, X, γ, r1&r2 are as defined in claim 1, 2, 4 or ,, and r3 represents a group of formula IV A (IV), independently of each other, CH, CF or N, 139377.doc -13· 201038571 R3 · 1 main one is not (a) Η, halogen, -ΝΗ2, Cw alkyl-ΝΗ, (Cu alkyl) 2Ν ,Ch alkyl-C(0)-NH,Ch alkyl-S(0)2-NH, -CN, -OH, -O-qOhNH-Cu alkyl, c!_4 alkyl, R3·1·1 -^·; alkylene, c2_4 alkenyl, c2_4 alkynyl, Ci-3, ketone, oxime, Ci.3 alkyl-S, Cl _3 alkyl or C!·3 alkyl-O- group, wherein Each methylene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms, _C(〇)-R31·2, -S(〇)2-R31.3, R311 represents (a) Η, C3-6 cycloalkyl, C5.6 cycloalkenyl, (R3,1,1-1)2n > substituted at the nitrogen atom via the group Rmi and at the carbon atom via one or two groups R3 ·1.2 Substituted saturated, anthracene, an unsaturated or diunsaturated 5- or 6-membered heterocyclic group, or a heteroaryl group substituted at the carbon atom via a group Rm·2, R3·1.1,1 Independently from each other, H, Cw alkyl, c3.6 cycloalkyl, heterocyclic, aryl-cG.3 alkyl or heteroaryl_Cq_3 alkyl, 139377.doc -14- 201038571 R3,1 ·1.2 each other Stand for H, F, c!.3 alkyl, -CN, -OH, -0-(:, .3 alkyl, -CO(0)R3mi, H2n, (Cw alkyl)-NH, (Cw alkane 2N, phenyl or phenyl-CH2, C1-3 alkyl or -O-Cw alkyl, wherein each fluorenylene group is substituted with up to 2 'fluoro atoms and each fluorenyl group has up to 3 fluorine atoms Substituting, or ° R3.1·1.2·1 represents Η, C丨-6 alkyl, benzyl, R3·1·2 represents -OC丨-3, 〇H, -NR3·1·2· 1!^3.1.2·2, R3·1·2·1 represents H' Cw alkyl, R3·1·2·2 represents Η, C _3 alkyl, R3·1·3 represents -NR3.1· 3·1!^3·1.3·2, R3·1·3·1 represents Η, Cw alkyl, R3·1·3·2 represents Η, CN3 alkyl, R3_2 represents (4) Η, halogen, -NH2, Cw Alkyl-indole, (Cw alkyl) 2Ν, Cw alkyl-C(0)-NH, C, .3 alkyl-S(0)2-NH '-CN, -OH, • -O-QCO- NH-Cu alkyl, Cw alkyl, c2_4 alkenyl, c2_4 alkynyl, CN3 alkyl-O, cv3 alkyl-S, Cl-3, or Ci.3 alkyl-〇- group, each of which The fluorenylene group is substituted with up to 2 fluorine atoms and each methyl group is subjected to up to 3 fluorine atoms. 139377.doc •15· 201038571 generation, -C( 0)-R3·21, -s(o)2-r3·2·2, R3·2·1 represents -OC, 3 alkyl, -OH, -NR3 211R3·2·12, R3·2·1· 1 represents H, Cw alkyl, R3.2.1·2 represents H, C 3 alkyl, R3·2.2 represents -NR3·2'2, 1!^·2'2, 2, R3·2'2'^ Represents H, Cu alkyl, R3·2'2'2 represents H, CN3 alkyl, R3·3 represents (a) H, halogen, -NH2, Cw alkyl-NH, (Ci.4 alkyl) 2N, Cu alkyl-C(0)-NH, Cu alkyl-S(0)2-NH, -CN, -OH, -OC^CO-NH-Ch alkyl, 匸1-4 alkyl, 〇2- 4 dilute base, 匸2-4 fast radical, 〇1.3 炫基-0, (^1-3 院-s, Cw alkyl or Cw alkyl-o- group, wherein each methylene group is at most 2 Each fluorine atom is substituted and each methyl group is substituted with up to 3 fluorine atoms, -C(0)-R3·31, -s(o)2-r3.3·2, R3·3.丨 represents -0-C 3 alkyl, -OH, -NR3·3.1·1!^.3·1.2, R3·3·1·1 represents Η, Cw alkyl, R3·3·1·2 represents Η, Cw alkyl, 139377 .doc -16- 201038571 3 3 2 R · · represents -o-Cw alkyl, _NR3.3.2.1r3.322 R3·3.2.1 represents η, Cw alkyl, R3·3·2'2 represents Η, C丨-3 alkyl, or R3·2 and R3·3 together with it a heterocyclic group or a monounsaturated or betaryl group in which a carbon atom together form a monounsaturated 5-membered unsaturated 6-membered heterocyclic group or 5 to 6 Ο. The previously mentioned heterocyclic ring may contain hydrazine. a carbonyl group, a sulfur thiol group or a carbylene group adjacent thereto, and may be optionally substituted by a group R at one of two nitrogen atoms, respectively, and .3. The atom is substituted by a group R3·3·4, or two R3·3·3 independently of each other represents a C 1 -4 alkyl group, or a C3-6 ring-based group, R3·3·4 independently of each other represents a Cl_4 alkyl group, a C3.6 cycloalkyl group, a hydroxyl group, a CN, a Cl-3 group, a 〇__, a _NH 2 , a C 3 · alkyl group or a Ci 3 alkyl group. a group of two more fluorine atoms substituted for each deuteration, wherein each subunit is passed through up to three fluorine atoms to its tautomer, diastereomer, enantiomer, hydration And mixtures of the substances, mixtures and salts thereof, and hydrates of such salts, in particular with physiologically acceptable salts of inorganic or organic acids or bases. 139377.doc •17· 201038571 9. As requested! A compound of the formula j wherein υ, ν, χ, ¥, 111 and ]1 are as defined in claim 1, 2, 4 or 6, and r3 represents a group of formula IV R31 A is produced 2 λ Ι 33 AR (IV), A R3 independently of each other represents CH, CF or N, and represents (4) Η, dentate, -ΝΗ2, Ci-4 alkyl_ΝΗ, (Cl 4 alkyl) 2ν, Cl-3 alkyl-C(0 )-NH, -CN, -〇H, -OC^CO-NH-Cw alkyl, C]-4 alkyl 'c2.4 alkenyl' c2.4 alkynyl, Ci.3 alkyl-hydrazine, CU3 Alkyl-s, Cl.3 alkyl or C!.3 alkyl-hydrazine group wherein each fluorenylene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms, R3_2 Indicates (4) Η, (b) dentate, -NH2, Cw alkyl-hydrazine, (Cu alkyl) 2N, Cw alkyl-C(0)-NH, -CN, -OH, -OC^CO-NH-Cw Acryl group, (C) Ci-4 alkyl, C2-4 dilute, C2.4 alkynyl, Cu alkyl-O, C i -3 alkyl-S, 139377.doc •18· 201038571 (d) C a 3-alkyl or Cw alkyl-hydrazine group in which each methylene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms, and R3·3 represents hydrazine, halogen, - ΝΗ2, Cb4 alkane _ΝΗ, (Cl4 alkyl) 2ν, Cl_3 alkyl group -C (0) -NH, -CN, -OH, -O-CCCO-NH-Cu alkyl group, Cj-4 alkyl, c2_4 alkenyl, c2_4 alkynyl, cN3 alkyl-o' Ci.3 alkyl-s, Ci-3 alkyl or Cl_3 alkyl group, wherein each methylene group is up to 2 a fluorine atom is substituted and each methyl group is substituted with up to 3 fluorine atoms, and kappa and R together with the carbon atom to which they are attached form a monounsaturated 5 membered heterocyclic group or a monounsaturated or diunsaturated 6 membered heterocyclic group. Or a 5-membered heteroaryl group, wherein the previously mentioned heterocyclic ring may contain a carbonyl group, a thiocarbonyl group or a cyanoimino group adjacent to the nitrogen atom, and may additionally be in the case of - or two nitrogen atoms R3·3, respectively. · 3 substitutions, and the bases may be substituted by one group R3·3.4 at one or two carbon atoms, respectively, and the two groups r3·3·3 independently represent c 1 ·4 yards or 139377.doc -19 · 201038571 〇3·6 cycloalkyl, R3·3·4 independently of each other means Cl-4 alkyl, c3.6 cycloalkyl, halogen, CN, ci-3 alkyl-0-, -NH2, Cl· The 3 alkyl or C -3-alkyl 〇 〇 group is substituted with 2 more fluorine atoms and each generation, 'where each fluorenyl group passes through to the methyl group, up to 3 fluorine atoms take its tautomer, non Enantiomer Enantiomers, in terms of hydrates, mixtures and salts and hydrates of such salts, and certain of its physiologically acceptable inorganic or organic acids or bases of the salt. Ίο. The compound of formula J, wherein, wherein U, V, χ, γ, R1 and R2 are as defined in claim 1, 2, 4 or 6, and R3 represents a group R31 of formula IVa Huan: R (Iva), R3" means (4) Η, F, Cl, Br, -ΝΗ2, C 丨·3 alkyl-ΝΗ, (C _3 alkyl) 2Ν, Ci-3 alkyl-C(0)- NH, -CN, -OH, Cn4 alkyl, c2_4 alkenyl, c2_4 alkynyl, Cw alkyl-O, Cw alkyl-s, C i -3 or C i _3 alkyl-〇-group Wherein each "anthracene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms 139377.doc -20- 201038571, and R3·2 represents (a) Η, F, α, Br, Η2Ν, (Cw base) · ΝΗ, (Cl 4 yard base), (Cu alkyl)-C(0)-NH, -〇Η, C]-4 alkyl, Cl·3 alkyl or Ci·3 a thiol-group in which each fluorenylene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms, R3·3 represents (4) fluorene, (b) F, Cl, Br, H2N, (Cw alkyl)_NH, (Cw alkyl) 2N, (Cb3)-C(0)-NH, -OH, (c) C 1 ·4 alkyl, (d) C,.3 alkyl or C]_3 alkyl-〇 a group in which each methylene hydrazine is substituted with up to 2 fluorine atoms and each fluorenyl group is substituted with up to 3 dry atoms. • R3'2 and r3·3 together with the carbon atom to which they are attached form a monounsaturated group. a 5-membered heterocyclic group or a monounsaturated or diunsaturated 6-membered heterocyclic group or a 5- to 6-membered heteroaryl group, wherein the heterocyclic ring mentioned above may contain a carbonyl group adjacent to the nitrogen atom, a thiol group or a cyanimido group, and may be optionally substituted at one or two nitrogen atoms via a group R3·3·3, respectively, and 139377.doc •21 · 201038571 may additionally be one or two, respectively Carbon ^ ^ . ', thousand radicals - a group R3.3·4 substituted, 4 two R3·3·3 independently of each other to represent C 1 _4 alkyl or C 3-6 ring, R3·3·4 Independently from each other, C!-4 alkyl, 〇3-6, and m^n: chitosan, CN, Cw alkyl C, ·3 alkyl or Cl_3 alkyl-fluorene-group, each of which - methylene is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms, and R3·4 represents deuterium or F, its tautomers, diastereomers, enantiomers Body, hydrate Mixtures and salts and hydrates of such salts, and more in terms of its physiologically acceptable inorganic or organic acids or bases of the salt. U·If the formula 1 is the formula! A compound, wherein U, ν, χ, γ, RW are as defined in claim 1, 2, 4 or 6, and R represents a group selected from the group consisting of: 139377.doc 22- 201038571 a tautomer, a diastereomer, an enantiomer, a hydrate, a mixture thereof and a salt thereof, and a hydrate of the salt, in particular, physiologically or in combination with an inorganic or organic acid Accept the salt. 12. The compound of formula I according to claim 1, wherein U, V, X, Y, R1 and R2 are as defined in claim 1, 2, 3, 4, 5, 6 or 7, and R3 represents a formula Group of IVb 139377.doc 23· 201038571 (4) Η, F, a, Br, -NH2, C丨-3 alkyl-ΝΗ, (Cu alkyl) 2Ν, C].3 alkyl-C(0)-NH, -CN, -OH, Cl-4, C2-4 fluorenyl, C2_4 alkynyl, Cb3, ke, ke, s, s, s, s, s, s, s, s, s, s, Wherein each methylene group is substituted with up to 2 fluorine atoms and each methyl group is substituted with up to 3 fluorine atoms, and R3·2 and R3·3 together with the carbon atom to which they are bonded form a monounsaturated 5-membered heterocyclic group. a mono- or monounsaturated or diunsaturated 6-membered heterocyclic group or a 5-membered heteroaryl group, wherein the heterocyclic ring previously mentioned has a carbonyl group adjacent to a nitrogen atom, a furnace carbonyl group or a cyanoimine group. And "1· may each be additionally substituted in the case of - or two, in the case of R3.3.3, and the ^ group or the two may each be replaced by one or two carbon atoms at the same time as the group R3.3.4, R ·3·3 independently of each other to represent Ci_4 alkyl or C3-6, and r3'3'4 independently of each other represents Cl.4 alkyl, c3-6 cycloalkyl, halogen, -CN, _〇_ Ci-3 alkyl, _Nh2, 139377.doc -24- 201038571 C!-3 alkyl or Ci_3 alkyl a group of two fluorine atoms substituted and each substituted, its tautomer, diastereomeric ^w ^ open group enantiomer, hydrate, mixture and salt thereof and the salt of the water 'Specifically a physiologically acceptable salt thereof with an inorganic or organic acid or base. A compound of the formula t of claim 1 wherein u'v, x, yhr2 Wherein each methylene group passes through up to 3 fluorine atoms to the methyl group. 13. As claimed in claims 1, 2, 3, 4, 5 R3 represents a group 6 or 7 of the formula IVb, and R31 represents (Ivb), (4) Η, FC, Br, -NH2, Cy alkyl_NH, (Ci-3 alkyl) 2ν, Ci_3 alkyl-C(〇)-NH, -CN, .OH, Cl-4 alkyl , C2.4 alkenyl, c2-4 alkynyl, Cl.3 alkyl-◦, Cl_3 alkyl-s, C1-3 alkyl or C!·3 alkyl·〇_ group, wherein each Substituting two morphological atoms and each methyl group is substituted with up to three fluorine atoms, and R and R together with the carbon atom to which they are bonded form a monounsaturated 5-membered heterocyclic group or a 5-membered heteroaryl group. The heterocyclic ring mentioned in the first seven contains a carbonyl group adjacent to a nitrogen atom, sulfur 139377.doc -25^201038571 carbonyl or a cyanoimine group, and may be additionally in the case of - or two nitrogen atoms. The group R3·3·3 is substituted, and may be substituted by z or a rain group R3·3·4, respectively, at the two carbon atoms, and R3.3·3 independently represents (a) C1. 4 alkyl or (b) C3_6 cycloalkyl, and R3·3·4 independently of each other represent (a) Ch alkyl, c3.6 cyclo, (b) i, -CN, -〇_Cl_3 alkane a group, _Nh2, (c) a Ch alkyl or a Cl_3 alkyl 〇 基 group, wherein each fluorenylene group has up to 2 gas atoms And each methyl group is substituted with up to 3 gas atoms, its tautomers, diastereomers, enantiomers, hydrates, mixtures and salts thereof, and hydrates of such salts, It is a physiologically acceptable salt with an inorganic or organic acid. 14. A compound of formula I according to claim 1, wherein u, v, x, Y, Ri 2 are as defined in claim 1, 2'3, 4, 5, 6 or 7, and R3 represents a formula Group of IVc (Ivc), T represents 〇, S, CH2, NH or N-R3.3.3, 139377.doc -26- 201038571 R3·1 represents (a) Η, (b) F, Cl, Br, _nh2, Cl_3 alkyl · ΝΗ, (Cw alkyl) 2N, Cm alkyl _C(0)_NH, _CN, _〇h, (c) Cw alkyl, C24 alkenyl, c24 alkynyl, Cl_3 alkyl-hydrazine, C i - 3 alkyl group S, (d) a Cw alkyl group or a Ci.3 alkyl group, wherein each fluorenylene group is substituted with up to 2 fluorine atoms and each fluorenyl group is substituted with up to 3 fluorine atoms, and R3·3.3 independently of each other represents (a) C]_4 alkyl or (b) <:3_6 cycloalkyl, tautomers, diastereomers, enantiomers, hydrates, mixtures thereof And salts thereof and hydrates of such salts, in particular with inorganic or organic acids or physiologically acceptable salts thereof. ❹ 15_ as defined in the general formula of the formula, u, y λ, γ, R and R2 are as defined in claim 1, 2, 3, 4, 5, 6 or 7, and R3 is selected from the following The group of each: I39377.doc -27- 201038571 Its tautomers, diastereomers, enantiomers, hydrates, mixtures and salts thereof, and hydrates of such salts, in particular, physiologically compatible with inorganic or organic acids or bases Accept the salt. R2 and R3 are as in the case of 11, 12 '13, 16. The compound of the general formula I of claim 1, wherein γ, Rl, the item 1, 2, 3, 4, 5, 6, 7, 8, 9, 1 〇, I4 or I5, and UVX represents a group selected from the group consisting of: -N=N-(C-R6)= > -N = (C-R5)-N=, -N=( C-R5)-(C-R6)=, -(N-oxide)=(C-Rs)-(CR6)=, -(cr4)=NN=, -(CR4)=n_(CR)=, -(C-R4)=N(oxide)-(c_r6)=, N=, -(CR4)=(C-R5)-(N-oxide)=, -(cr4)=(c_rs)_ ( Cr6)=, and R4 represents (4)H, (b) C 〖6 alkyl or Ci·3 alkyl-〇- group, which are respectively substituted by the group r4.i, (c) R4'2R4'3N, rUrUn -Cw alkylene, (d) halogen, -CN, -OH, -COOH, Cw alkyl-hydrazine, c, alkyl group - hydrazine-Ce3 extension alkyl group, C3·6 cycloalkyl group, C34 ring Keji•Ci-4 stretching base, C!-3 alkyl group-C(0)-0-Ci.3 stretching base, 139377.doc -28 - 201038571 (e) Ci_3 burning base or Ci·3 burning base a 〇-group in which each - Methylene & is substituted with up to 2 I atoms and each thiol is substituted with up to 3 atoms, R4·1 represents Η, ΟΗ or -0-CH3, and R4·2 represents Η Or Cw alkyl, R4·3 represents Η or C The w alkyl group, or R4'2 and R4·3 together with the nitrogen atom to which it is bonded, represents a 3- to 6-membered heterocyclic group, ^ ❹ 5 R represents (a) Η, (b) Cu alkyl group or Ci· a tricalcyl-hydrazine-group substituted by a group RSa, (c) -nr5_2r5·3, nr5.2r5 human Cl.3 alkyl, (d) halogen, -CN, -OH, Ci_3 alkyl _〇_Cl3 alkylene, C3_6 cycloalkyl, C 3.6 cycloalkyl _ C ! _ 4 stretching base, C ! · 3 tiger base ❹ -C(0)-0-Ci.3 stretching base, (e) an aryl-C〇-3 extended alkyl-oxime group, (f) a Ci-3 alkyl or a Ci_3 alkyl-oxime group, wherein each methylene group is substituted with up to two fluorine atoms And each methyl group is substituted with up to 3 fluorine atoms, R5·1 represents Η, OH or -〇-CH3, Rs·2 represents an alkyl group, and R5·3 represents H, Cw alkyl or -S〇2-Cl_3 alkane Base, R6 represents 139377.doc •29· 201038571 (4)Η, (b) Cw or a calcinyl-hydrazide-group is substituted by a group ru, (c) R6_2R6_3N, RUrHN-Cw alkyl, ( d) halogen, -CN, -OH, -COOH, Cu, ketone, 〇, ^, ke-OC, .3, alkyl, C3, 6 ring, 03_6, environmental formula, Cw alkyl, Cw alkyl -CCCO-O-Cu stretched (e) a C!·3 alkyl or Cu alkyl-fluorene group in which each & T storm is substituted with up to 2 appearance atoms and each methyl group is substituted with up to 3 atoms, R6·1 represents Η, ΟΗ or -0-CH3, R6·2 represents HiCw alkyl, R6·3 represents HiCw alkyl, or 3 to 6-membered heterocyclic rings R6·2 and R6·3 together with the nitrogen atom bonded thereto a group, a tautomer, a diastereomer, an enantiomer, a hydrate, a mixture thereof and a salt thereof, and a hydrate of the salt, in particular, a physiology with an inorganic or organic acid or base A salt that is acceptable for learning. Request, 9, W, 11, 12, 13, 14 17. A compound of the general formula I according to claim 1, wherein γ, R1, r2 and R3 are as defined in items 1, 2, 3, 4'5'6, 7, Or as defined in 15, and Indicates a group selected from the following groups 139377.doc •30· 201038571 OH A 139377.doc -31 - 201038571 Its tautomers, diastereomers, enantiomers, hydrates, mixtures and salts thereof, and hydrates of such salts, in particular, physiologically compatible with inorganic or organic acids or bases Accept the salt. A compound of the formula I according to claim 1, wherein R1 represents a group selected from the group consisting of: R2 represents Η, and R3 represents a group selected from the following: 139377.doc •32· 201038571 139377.doc -33- 201038571 Its tautomers, diastereomers, enantiomers, hydrates, mixtures and salts thereof, and hydrates of such salts, in particular, physiologically compatible with inorganic or organic acids or bases Accept the salt. 19. The compound of formula I according to claim 1, wherein R1 and R2 together with the nitrogen atom to which they are bonded represent a group selected from the group consisting of: 139377.doc • 34- 201038571 R3 Ο represents a group selected from the following: The table is not selected from the following groups 139377.doc -35- 201038571 Its tautomers, diastereomers, enantiomers, hydrates, mixtures and salts thereof, and hydrates of such salts, in particular, physiologically compatible with inorganic or organic acids or bases Accept the salt. 20. The following compound of formula I as claimed in claim 1: 139377.doc -36 - 201038571 No. Structure (2) (3) (4) ^caKJ3vd:; (5) (6) (7) ch3 N-"' ch3 (8) (9) N^Xx, Ajy^iF Its enantiomer, non Enantiomers, hydrates, mixtures and salts thereof and hydrates of such salts, in particular their physiologically acceptable salts with inorganic or organic acids or bases. 139377.doc -37- 201038571 21. 22. 23. 24. 25. The compound according to any one of claims 1 to 2, which is a physiologically acceptable salt with an inorganic or organic acid or base. A pharmaceutical composition comprising a compound of any of the claims or a physiologically acceptable salt thereof, optionally with the same or a plurality of carriers and/or diluents. Month A use of a compound according to any one of claims 121, or a physiologically acceptable salt thereof, for the manufacture of a pharmaceutical composition for acute and prophylactic treatment of headache, especially migraine or cluster headache. The use of a compound according to any one of items 1 to 21 or a physiologically versatile use thereof for the preparation of a pharmaceutical composition for treating non-insulin dependent diabetes mellitus ( NIDDM); Complex Regional Pain Syndrome (CRPS1); vascular disease; morphine tolerance, diarrhea caused by Clostridium toxin; skin disease 'especially heat and radiation induced skin damage, including sun Inflammation: Inflammation: 'Sickness such as rhythmic joint disease (arthritis), neurogenic oral mucosal inflammation, inflammatory lung disease, allergic rhinitis, asthma; accompanied by excessive & expansion and resulting reduction in vascular blood flow Diseases, such as shock pus, for pain relief, or for prophylactic or acute therapeutic treatment of estrogen-deficient women and hormone-treated patients with prostate cancer caused by blood cell expansion and increased blood flow The symptoms of hot flashes. A method of preparing a pharmaceutical composition according to claim 22, characterized in that the compound according to any one of the claims or a physiologically acceptable salt thereof is incorporated into one or more of the inertities by a non-chemical method. In the carrier and / or diluent. J39377.doc -38- 201038571 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 5. If there is a chemical formula in this case, please reveal the best display. Chemical formula of the inventive feature: , (1) 139377.doc