AU2006261048A1 - Non-steroidal progesterone receptor modulators - Google Patents

Description

WO 2006/136461 PCT/EP2006/006531 Non-steroidal progesterone receptor modulators The present invention relates to non-steroidal progesterone receptor modulators, to a 5 process for their preparation, to the use of the progesterone receptor modulators for producing medicaments, and to pharmaceutical compositions which comprise these compounds. The steroid hormone progesterone controls in a decisive manner the reproductive 10 process in the female body. Progesterone is secreted in large quantities during the cycle and pregnancy respectively by the ovary and the placenta. Progesterone in cooperation with oestrogens brings about cyclic changes in the uterine mucosa (endometrium) during the menstrual cycle. Elevated progesterone levels after ovulation influence the uterine mucosa to convert it into a state permitting nidation of an embryo 15 (blastocyst). During pregnancy, progesterone controls the relaxation of the myometrium and maintains the function of the decidual tissue. It is further known that progesterone inhibits endometrial proliferation by suppressing oestrogen-mediated mitosis in uterine tissue (K. Chwalisz, R.M. Brenner, U. Fuhrmann, 20 H. Hess-Stumpp, W. Elger, Steroids 65, 2000, 741-751). Progesterone and progesterone receptors are also known to play a significant part in pathophysiological processes. Progesterone receptors have been detected in the foci of endometriosis, but also in tumours of the uterus, of the breast and of the CNS. It is 25 further known that uterine leiomyomas grow progesterone-dependently. The effects of progesterone in the tissues of the genital organs and in other tissues occur through interactions with progesterone receptors which are responsible for the cellular effects. 30 Progesterone receptor modulators are either pure agonists or inhibit the effect of progesterone partly or completely. Accordingly, substances are defined as pure agonists, partial agonists (SPRMs) and pure antagonists. 35 In accordance with ability of progesterone receptor modulators to influence the effect of the progesterone receptor, these compounds have a considerable potential as WO 2006/136461 PCT/EP2006/006531 therapeutic agents for gynaecological and oncological indications and for obstetrics and fertility control. Pure progesterone receptor antagonists completely inhibit the effect of progesterone on 5 the progesterone receptor. They have anti-ovulatory properties and the ability to inhibit oestrogen effects in the endometrium, as far as complete atrophy. They are therefore particularly suitable for intervening in the female reproductive process, e.g. post ovulation, in order to prevent nidation, during pregnancy in order to increase the reactivity of the uterus to prostaglandins or oxytocin, or in order to achieve opening and 10 softening ("ripening") of the cervix, and to induce a great readiness of myometrium to contract. A beneficial effect on the pathological event is expected in foci of endometriosis and in tumour tissues which are equipped with progesterone receptors after administration of pure progesterone receptor antagonists. There might be particular advantages for 15 influencing pathological states such as endometriosis or uterine leiomyomas if ovulation inhibition can additionally be achieved by the progesterone receptor antagonists. Ovulation inhibition also dispenses with some of the ovarian hormone production and thus the stimulating effect, deriving from this proportion, on the pathologically altered tissue. 20 The first progesterone receptor antagonist described, RU 486 (also mifepristone), was followed by a large number of analogues with progesterone receptor-antagonistic activity of varying strength. Whereas RU 486 shows an antiglucocorticoid effect in addition to the progesterone receptor-antagonistic effect, compounds synthesized later 25 are notable in particular for a more selective effect as progesterone receptor antagonists. Besides steroidal compounds such as onapristone or lilopristone, which are notable by comparison with RU 486 for a better dissociation of the progesterone receptor 30 antagonistic effect and the antiglucocorticoid effect, also known from the literature are various non-steroidal structures whose antagonistic effect on the progesterone receptor is being investigated [see, for example, S. A. Leonhardt and D. P. Edwards, Exp. Biol. Med. 227: 969-980 (2002) and R. Winneker, A. Fensome, J. E. Wrobel, Z. Zhang, P. Zhang, Seminars in Reproductive Medicine, Volume 23: 46-57 (2005)]. However, 35 compounds disclosed to date have only moderate antagonistic activity compared with the known steroidal structures. The most effective non-steroidal compounds are 2 WO 2006/136461 PCT/EP2006/006531 reported to have in vitro activities which are 10% of the activity of RU 486. The antiglucocorticoid activity is disadvantageous for therapeutic use, where the inhibition of progesterone receptors is at the forefront of the therapy. An 5 antiglucocorticoid activity causes unwanted side effects at the dosages necessary for therapy. This may prevent administration of a therapeutically worthwhile dose or lead to discontinuation of the treatment. Partial or complete reduction of the antiglucocorticoid properties is therefore an important precondition for therapy with progesterone receptor antagonists, especially for 10 those indications requiring treatment lasting weeks or months. In contrast to the pure antagonists, partial progesterone receptor agonists (SPRMs) show a residual agonistic property which may vary in strength. This leads to these substances showing potentially agonistic effects on the progesterone receptor in certain 15 organ systems (D. DeManno, W. Elger, R. Garg, R. Lee, B. Schneider, H. Hess Stumpp, G. Schuber, K. Chwalisz, Steroids 68, 2003, 1019-1032). Such an organ specific and dissociated effect may be of therapeutic benefit for the described indications. 20 It is therefore an object of the present invention to provide further non-steroidal progesterone receptor modulators. These compounds are intended to have a reduced antiglucocorticoid effect and therefore be suitable for the therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea. The compounds according to the invention 25 are additionally intended to be suitable for the therapy and prophylaxis of hormone dependent tumours, for example of breast, endometrial, ovarian and prostate carcinomas. The compounds are intended furthermore to be suitable for use in female fertility control and for female hormone replacement therapy. 30 The object is achieved according to the present invention by the provision of non steroidal compounds of the general formula I A R3 BN R3 0 3 WO 2006/136461 PCT/EP2006/006531 in which R' and R 2 are independently of one another a hydrogen atom, a linear or nonlinear, branched or unbranched C 1

-C

5 -alkyl group, further forming 5 together with the C atom of the chain a ring having a total of 3-7 members, R3 is a radical C=C-Ra, where Ra is a hydrogen or a C 1

-C

8 -alkyl, C 2 -CB-alkenyl, C 2

-C

8 alkynyl, C 3

-C

10 -cycloalkyl, heterocycloalkyl optionally 10 substituted one or more times, identically or differently, by K, or an aryl or heteroaryl optionally substituted one or more times, identically or differently by L, K is a cyano, halogen, hydroxy, nitro, -C(O)R,

CO

2 R, -O-Rb, -S-Rb, SO 2 NRCRd, -C(O)-NRCRd, 15 -OC(O)-NRcRd, -C=NORb -NRcRd or C 3

-C

10 -cyclo alkyl, heterocycloalkyl optionally substituted one or more times, identically or differently, by M, or aryl or heteroaryl optionally substituted one or more times by L, 20 L is C-C 8 -alkyl, C 2 -Co-alkenyl, C 2

-C

8 -alkynyl, C 1

-C

6 perfluoroalkyl, C-C 6 -perfluoroalkoxy, C-C 6 -alkoxy Cl-C 6 -alkoxy, (CH 2 )p-C 3

-C

1 o-cycloalkyl, (CH 2 )p heterocycloalkyl, (CH 2 )pCN, (CH 2 )pHal, (CH 2 )pNO 2 ,

(CH

2 )p-C 6

-C

12 -aryl, (CH 2 )p-heteroaryl, 25

-(CH

2 )pPO 3 (Rb) 2 ,

-(CH

2 )pNRcRd, -(CH 2 )pNReCOR,

-(CH

2 )pNReCSRb, -(CH 2 )pNReS(O)Rb,

-(CH

2 )pNReS(O) 2 Rb, -(CH 2 )pNReCONRCRd,

-(CH

2 )pNReCOORb, -(CH 2 )pNReC(NH)NRcRd, 30 -(CH 2 )pNReCSNRcRd, -(CH 2 )pNReS(O)NRcRd,

-(CH

2 )pNReS(O) 2 NRcRd, -(CH 2 )pCORb,

-(CH

2 )pCSR, -(CH 2 )pS(O)R,

-(CH

2 )pS(O)(NH)R, -(CH 2 )pS(O) 2 R,

-(CH

2 )pS(O) 2 NRcRd, -(CH 2 )pSO 2 OR, 35 -(CH 2 )pCO 2 Rb, -(CH 2 )pCONRcRd,

-(CH

2 )pCSNRcRd, -(CH 2 )pOR, -(CH 2 )pSR, 4 WO 2006/136461 PCT/EP2006/006531 5b

-(CH

2 )pCR'(OH)-R*, -(CH 2 )p-C=NOR ,

-O-(CH

2 )n-O-, -O-(CH 2 )n-CH 2 -, -O-CH=CH- or

-(CH

2 )n.

2 -, where n is 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked 5 to directly adjacent ring carbon atoms, M is C 1

-C

6 -alkyl or a group -COR , CO 2 R, -O-Rb, or -NRcRd, where R b is a hydrogen or a Cl-C 6 -alkyl, C 2

-C

8 10 alkenyl, C 2

-C

8 -alkynyl, C 3

-C

1

O

cycloalkyl, C 8

-C

12 -aryl or CI-C 3 perfluoroalkyl and Rc and Rd are independently of one another a hydrogen, Cl-C 6 -alkyl, C 2 -Ca-alkenyl, 15 C 2

-C

8 -alkynyl, C 3 -CI -cycloalkyl, C6-C 12 -aryl, C(O)R b or a hydroxy group, where if Rc is a hydroxy group, then R d can only be a hydrogen, a Cl-C 6 -alkyl, C 2

-CB

20 alkenyl, C 2

-C

8 -alkynyl, C 3 -Cl 0 cycloalkyl or C 6

-C

12 -aryl and vice versa, and is a hydrogen, C 1

-C

6 -alkyl, C2-CB alkenyl, C 2

-C

8 -alkynyl, C 3

-C

10 -YCIo 25 alkyl or C6-C 1 2 -aryl, and p can be a number from 0-6, or R is a radical C=CRg , where 30 R9 and R h are independently of one another a hydrogen or a Ch-C 8 -alkyl, C 2

-C

8 -alkenyl or C 2 -CB-alkynyl optionally substituted one or more times, identically or differently, by X, in which X is a cyano, halogen, hydroxy, nitro, 35 C(O)R , C 2 R , C2-C-aly(O)NRcR-, NRcRsd with the meanings already 5 WO 2006/136461 PCT/EP2006/006531 mentioned before for Rb, Rc and Rd, and R 4 is a hydrogen atom, a methyl or an ethyl group or a partly or completely fluorinated C 1

-C

3 -alkyl group, 5 A is a mono- or bicyclic carbocyclic or heterocyclic aromatic ring which may optionally be substituted one or more times by C 1

-C

8 -alkyl, C 2

-CB

alkenyl, C 2

-C

8 -alkynyl, C 1

-C

6 -perfluoroalkyl, C 1

-C

6 -perfluoroalkoxy,

C

1

-C

6 -alkoxy-C 1

-C

6 -alkyl, C 1

-C

6 -alkoxy-C 1

-C

6 -alkoxy, (CH 2 )p-C 3

-C

1 o cycloalkyl, (CH 2 )p-heterocycloalkyl, (CH 2 )pCN, (CH 2 )pHal, (CH 2 )pNO 2 , 10 (CH 2 )p-C 6

-C

12 -aryl, (CH 2 )p-heteroaryl,

-(CH

2 )pPO 3 (Rb) 2 , -(CH 2 )pNRcRd, -(CH 2 )pNReCORb, -(CH 2 )pNReCSRb,

-(CH

2 )pNReS(O)Rb, -(CH 2 )pNReS(O) 2 Rb, -(CH 2 )pNReCONRcRd,

-(CH

2 )pNReCOORb, -(CH 2 )pNReC(NH)NRcRd, -(CH 2 )pNReCSNRcRd

-(CH

2 )pNReS(O)NRcRd, -(CH 2 )pNReS(O) 2 NRcRd, -(CH 2 )pCORb, 15 -(CH 2 )pCSR , -(CH 2 )p S(O)Rb, -(CH 2 )pS(O)(NH)R , -(CH 2 )pS(O) 2 Rb,

-(CH

2 )pS(O) 2 NRcRd, -(CH 2

)PSO

2 OR , -(CH 2 )pCO 2 R , -(CH 2 )pCONRcRd,

-(CH

2 )pCSNRcRd, -(CH 2 )pOR , -(CH 2 )pSR , -(CH 2 )pCR (OH)-Rd,

-(CH

2 )p-C=NORb, -O-(CH 2 )n-O-, -O-(CH 2 )n-CH 2 -, -O-CH=CH- or

-(CH

2 )n+ 2 -, where n is 1 or 2, and the terminal oxygen atoms and/or 20 carbon atoms are linked to directly adjacent ring carbon atoms, or A is a radical -CO 2 R , C(O)NRcRd, CORb, or 25 A is an alkenyl group -CR=CR R , where 5 6 7 R , R and R are identical or different and are independently of one another hydrogen atoms, halogen atoms, aryl radicals or an unsubstituted or partly or completely 30 fluorinated C 1

-C

5 -alkyl group, or A is an alkynyl group -C=CR5, with the meaning stated above for R , and B is a carbonyl or a CH 2 group, 35 and their pharmaceutically acceptable salts. 6 WO 2006/136461 PCT/EP2006/006531 The compounds according to the invention of the general formula I may, owing to the presence of centres of asymmetry, exist as different stereoisomers. Both the racemates and the separate stereoisomers belong to the subject matter of the present invention. 5 The present invention further includes the novel compounds as active pharmaceutical ingredients, the preparation thereof, their therapeutic use and pharmaceutical dosage forms which comprise the novel substances. The compounds according to the invention of the general formula (1) or their 10 pharmaceutically acceptable salts can be used to produce a medicament, in particular for the treatment and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea. The compounds according to the invention may further be used for the treatment and prophylaxis of hormone-dependent tumours such as, for example, for breast, prostate and endometrial 15 carcinoma. The compounds according to the invention of the general formula (1) or their pharmaceutically acceptable salts are suitable for use for female fertility control or for female hormone replacement therapy. 20 The present invention additionally relates to a process for preparing the compounds of the general formula (1). The substituent R 3 is introduced by selective addition reaction of organometallic compounds such as lithium alkynyls or magnesium haloalkynyls onto a keto group. This leads either directly or after carrying out further modificiations to the compounds according to the invention of the general formula (1). 25 HR R 3 -Li or R 3 -MgHal R R2 4 R R H , H ABN A 3 BN B" A>U 4 BN N R 3 / 0 0 O The compounds according to the invention are prepared by selective addition of organometallic compounds onto keto amides which have been described for example in 30 the published specifications US 2002/0077356, US 6,323,199B1, WO 200375915 and WO 9854159. The organometallic compounds may be for example lithium alkynyl or magnesium haloalkynyl compounds. These are generated for example by reacting the appropriate alkynes with butyllithium or Grignard compounds. The corresponding 7 WO 2006/136461 PCT/EP2006/006531 organometallic alkenyl compounds can also be prepared in analogy thereto. The reactivity of the keto groups is in this case distinctly higher by comparison with the amide carbonyl and with the benzoxazinone, so that a selective addition is achieved on suitable choice of the reaction conditions. Alternatively, the alkynyl or alkenyl radicals 5 introduced as R 3 can also be further modified later. Reactions suitable for these modifications are those known to the skilled person, such as oxidation, reduction, substitution, alkylation, palladium-catalysed reaction. Any protective groups present are eliminated at a suitable time. 10 The non-steroidal compounds according to the invention of the general formula I have strong antagonistic or strong partial agonistic effects on the progesterone receptor. They show a strong dissociation of effects in relation to their strength of binding to the progesterone receptor and to the glucocorticoid receptor. Whereas known progesterone receptor antagonists such as mifepristone (RU 486) show, besides the desired high 15 binding affinity for the progesterone receptor, likewise a high affinity for the glucocorticoid receptor, the compounds according to the invention are notable for a very low glucocorticoid receptor binding with simultaneously a high progesterone receptor affinity. 20 The substituents, defined as groups, of the compounds according to the invention of the general formula I may in each case have the following meanings:

C

1

-C

5 -, Cr1C6- and C 1

-C

8 -alkyl group means linear or nonlinear, branched or unbranched alkyl radicals. Examples thereof are a methyl, ethyl, n-propyl, isopropyl, n-, 25 iso-, tert-butyl, an n-pentyl, 2,2-dimethylpropyl, 3-methylbutyl, hexyl, heptyl or octyl group. Preferred in the meaning of Ra in this connection are the methyl, ethyl, n-propyl or n-butyl group and an n-pentyl group. Preferred in the meaning of R' and R 2 are methyl or ethyl. 30 Alkenyl means linear or nonlinear, branched or unbranched alkenyl radicals. Examples of the meaning of a C 2 -Cs-alkenyl group in the context of the invention are the following: vinyl, allyl, 3-buten-1-yl or 2,3-dimethyl-2-propenyl. If the aromatic system A is substituted by a C 2

-C

8 -alkenyl radical, it is preferably a vinyl group. 35 Alkynyl means linear or nonlinear, branched or unbranched alkynyl radicals. A C2-CB 8 WO 2006/136461 PCT/EP2006/006531 alkynyl radical is intended to be for example an ethynyl, propynyl, butynyl, pentynyl, hexynyl and octynyl group, preferably an ethynyl or propynyl group. Examples which may be mentioned of C 3

-C

10 -cycloalkyl are cyclopropyl, cyclobutyl, 5 cyclopentyl and cyclohexyl. Cyclopropyl, cyclopentyl and cyclohexyl are preferred. Heterocycloalkyl in the meaning of Ra, K and L means 3-8-membered heterocycloalkyl radicals. Examples of heterocycloalkyl are morpholinyl, tetrahydrofuranyl, pyranyl, piperazinyl, piperidinyl, pyrrolidinyl, oxiranyl, oxetanyl, aziridinyl, dioxolanyl and 10 dioxanyl. In this connection, the position of the heteroatom in relation to the point of linkage can be any chemically possible position. Possible examples of C 1

-C

6 -alkoxyl-C 1

-C

6 -alkoxy group are methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy. 15 A radical ORb in the context of the invention. is a hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-, iso-, tert-butoxy or n-pentoxy, 2,2-dimethylpropoxy or 3-methylbutoxy group. Hydroxy, methoxy and ethoxy are preferred. 20 Suitable for a partly or completely fluorinated C-C 5 -alkyl group are the perfluorinated alkyl groups above. Of these, preference is given in particular to the trifluoromethyl or pentafluoroethyl group and, partly fluorinated alkyl groups, for example the 5,5,5,4,4 pentafluoropentyl or 5,5,5,4,4,3,3-heptafluoropentyl group. 25 A halogen atom may be a fluorine, chlorine, bromine or iodine atom. Fluorine, chlorine or bromine is preferred here. If R 1 and R 2 form together with the C atom of the chain a 3-7 membered ring, this is for example a cyclopropyl, -butyl, -pentyl or -hexyl ring. The cyclopropyl and the cyclopentyl 30 ring are preferred. The mono- or bicyclic carbocyclic aromatic ring A, which may be substituted more than once, is a carbocyclic or heterocyclic aryl radical. In the former case it is for example a phenyl or naphthyl radical, preferably a phenyl 35 radical. It is possible to use as heterocyclic radical for example a monocyclic heterocyclic 9 WO 2006/136461 PCT/EP2006/006531 radical, for example the thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazanyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radical, in particular all the possible isomers in relation to the positions of the heteroatoms. 5

R

3 means in the case of an aryl radical an optionally substituted phenyl, 1- or 2-naphthyl radical, with preference for the phenyl radical. Examples of a heteroaryl radical are the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2- or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or 3- or 4-pyridazinyl radical. 10 The number p for a (CH 2 )p radical may be a number from 0 to 6, preferably 0 to 2. "Radical" means according to the invention all functional groups stated in connection with (CH 2 )p. 15 In the case where the compounds of the general formula I (B = -CH 2 -) are in the form of salts, this is possible for example in the form of the hydrochloride, sulphate, nitrate, tartrate, citrate, fumarate, succinate or benzoate. If the compounds according to the invention are in the form of racemic mixtures, they 20 can be fractionated by methods of racemate resolution familiar to the skilled person into the pure optically active forms. For example, the racemic mixtures can be separated into the pure isomers by chromatography on a support material which is itself optically active (CHIRALPAK AD*). It is also possible to esterify the free hydroxy group in a racemic compound of the general formula I with an optically active acid, and to separate 25 the resulting diastereoisomeric esters by fractional crystallization or chromatography and to hydrolyse the separated esters in each case to the optically pure isomers. It is possible to use as optically active acid for example mandelic acid, camphorsulphonic acid or tartaric acid. 30 The compounds specified below, and the use thereof, are preferred according to the invention: 10 WO 2006/136461 PCT/EP2006/006531 No. Racemic or R3 enantiomer 1 rac

R

3 OH 2 4' 0 H 3 + 0 4 rac N 5 + 6 7 rac H 8 + 9 10 rac 11 + 12 13 rac 14 + 15 16 rac rF. 17 + 18 19 rac 20 + N 21 22 rac * 23 + 24 25 rac 26 + 27 28 rac F 29 + 30 31 rac 32 + 33 34 rac 35 + 36 37 rac 0 38 + 39 40 rac N 41 + 42 - 43 rac 44 + 45 -_-' 46 rac 47 + NO, 48- WO 2006/136461 PCT/EP2006/006531 49 rac 50 + 51 No. Racemic or R3 enantiomer R OH 52 rac ci 53 H // N 54 + 55 rac 00 56 + F 0 57 58 rac 59 + 60 61 rac 62 + 63 64 rac 65 + 66 67 rac 68 + 69 70 rac 71 + 72N 73 rac 74 + 75 No 76 rac 77 + 78 79 rac CF 80 + 81 82 rac 83 + 84 85 rac 86 + 87 88 rac 0 89 + 90 91 rac N 92 + 93 94 rac 95 + I 96 12 WO 2006/136461 PCT/EP2006/006531 97 rac -N 98 + 99 100 rac 191 + 102 racOH 103 rac "o 104 + 105 No. Racemic or R3 enantiomer R 3 106 rac 107 H 108 + N 109 rac 0 0 110 +0 112 rac H 113 + 114 115 rac 116 + 117 118 rac 119 + 120 121 rac 122 + 123 124 rac 125 + 126 127 rac 0 128 + 129 130 rac 131 + 132 133 rac CF, 134 + 135 136 rac \V 137 + 138 139 rac 140 + 141 142 rac 143 + 144 13 WO 2006/136461 PCT/EP2006/006531 145 rac N 146 + 147 148 rac 149 + 150 151 rac 152 + NO, 153 154 rac 155 + N 156 157 rac 158 + 159 160 rac 161 + 162 163 rac 164 + 165 166 rac OH 167 + 168 No. Racemic or R3 enantiomer R OH 169 rac 170 H 171 + N 172 rac 0 0 173 + 174 175 rac 176 + 177 178 rac 179 + 180 181 rac 182 + 183 184 rac 185 + CF, 186 187 rac 188 + 189 190 rac 191 + 192 14 WO 2006/136461 PCT/EP2006/006531 193 rac 194 + 195 196 rac 197 + 198 199 rac 200 + 201 202 rac 203 + 204 205 rac 206 + 207 208 rac 209 + 210 211 rac 212 + 213 214 rac NO, 215 + 216 217 rac 218 + 219 220 rac CF 221 + 222 223 rac 224 + 225 226 rac 227 + 228 229 rac on_ 230 + 231 No. Racemic or R3 R 3 enantiomer OH 232 rac H cFa NN 233 - _N 234 + 0 0 235 rac 236 + 237 238 rac 239 + H 240 15 WO 2006/136461 PCT/EP2006/006531 241 rac 242 + 243 244 rac 245 + 246 247 rac 248 + CFa 249 ra 250 rac 251 + 252 253 rac 0 254 + 255 256 rac 257 + 258 259 racF 260 + 261 262 rac 263 + 264 265 rac 266 + 267 268 rac 269 + 270 271 rac N 272 + 273 274 rac 275 + 276 277 rac 278 + NO, 279 280 rac 281 + 282 283 rac CF, 284 + 285 286 rac 287 + 288 289 rac 290 + 291 16 WO 2006/136461 PCT/EP2006/006531 [292 rac 293 + 294 No. Racemic or R3 R OH enantiomer H 295 rac N N 296 1 297 + / 298 rac F 299 + 300 301 rac 302 + H 303 304 rac 305 + 306 307 rac 308 + 309 310 rac 311 + 312 ra 313 rac 314 + 315 ' 316 rac 317 + 317 ' 319 rac 320 + 321 322 rac F 323 + 324 325 rac 326 + 327 328 rac 329 + 330 331 rac 332 + 333 334 rac 1 335 + 336 337 rac 338 + 1339 ' 17 WO 2006/136461 PCT/EP2006/006531 340 rac 341 + N 342 343 rac 344 + 345 346 rac 347 + 348 349 rac 350 + 351 352 rac 353 + 354 355 rac O 356 + 357 No. Racemic or R3 enantiomer R 3 358 rac OH 359 H 360 + N N 361 rac 0 0 362 + 363 364 rac 365 + 366 367 rac 368 + 369 370 rac 371 + 372 373 rac 374 + 375 376 rac 377 + 378 379 rac 0 380 + 381N 382 rac 383 + 384 385 rac F 386 + 387 18 WO 2006/136461 PCT/EP2006/006531 388 rac 389 + 390 391 rac 392 + 393 394 rac 395 + 396 397 rac 398 + 399 400 rac 401 + 402 403 rac NO, 404 + N 405 406 rac 407 + 408 409 rac CF 410 + 411 412 rac 413 + 414 415 rac 416 + 417 418 rac 419 + 420 No. Racemic or R3 enantiomer 421 rac R 3 422 OH 423 + H 424 rac N N 425 + 0 0 426 427 rac 428 + H 429 430 rac 431 + 432 433 rac 434 + 435 19 WO 2006/136461 PCT/EP2006/006531 436 rac CF 437 + 438 439 rac 440 + 441 442 rac 443 + 4 445 rac 446 + 447 448 rac 449 + 450 451 rac 452 + 453 454 rac 455 + 456 457 rac 458 + 459 460 rac 461 + 462 463 rac 464 + 465 466 rac 467 + NO 468 N 469 rac 470 + 471 472 rac CF 473 + 474 475 rac 476 + 477 478 rac 479 + 480 481 rac - OH 482 + 483 20 WO 2006/136461 PCT/EP2006/006531 No. Racemic or R3 enantiomer R 3 484 rac NO 485 H 486 + N N 487 rac Ic 0 488 + F 0 489 490 rac 491 + 492 493 rac 494 + 495 496 rac 497 + 498 499 rac 500 + 501 502 rac 503 + N 504 505 rac 0 506 + 507 508 rac 509 + 510 511 rac CF, 512 + 513 514 rac 515 + 516 517 rac 518 + 519 520 rac 521 + 522 523 rac N 524 + 525 526 rac 527 + 528 529 rac NO 530 + 531 532 rac 533 +21 534N 21 WO 2006/136461 PCT/EP2006/006531 535 rac 536 + 537 538 rac 539 + 540 541 rac 542 + 543 544 rac H 545 + 546 No. Racemic or R3 enantiomer R 3 547 rac 548 -F H 549 + /CF 3 N 550 rac 0 0 551 + 0 552 553 rac H 554 + 555 556 rac 557 + 558 559 rac 560 + 561 562 rac 563 + 564 N 565 rac 566 + N 567 568 rac 569 + 570 571 rac 572 + 573 574 rac 575 + 576 577 rac \ 578 + 579 580 rac 581 + 582 22 WO 2006/136461 PCT/EP2006/006531 583 rac 584 + 585 586 rac 587 + 588 589 rac 590 + 591 592 rac NO 593 + N 594 595 rac 596 + 597 598 rac 599 + CF 600 601 rac 602 + 603 604 rac 605 + 606 607 rac 608 + 609 No. Racemic or R3 enantiomer 610 rac R OH 611 A/ / H 612 + N 613 rac 614 + F O 615 -CF 3 616 rac 617 + 618 619 rac 620 + 621 622 rac 623 + N 624 625 rac 626 + CF, 627 628 rac 629 + N 630 23 WO 2006/136461 PCT/EP2006/006531 631 rac 632 + 633 634 rac 635 + 636 637 rac F 638 + 639 640 rac 641 + 642 643 rac 644 + o 645 646 rac 647 + 0 648 649 rac N 650 + 651 652 rac 653 + 654 655 rac 656 + N 657N 658 rac 659 + 660 661 rac 662 + 663 664 rac 665 + 666 667 rac 668 + 669 670 rac O 671 + 672 No. Racemic or R3 enantiomer R3 673 rac OH 674 /FH 675 + N N 676 rac 0 0 677 + CFa 0 678 24 WO 2006/136461 PCT/EP2006/006531 679 rac H 680 + 681 682 rac 683 + 684 685 rac 686 + 687 688 rac 689 + 690 691 rac 692 + - N 693 694 rac 695 + 696 697 rac 698 + 699 700 rac F 701 + 702 703 rac \N 704 + 705 706 rac 707 + 708 709 rac 710 + ON 711 712 rac 713 + 714 715 rac 716 + 717N 718 rac NO, 719 + 720 721 rac 722 + -OrN 723 724 rac 725 + 726 727 rac 728 + 729 25 WO 2006/136461 PCT/EP2006/006531 730 rac 731 + 732 | 733 rac 734+ 175 No. Racemic or R3 enantiomer R3 736 rac 737 - H 738 + N 739 rac 0 740 + 0 741 742 rac H 743 + 744 745 rac 746 + 747 748 rac 749 + 750 751 rac 752 + 753 754 rac 755 + 756 757 rac 0 758 + 759 760 rac 761 + 762 763 rac CF 764 + 765 766 rac 767 + 768 769 rac 770 + 771 772 rac 0 773 + 774 775 rac N 776 +2 1777N 26 WO 2006/136461 PCT/EP2006/006531 778 rac 779 + 780 781 rac 782 + NO, 783 784 rac 785 + 786 787 rac CF, 788 + 789 790 rac 791 + 792 793 rac 794 + 795 796 rac 797 + 798 No. Racemic or R3 R 3 enantiomer OH 799 rac -o 800 - _N 801 + | 0 . 802 rac cl 803 + 804 805 rac H 806 + 807 808 rac 809 + 810 811 rac 812 + 813 814 rac 815 + 816 817 rac 818 + 819 N 820 rac 821 + 822 823 rac 824 + 825 - _ 27 WO 2006/136461 PCT/EP2006/006531 826 rac F 827 + 828 829 rac 830 + 831 832 rac 833 + 834 835 rac 0 836 + 837 838 rac 839 + 840 841 rac 842 + 843 844 rac 845 + No2 846 847 rac 848 + 849 850 rac 851 + 852 853 rac 854 + j~i 855 856 rac 857 + 858 859 rac 860 + 861 No. Racemic or R3 enantiomer R OH 862 rac 863 H 864 + N 865 rac 0 0 866 + F 0 867 868 rac 869 + H 870 871 rac 872 +2 873 _______ 28 WO 2006/136461 PCT/EP2006/006531 874 rac 875 + 876 877 rac 878 + 879 880 rac 881 + N 882 883 rac 884 885 886 rac 887 + 888 889 rac F 890 + 891 -_ 892 rac 893 + 894 895 rac 896 + 897 898 rac 0 899 + 900 901 rac N 902 + 903 904 rac 905 + 906 < 907 rac 908 + 909 910 rac 911 + 912 913 rac 914 + 915 916 rac 917 + 918 919 rac 920 + 921 922 rac ON 923+ 924 29 WO 2006/136461 PCT/EP2006/006531 No. Racemic or R3 R OH enantiomer O 925 rac N N 926 0 0 927 + 928 rac F 0 929 + 930 931 rac 932 + 933 934 rac 935 + 936 937 rac 938 + 939 940 rac CF 941 + 942 943 rac 944 + 945 Na 946 rac 947 + 948 N 949 rac 950 + 951 952 rac 953 + 954 -_.- _ 955 rac 956 + 957 N 958 rac 959 +N 960 961 rac 962 + 963 964 rac 965 + N 966 967 rac 968 + 969 N 970 rac NO, 971 + N 972 - -' 30 WO 2006/136461 PCT/EP2006/006531 973 rac 974 + 975 976 rac 977 + 978 979 rac 980 + 981 982 rac 983 + 984 985 rac 986 + 987 No. Racemic or R3 R enantiomer OH 988 rac Br 989 N N 990 + 991 rac 992 + F O 993 994 rac 995 + 996 997 rac 998 + 999 1000 rac 1001 + 1002 1003 rac 1004 + 1005 1006 rac 1007 + 1008 1009 rac 1010 + 1011 1012 rac 1013 + 1014 1015 rac CF 1016 + 1017 1018 rac 1019 + 1020 31 WO 2006/136461 PCT/EP2006/006531 1021 rac 1022 + 1023 1024 rac 0 1025 + 1026 1027 rac 1028 + 1029 1030 rac 1031 + I 1032 1033 rac 1034 + 1035 1036 rac 1037 + 1038 1039 rac 1040 + 1041 1042 rac 1043 + 1044 1045 rac 1046 + 1047 1048 rac OH 1049 + 1050 No. Racemic or R3 enantiomer R3 1051 rac OH 1052 H 1053 + N N 1054 rac o o 1055 +

CF

3 1056 1057 rac 1058 + 1059 1060 rac 1061 + 1062 1063 rac 1064 + 1065 1066 rac 1067 + 1068 32 WO 2006/136461 PCT/EP2006/006531 1069 rac 1070 + . 1071 < 1072 rac 1073 + 1074 1075 rac 1076 + 1077 1078 rac 1079 + 1080 1081 rac 1082 + 1083 1084 rac 1085 + 1086 1087 rac 1088 + 1089 1090 rac N 1091 + 1092 1093 rac 1094 + 1095 1096 rac 1097 + 1098 1099 rac 1100 + 1101 1102 rac 1103 + 1104 1105 rac 1106 + 1107 1108 rac 1109 + 1110 1111 rac OH 1112 + H 1113 33 WO 2006/136461 PCT/EP2006/006531 No. Racemic or R3 enantiomer R3 1114 rac OH 1115 -

CF

3 H 1116 + N N 1117 rac 0 o 1118 + F 1119 1120 rac 1121 + 1122 1123 rac 1124 + 1125 1126 rac 1127 + 1128 1129 rac CF3 1130 + 1131 1132 rac 1133 + 1134 1135 rac 1136 + 1137 1138 rac 1139 + 1140 1141 rac CF 1142 + 1143 1144 rac 1145 + 1146 1147 rac 1148 + 1149 1150 rac 1151 + N 1152 1153 rac N 1154+N 155 1156 rac 1157 + N 1158 1159 rac NO, 1160 +N 1161 1162 rac 1163 + 1164 34 WO 2006/136461 PCT/EP2006/006531 1165 rac 1166 + 1167 1168 rac 1169 + 1170 1171 rac 1172 + 1173 1174 rac OH 1175 + 1176 No. Racemic or R3 enantiomer R 3 1177 rac OH 1178 -

CF

3 H 1179 + N N 1180 rac o o 1181 + 1182 1183 rac 1184 + 1185 1186 rac 1187 + 1188 1189 rac 1190 + 1191 1192 rac CF, 1193 + 1194 1195 rac 1196 + 1197 N 1198 rac 1199 +N 1200 1202 rac 1202 + 1203 1204 rac F, 1205 + 1206 1207 rac

\

1208 + 1209 1210 rac 1211 + 1212 35 WO 2006/136461 PCT/EP2006/006531 1213 rac 1214 + 1215 1216 rac 1217 + N 1218 1219 rac 1220 + 1221 1222 rac 1223 + NO 1224 1225 rac 1226 + 1227 1228 rac 1229 + 1230 1231 rac 1232 + 1233 1234 rac 1235 + 1236 1237 rac O 1238 + 1239 No. Racemic or R3 enantiomer R 3 1240 rac OH 1241 CF 3 H 1242 + N N 1243 rac o 1244 +F 1245 1246 rac 1247 + 1248 1249 rac 1250 + 1251 N 1252 rac 1253 + 1254 1255 rac CF3 1256 + 1257 1258 rac 1259 + 1260 36 WO 2006/136461 PCT/EP2006/006531 1261 rac 1262 + 1263 1264 rac 1265 + 1266 1267 rac CF, 1268 + 1269 1270 rac 1271 + 1272 1273 rac 1274 + 1275 1276 rac Os 1277 + 1278 1279 rac N 1280 + 1281 1282 rac 1283 + 1284 1285 rac NO, 1286 + N 1287 1288 rac 1289 + 1290 1291 rac 1292 + 1293 1294 rac 1295 + 1296 1297 rac 1298 + 1299 1300 rac 1301 + 1302 No. Racemic or R3 enantiomer R 3 1303 rac OH 1304 ci H 1305 + N N 1306 rac 1307 + 0F- 0 1308 37 WO 2006/136461 PCT/EP2006/006531 1309 rac 1310 + 1311 1312 rac 1313 + 1314 1315 rac 1316 + 1317 1318 rac CF 1319 + 1320 1321 rac 1322 + 1323 1324 rac 1325 + 1326 1327 rac 1328 + 1329 1330 rac F 1331 + 1332 1333 rac 1334 + 1335 1336 rac 1337 + 1338 1339 rac 1340 + 1341 1342 rac N 1343 + N 1344 1345 rac 1346 + 1347 1348 rac NO 1349 + NO 1350 1351 rac 1352 + 1353 1354 rac 1355 + 1356 1357 rac 1358 + 1359 38 WO 2006/136461 PCT/EP2006/006531 1360 rac 1361 + 1362 1362 rac OH 1364 + 1365 No. Racemic or R3 enantiomer R3 1366 rac OH 1367 -

F

3 H 1368 +/N N N 1369 rac - o 1370 + 1371 1372 rac 1373 + 1374 1375 rac 1376 + 1377 1378 rac 1379 + 1380 1381 rac 1382 + 1383 1384 rac 1385 + 1386 r 1387 rac 1388 + 1389 1390 rac 1391 + 1392 -_ 1393 rac CF 1394 + 1395 1396 rac 1397 + 1398 1399 rac 0 1400 + 1401 1402 rac 1403 + 1404 1405 rac 1406 + 1407 39 WO 2006/136461 PCT/EP2006/006531 1408 rac 1409 + 1410 1411 rac 1412 + N 1413 1414 rac C 1415 + 1416 1417 rac 1418 + 1419 1420 rac 1421 + 1422 1423 rac 1424 + 1425 1426 rac 1427 +N 1428 No. Racemic or R3 enantiomer 1429 rac OH 1430

CF

3 H 1431 + N N 1432 rac 0 O 1433 + 1434 1435 rac 1436 + 1437 1438 rac 1439 + 1440 1441 rac 1442 + 1443 1444 rac CF, 1445 + 1446 1447 rac 1448 + 1449 1450 rac 1451 + 1452N 1453 rac 1454 + 1455 40 WO 2006/136461 PCT/EP2006/006531 1456 rac F, 1457 + 1458 1459 rac \ 1460 + 1461 1462 rac 1463 + 1464 1465 rac 0, 1466 + 1467 1468 rac 1469 + 1470 -_ 1471 rac 1472 + 1473 1474 rac NO, 1475 + 1476 1477 rac 1478 + 1479 1480 rac 1481 + 1482 1483 rac 1484 + 1485 1486 rac 1487 + 1488 1489 rac 1490 + 1491 No. Racemic or R3 enantiomer R 3 1492 rac OH 1493 -, H 1494 + N N 1495 rac 0 o 1496 + 1497 0 1498 rac 1499 + 1500 1501 rac 1502 + 1503 41 WO 2006/136461 PCT/EP2006/006531 1504 rac 1505 + 1506 1507 rac CF 1508 + 1509 1510 rac 1511 + 1512N 1513 rac 1514 + 1516 rac 1517 + 1518 1519 rac CF, 1520 + 1521 1522 rac \ 1523 + 1524 1525 rac 1526 + 1527 1528 rac o 1529 + 1530 1531 rac N 1532 + N 1533 1534 rac 1535 + 1536 1537 rac NO 1538 + N 1539 1540 rac 1541 + 1542 1543 rac 1544 + 1545 1546 rac 1547 + 1548 1549 rac 1550 + 1551 1552 rac - ON 1553 + 1554 42 WO 2006/136461 PCT/EP2006/006531 No. Racemic or R3

R

3 OH enantiomer oder ci Enantiomer H 1555 rac N 1556 0 0 1557 + 0 1558 rac 1559 + 1560 1561 rac 1562 + 1563 1564 rac 1565 + 1566 1567 rac 1568 + 1569 1570 rac CF, 1571 + 1572 1573 rac 1574 + 1575 1576 rac 1577 + 1578 1579 rac 1580 + 1581 - 1582 rac 1583 + 1584 -_ 1585 rac 1586 + 1587 1588 rac 1589 + 1590 1591 rac 1592 + 1593 1594 rac 1595 + N 1596 1597 rac 1598 + 1599 1600 rac 1601 + N 1602 - _-' 43 WO 2006/136461 PCT/EP2006/006531 1603 rac 1604 + 1605 1606 rac 1607 + 1608 1609. rac 1610 + 1611 1612 rac 1613 + 1614 1615 rac 1616 + 1617 -__ __ _ _ __ _ _ __ _ _ No. Racemic or R3 enantiomer R 3 1618 rac OH 1619 CF 3 H 1620 + N N 1621 rac 0 o 1622 + F 1623 1624 rac 1625 + 1626 1627 rac 1628 + 1629 1630 rac 1631 + 1632 1633 rac CF, 1634 + 1635 1636 rac 1637 + 1638 1639 rac 0 1640 + 1641 1642 rac 1643 + 1644 1645 rac CF 1646 + 1647 1648 rac 1649 + 1650 44 WO 2006/136461 PCT/EP2006/006531 1651 rac 1652 + 1653 1654 rac o 1655 + 1656 1657 rac 1658 + N 1659 1660 rac 1661 + 1662 1663 rac NO, 1664 + N 1665 1666 rac 1667 + 1668 1669 rac 1670 + 1671 1672 rac 1673 + 1674 1675 rac 1676 + 1677 1678 rac 0 1679 + 1680 No. Racemic or R3 enantiomer 1681 rac R 3 OH 1682

-

o H 1683 + 0 N N 1684 rac 1685 + 0 0 1686 1687 rac 1688 + 1689 1690 rac 1691 + 1692 1693 rac 1694 + 1695 1696 rac 1697 + 1698 45 WO 2006/136461 PCT/EP2006/006531 1699 rac 1700 + N.. 1701 1702 rac 1703 + 1704 1705 rac 1706 + 1707 1708 rac F 1709 + 1710 1711 rac 1712 + 1713 1714 rac 1715 + 1716 1717 rac 1718 + 1719 1720 rac 1721 + N 1722 1723 rac 1724 + 1725 1726 rac 1727 + N 1728 1729 rac 1730 + 1731 1732 rac 1733 + 1734 1735 rac 1736 + 1737 1738 rac 1739 + 1740 1741 rac 1742 + 1743 46 WO 2006/136461 PCT/EP2006/006531 No. Racemic or R3 enantiomer R3 1744 rac OH 1745 H c 1746 + N N 1747 rac o o 1748 + F 1749 0 1750 rac 1751 + H 1752 1753 rac 1754 + 1755 1756 rac 1757 + 1758 1759 rac CF 1760 + 1761 1762 rac 1763 + N 1764 1765 rac 1766 + 1767 1768 rac 1769 + 1770 1771 rac CF 1772 + 1773 1774 rac 1775 + 1776 1777 rac 1778 + 1779 1780 rac 1781 + 1782 -_ 1783 rac N 1784 + 1785 1786 rac 1787 + 1788 1789 rac 1790 + NO, 1791 1792 rac 1793 + 1794 47 WO 2006/136461 PCT/EP2006/006531 1795 rac 1796 + 1797 1798 rac 1799 + 1800 1801 rac 1802 + 1803 1804 rac 1805 + 1806 1807 rac 1808 + 1809 1810 rac 1811 + 1812 No. Racemic or R3 enantiomer R 3 1813 rac OH 1814 - 0 H 1815 + N N 1816 rac o 1817 + 1818 0 1819 rac 1820 + 1821 1822 rac 1823 + 1824 1825 rac 1826 + 1827 1828 rac F 1829 + 1830 1831 rac 1832 + N 1833 1834 rac 1835 + 1836 1837 rac 1838 + 1839 1840 rac CF 1841 + 1842 48 WO 2006/136461 PCT/EP2006/006531 1843 rac 1844 + 1845 1846 rac 1847 + 1848 -_ 1849 rac 1850 + 1851 1852 rac 1853 + N 1854 1855 rac 1856 + 1857 1858 rac NO, 1859 + N 1860 1861 rac 1862 + 1863 1864 rac 1865 + )0 1866 1867 rac 1868 + 1869 1870 rac 1871 + 1872 1873 rac 1874 + 1875 No. Racemic or R3 enantiomer R 3 1876 rac OH 1877 c H 1878 + N N 1879 rac 0 o 1880 + 1881 1882 rac 1883 + 1884 ._ 1885 rac 1886 + 1887 1888 rac 1889 + 1890 49 WO 2006/136461 PCT/EP2006/006531 1891 rac CF, 1892 + 1893 1894 rac 1895 + 1896 1897 rac 1898 + 1899 1900 rac 1901 + 1902 1903 rac 1904 + 1905 1906 rac 1907 + 1908 1909 rac 1910 + 1911 1912 rac s 1913 + 1914 1915 rac N 1916 + N 1917 1918 rac 1919 + 1920 1921 rac NO 1922 + N 1923 1924 rac 1925 + 1926 1927 rac 1928 + 1929 1930 rac 1931 + 1932 1933 rac 1934 + 1935 1936 rac 1937 + 1938 50 WO 2006/136461 PCT/EP2006/006531 No. Racemic or R3 enantiomer R 3 1939 rac OH 1940 H/-0 1941 + N N 1942 rac o o 1943 + 1944 1945 rac 1946 + 1947 1948 rac 1949 + 1950 1951 rac 1952 + 1953 1954 rac C 1955 + 1956 1957 rac 1958 + 1959 1960 rac 1961 + 1962 1963 rac 1964 + 1965 1966 rac CF 1967 + 1968 1969 rac 1970 + 1971 1972 rac 1973 + 1974 1975 rac o 1976 + 1977 1978 rac 1979 + N 1980 1981 rac 1982 + 1983 N 1984 rac 1985 + N 1986 1987 rac 1988 + s 1989 51 WO 2006/136461 PCT/EP2006/006531 1990 rac 1991 + 1992 1993 rac 1994 + 1995. 1996 rac 1997 + 1998 1999 rac 2000 + 2001 No. Racemic or R3 enantiomer R 3 2002 rac OH 2003 ci H 2004 + / N N 2005 rac o 2006 + 2007 0 2008 rac 2009 + 2010 2011 rac 2012 + 2013 2014 rac 2015 + 2016 2017 rac CF, 2018 + 2019 2020 rac 2021 + 2022 2023 rac 0 2024 + 2025 2026 rac 2027 + 2028 2029 rac CF, 2030 + 2031 2032 rac 2033 + 2034 2035 rac 2036 + 2037 52 WO 2006/136461 PCT/EP2006/006531 2038 rac 0 2039 + 2040 2041 rac 2042 + 2043 2044 rac 2045 + 2046 2047 rac NO, 2048 + 2049 2050 rac 2051 + 2052 2053 rac 2054 + 2055 2056 rac 2057 + 2058 2059 rac 2060 + 2061 2062 rac 2063 + 2064 No. Racemic or R3 enantiomer R 3 2065 rac OH 2066 cl 2067 + N N 2068 rac o 2069 + 2070 2071 rac 2072 + 2073 2074 rac 2075 + 2076 2077 rac 2078 + 2079 2080 rac CF, 2081 + 2082 2083 rac 2084 + 2085 53 WO 2006/136461 PCT/EP2006/006531 2086 rac 2087 + 2088 2089 rac 2090 + 2091 -_ 2092 rac F 2093 + 2094 | 2095 rac 2096 + 2097 2098 rac 2099 + 2100 2101 rac s 2102 + 2103 2104 rac 2105 + N 2106 2107 rac 2108 + 2109 2110 rac NO, 2111 + N 2112 2113 rac 2114 + 2115 2116 rac 2117 + 2118 2119 rac 2120 + 2121 2122 rac 2123 + 2124 2125 rac 2126 + 2127 No. Racemic or R3 enantiomer R 3 2128 rac OH 2129 7 H 2130 + / N 2131 rac 0 o 2132 + F 2133 0 54 WO 2006/136461 PCT/EP2006/006531 2134 rac 2135 + 2136 2137 rac 2138 + 2139 2140 rac 2141 + 2142 2143 rac C, 2144 + 2145 2146 rac 2147 + N 2148 2149 rac 2150 + 2151 2152 rac 2153 + 2154 2155 rac 2156 + 2157 2158 rac 2159 + 2160 2161 rac 2163 + 2163 2164 rac 2165 + 2166 2167 rac 2168 + N 2169 2170 rac 2171 + N 2172 2173 rac 2174 + 2175 2176 rac 2177 + 2178 2179 rac 2180 +CF 2181 2182 rac 2183 + 2184 55 WO 2006/136461 PCT/EP2006/006531 2185 rac 2186 + 2187 2188 rac -O 2189 + 2190 | No. Racemic or R3 enantiomer R3 2191 rac OH 2192

CF

3 H 2193 + N N 2194 rac 0 o 2195 + F 2196 2197 rac 2198 + 2199 2200 rac 2201 + 2202 2203 rac 2204 + 2205 2206 rac CFa 2207 + 2208 2209 rac 2210 + 2211N 2212 rac 2213 + N 2214 2215 rac 2216 + 2217 2218 rac CF, 2219 + 2220 2221 rac 2222 + 2223 2224 rac 2225 + 2226 2227 rac 2228 + 2229 2230 rac 2231 + N 2232 56 WO 2006/136461 PCT/EP2006/006531 2233 rac 2234 + 2235 2236 rac 2237 + NOl 2238 2239 rac 2240 + 2241 2242 rac 2243 + 2244 2245 rac 2246 + 2247 2248 rac 2249 + 2250 2251 rac O 2252 + 2253 No. Racemic or R3 enantiomer 2254 rac OH 2255 - H 2256 + N N 2257 rac O o 2258 + 2259 2260 rac 2261 + 2262 2263 rac 2264 + 2265 2266 rac 2267 + 2268 2269 rac CF, 2270 + 2271 2272 rac 2273 + 2274 2273 rac 2276 + 2277 2278 rac 2279 + 2280 57 WO 2006/136461 PCT/EP2006/006531 2281 rac F, 2282 + 2283 2284 rac N 2285 + 2286 2287 rac 2288 + 2289 2290 rac 0 2291 + 2292 2293 rac 2294 + N 2295 2296 rac 2297 + 2298 2299 rac NO, 2300 + 2301 2302 rac 2303 + 2304 2305 rac 2306 + 2307 2308 rac 2309 + 2310 2311 rac 2312 + 2313 2314 rac OH 2315 + 2316 No. Racemic or R3 enantiomer R 3 2317 rac OH 2318 H 2319 + N N 2320 rac o o 2321 + 2322 2323 rac 2324 + H 2325 2326 rac 2327 + 2328 58 WO 2006/136461 PCT/EP2006/006531 2329 rac 2330 + 2331 2332 rac CF, 2333 + 2334 2335 rac 2336 + N 2337 2338 rac 0 2339 + 2340 2341 rac 2342 + 2343 2344 rac 2345 + 2346 - 2347 rac 2348 + 2349 2350 rac 2351 + 2652 2353 rac 2354 + 2355 2356 rac N 2357 + N 2358 2359 rac 2360 + 2361 2362 rac NO, 2363 + N 2364 2365 rac 2366 + 2367 2368 rac 2369 + 2370 2371 rac 2372 + 2373 2374 rac 2375 + 2376 2377 rac OH 2378 + 2379 59 WO 2006/136461 PCT/EP2006/006531 No. Racemic or R3 enantiomer R3 2380 rac OH 2381 0 H 2382 + N N 2383 rac 0 o 2384 + 2385 2386 rac 2387 + 2388 2389 rac 2390 + 2391 2392 rac 2393 + 2394 2395 rac 2396 + 2397 - 2398 rac 2399 + N 2400 2401 rac 2402 + 2403 2404 rac 2405 + 2406 - _ 2407 rac F 2408 + 2409 2410 rac 2411 + 2412 2413 rac 2414 + 2415 2416 rac 2417 + 2418 2419 rac N 2420 + 2421 2422 rac 2423 + 2424 2425 rac 2426 + NO, 2427 2428 rac 2429 + 2430 60 WO 2006/136461 PCT/EP2006/006531 2431 rac 2432 + 2433 2434 rac 2435 + 2436 2437 rac 2438 + 2439 2440 rac 2441 + 2442 No. Racemic or Structure enantiomer 2443 rac 2444 2445 + 2446 rac 2447 + 2448 2449 rac 2450 + 2451 2452 rac 2453 + 2454 2455 rac 2456 + 2457 2458 rac 2459 + 2460 2461 rac 2462 + 2463 2464 rac 2465 + 2466 2467 rac 2468 + 2469 2470 rac 2471 + 2472 2473 rac 2474 + 2475 - 61 WO 2006/136461 PCT/EP2006/006531 2476 rac 2477 + 2478 62 WO 2006/136461 PCT/EP2006/006531 Biological characterization of the compounds according to the invention Progesterone receptor modulators can be identified with the aid of simple methods, test programmes known to the skilled person. It is possible for this purpose for example to incubate a compound to be tested together with a progestogen in a test system for 5 progesterone receptors and to check whether the effect mediated by progesterone is altered in the presence of the modulator in this test system. The substances according to the invention of the general formula I were tested in the following models: 10 Progesterone receptor-binding assay Measurement of the receptor binding affinity: The receptor binding affinity was determined by competitive binding of a specifically binding 3 H-labelled hormone (tracer) and of the compound to be tested on receptors in 15 the cytosol from animal target organs. The aim in this case was receptor saturation and reaction equilibrium. The tracer and increasing concentrations of the compound to be tested (competitor) were coincubated at 0-4 0 C for 18 h with the receptor-containing cytosol fraction. After removal of unbound tracer with carbon-dextran suspension, the receptor-bound tracer 20 content was measured for each concentration, and the IC 5 0 was determined from the concentration series. The relative molar binding affinity (RBA) was calculated as ratio of the IC 50 values for reference substance and compound to be tested (x 100%) (RBA of the reference substance = 100%). 25 The following incubation conditions were chosen for the receptor types: Progesterone receptor: Uterus cytosol of the estradiol-primed rabbit, homogenized in TED buffer (20 mMTris/HCI, pH 7.4; 1 mM ethylenediaminetetraacetate, 2 mM dithiothreitol) with 30 250 mM sucrose; stored at -30 0 C. Tracer: 3 H-ORG 2058, 5 nM; reference substance: progesterone. Glucocorticoid receptor: Thymus cytosol from the adrenalectomized rat, thymi stored at -30OC; buffer: TED. 35 Tracer: 3 H-dexamethasone, 20 nM; reference substance: dexamethasone. 63 WO 2006/136461 PCT/EP2006/006531 The relative receptor binding affinities (RBA values) for the compounds according to the invention of the general formula (1) on the progesterone receptor are between 3 and 100% relative to progesterone. The RBA values at the glucocorticoid receptor are in the range from 3 to 30% relative to dexamethasone. 5 The compounds according to the invention accordingly have a high affinity for the progesterone receptor, but only a low affinity for the glucocorticoid receptor. Antagonism at the PR-B progesterone receptor 10 The transactivation assay is carried out as described in WO 02/054064. Agonism on the PR-B progesterone receptor The transactivation assay is carried out as described in Fuhrmann et al. (Fuhrmann U., Hess-Stump H., Cleve A., Neef G., Schwede W., Hoffmann J., Fritzemeier K.-H., 15 Chwalisz K., Journal of Medicinal Chem, 43, 26, 2000, 5010-5016). No. Antagonistic Activity Agonistic Acticity

IC

50 [nM] Efficacy [%] EC 50 [nM] Efficacy [%] 5 0,2 86 0,2 10 14 6 53 7 35 16 0,7 82 0,5 13 17b 0,03 88 n.b. 7 18 0,2 89 n.b. 8 24 2 100 0 35 2 100 0 Dosage The progesterone receptor modulators can be administered orally, enterally, 20 parenterally or transdermally for the use according to the invention. Satisfactory results are generally to be expected in the treatment of the indications mentioned hereinbefore when the daily doses cover a range from 1 pg to 500 mg of the compound according to the invention. 25 Suitable dosages of the compounds according to the invention in humans for the treatment of endometriosis, of leiomyomas of the uterus and dysfunctional bleeding and for use in fertility control and for hormone replacement therapy are from 50 pg to 64 WO 2006/136461 PCT/EP2006/006531 500 mg per day, depending on the age and constitution of the patient, it being possible to administer the necessary daily dose by single or multiple administration. The dosage range for the compounds according to the invention for the treatment of 5 breast carcinomas is 10 mg to 1000 mg per day. The pharmaceutical products based on the novel compounds are formulated in a manner known per se by processing the active ingredient with the carrier substances, fillers, substances influencing disintegration, binders, humectants, lubricants, 10 absorbents, diluents, masking flavours, colorants, etc. which are used in pharmaceutical technology, and converting into the desired administration form. Reference should be made in this connection to Remington's Pharmaceutical Sciences, 15 th ed. Mack Publishing Company, Easton, Pennsylvania (1980). 15 Suitable for oral administration are in particular tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, granules, pastilles, suspensions, emulsions or solutions. Preparations for injection and infusion are possible for parenteral administration. 20 Appropriately prepared crystal suspensions can be used for intraarticular injection. Aqueous and oily solutions for injection or suspensions and corresponding depot preparations can be used for intramuscular injection. 25 For rectal administration, the novel compounds can be used in the form of suppositories, capsules, solutions (e.g. in the form of enemas) and ointments, both for systemic and for local therapy. Furthermore, compositions for vaginal use may also be mentioned as preparation. 30 For pulmonary administration of the novel compounds, they can be used in the form of aerosols and inhalants. Patches are possible for transdermal administration, and formulations in gels, 35 ointments, fatty ointments, creams, pastes, dusting powders, milk and tinctures are possible for topical application. The dosage of the compounds of the general formula I 65 WO 2006/136461 PCT/EP2006/006531 in these preparations should be 0.01% - 20% in order to achieve an adequate pharmacological effect. Corresponding tablets can be obtained for example by mixing active ingredient with 5 known excipients, for example inert diluents such as dextrose, sugar, sorbitol, mannitol, polyvinylpyrrolidone, disintegrants such as maize starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc and/or means to achieve a depot effect such as carboxypolymethylene, carboxymethylcellulose, cellulose acetate phthalate or polyvinyl acetate. The tablets may also consist of a 10 plurality of layers. Correspondingly, coated tablets can be produced by coating cores produced in analogy to the tablets with compositions normally used in tablet coatings, for example polyvinylpyrrolidone or shellac, gum arabic, talc, titanium oxide or sugar. The tablet 15 covering may in this case also consist of a plurality of layers, it being possible to use the excipients mentioned above for tablets. Solutions or suspensions of the compounds according to the invention of the general formula I may additionally comprise taste-improving agents such as saccharin, 20 cyclamate or sugar, and, for example, flavourings such as vanillin or orange extract. They may additionally comprise suspending excipients such as sodium carboxymethylcellulose or preservatives such as p-hydroxybenzoates. Capsules comprising the compounds of the general formula I can be produced for 25 example by mixing the compound(s) of the general formula I with an inert carrier such as lactose or sorbitol and encapsulating it in gelatin capsules. Suitable suppositories can be produced for example by mixing with carriers intended for this purpose, such as neutral fats or polyethylene glycol or derivatives. 30 The compounds according to the invention of the general formula (1) or their pharmaceutically acceptable salts can be used, because of their antagonistic or partial agonistic activity, for producing a medicament, in particular for the treatment and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the 35 uterus, dysfunctional bleeding and dysmenorrhoea. They can furthermore be employed to counteract hormonal irregularities, for inducing menstruation and alone or in 66 WO 2006/136461 PCT/EP2006/006531 combination with prostaglandins and/or oxytocin to induce labour. The compounds according to the invention of the general formula (1) or their pharmaceutically acceptable salts are furthermore suitable for producing products for 5 female contraception (see also WO 93/23020, WO 93/21927). The compounds according to the invention or their pharmaceutically acceptable salts can additionally be employed alone or in combination with a selective estrogen receptor modulator (SERM) for female hormone replacement therapy. 10 In addition, the said compounds have an antiproliferative effect in hormone-dependent tumours. They are therefore suitable for the therapy of hormone-dependent carcinomas such as, for example, for breast, prostate and endometrial carcinomas. The compounds according to the invention or their pharmaceutically acceptable salts 15 can be employed for the treatment of hormone-dependent carcinomas both in first-line therapy and in second-line therapy, especially after tamoxifen failure. The compounds according to the invention, having antagonistic or partially agonistic activity, of the general formula (1) or their pharmaceutically acceptable salts can also be 20 used in combination with compounds having antiestrogenic activity (estrogen receptor antagonists or aromatase inhibitors) or selective estrogen receptor modulators (SERM) for producing pharmaceutical products for the treatment of hormone-dependent tumours. The compounds according to the invention can likewise be used in combination with SERMs or an antiestrogen (estrogen receptor antagonist or 25 aromatase inhibitor) for the treatment of endometriosis or of leiomyomas of the uterus. In the treatment of hormone-dependent tumours the progesterone receptor modulator and the antiestrogen (estrogen receptor antagonists or aromatase inhibitors) or the SERM can be provided for simultaneous or else for sequential administration. In the sequential administration, preferably the antiestrogen (estrogen receptor antagonists or 30 aromatase inhibitors) or SERM is administered first and subsequently the progesterone receptor modulator is administered. Suitable for combination with the non-steroidal progesterone receptor modulators according to the invention in this connection are for example the following antiestrogens 35 (estrogen receptor antagonists or aromatase inhibitors) or SERMs: tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulphinyl]pentyloxy}phenyl)-6 67 WO 2006/136461 PCT/EP2006/006531 phenyl-8,9-dihydro-7H-benzocyclohepten-2-o (WO 00/03979), ICI 182 780 (7alpha-[9 (4,4,5,5-pentafluoropentylsulphinyl)nonyl]estra-1,3,5(1 0)-triene-3,17beta-diol), 11 beta fluoro-7alpha-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulphanyl]propyl}amino)pentyl] estra-1,3,5(1 0)-triene-3,17beta-diol (W098/07740), 11 beta-fluoro-7alpha-{5 5 [methyl(7,7,8,8,9,9,10,10,1 0-nonafluorodecyl)amino]pentyl}estra-1,3,5(1 0)-triene-3,17 beta-diol (WO 99/33855), 11beta-fluoro-17alpha-methyl-7alpha-{5-[methyl(8,8,9,9,9 pentafluorononyl)amino]pentyl)estra-1,3,5(10)-triene-3,17beta-diol (WO 03/045972), clomifen, raloxifen, and further compounds having antiestrogenic activity, and aromatase inhibitors such as, for example, fadrozole, formestane, letrozole, anastrozole 10 or atamestane. Finally, the present invention also relates to the use of the compounds of the general formula 1, where appropriate together with an antiestrogen or SERM, for producing a medicament. 15 The present invention further relates to pharmaceutical compositions which comprise at least one compound according to the invention, where appropriate in the form of a pharmaceutically/pharmacologically acceptable salt, without or together with pharmaceutically acceptable excipients and/or carriers. 20 These pharmaceutical compositions and medicaments may be intended for oral, rectal, vaginal, subcutaneous, percutaneous, intravenous or intramuscular administration. Besides conventional carriers and/or diluents, they comprise at least one compound according to the invention. 25 The medicaments of the invention are produced with the conventional solid or liquid carriers or diluents and the excipients normally used in pharmaceutical technology appropriate for the desired mode of administration with a suitable dosage in a known manner. The preferred preparations consist of a dosage suitable for oral administration. 30 Examples of such dosage forms are tablets, film-coated tablets, sugar-coated tablets, capsules, pills, powders, solutions or suspensions or else depot forms. The pharmaceutical compositions comprising at least one of the compounds according to the invention are preferably administered orally. 35 Also suitable are parenteral preparations such as solutions for injection. Further 68 WO 2006/136461 PCT/EP2006/006531 preparations which may also be mentioned are for example suppositories and compositions for vaginal use. 69 WO 2006/136461 PCT/EP2006/006531 The following examples serve to illustrate the subject-matter of the invention in more detail without wishing to restrict it thereto. Preparation of the starting compounds 6-[4-(2-chloro-5-fluorophenyl)-4-methyl-2 5 oxovaleroylamino]-4-methyl-2,3-benzoxazin-1 -one, 6-[4-(2-chloro-4-fluorophenyl)-4 methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1 -one and 6-{3-[1-(2-chloro phenyl)cyclopentyl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1 -one has been described in the patent US 2002/0077356, the compound 6-[4-(2,3-dihydro-7 benzofuranyl)-4-methyl-2-oxopentanoylamino]-4-methyl-2,3-benzoxazinone in US 10 patent 6,323,199B1 (example 87 therein), the compound 6-(4-methyl-4-phenyl-2 oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one in the patent WO 199854159 and the compound 6-[3-[1-(2-fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionyl amino]-4-methyl-2,3-benzoxazin-1-one in the patent WO 200375915. 15 General methods 1-(Benzo[1,3]dioxol-4-yl)-1-methylethanol 57.2 ml of methyl magnesium chloride solution (3M in THF) were added to 25.5 g of 4-acetylbenzo[1,3]dioxole in 375 ml of THF at RT under argon. The mixture was stirred 20 at RT for 16 h and added to ice/2N hydrochloric acid. It was then extracted with ethyl acetate, and the organic phase was washed with water and brine and dried (Na 2

SO

4 ). 27.89 g of 1-[benzo(1,3)dioxol-4-yl]-1-methylethanol were obtained as a brown oil. 'H-NMR (CDCI 3 , ppm) = 1.6 (s, 6H), 5.95 (s, 2H), 6.76 (dd, 1H), 6.82 (t, 1H), 6.91 (dd, 1 H) 25 4-(Benzo[1,3]dioxol-4-yl)-4-methyl-2-oxopentanoic acid 47 ml of tin(IV) chloride were added to 9.5 g of 1-(benzo[1,3]dioxol-4-yl)-1 methylethanol and 14.2 g of ethyl 2-trimethylsilyloxyacrylate in 200 ml of dichloromethane at -70 0 C. After 15 minutes, the solution was added to potassium 30 carbonate solution. After extraction with diethyl ether, the organic phase was washed with water, dried and evaporated. 14.4 g of the ethyl 4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxopentanoate obtained in this way were stirred with 150 ml of 1 M sodium hydroxide and 300 ml of methanol at RT for 10 hours. The methanol was then removed in vacuo, and the remaining solution was 35 extracted with diethyl ether. The aqueous phase was acidified with 1 M hydrochloric acid and extracted with diethyl ether. Drying and evaporation resulted in 11.1 g of 70 WO 2006/136461 PCT/EP2006/006531 4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxopentanoic acid as yellowish oil. MS (ei) m/e: M* = 251 6-[4-(Benzo[1,3]dioxol-4-yl)-4-methyl-2-oxovaleroylamino-4-methyl-2,3-benzoxazin-1 5 one 10 g of 4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxopentanoic acid were dissolved in 125 ml of dimethylacetamide and, at -0*C under argon, 3.5 ml of thionyl chloride were added. After stirring at -3 to +3 0 C for 20 minutes, 7.6 g of 6-amino-4-methyl-2,3-benzoxazin-1 one (WO 00/32584) were added. The mixture was stirred at room temperature for 10 96 hours and, after addition of water, extracted with ethyl acetate, the organic phase was washed with water and dried (Na 2

SO

4 ), and evaporation of the solvent and chromatography of the crude product on silica gel with hexane/ethyl acetate (100:0 -> 60:40) resulted in 6.56 g of 6-[4-(benzo[1,3]dioxol-4-yl)-4-methyl-2-oxovaleroylamino]-4 methyl-2,3-benzoxazin-1-one as a beige solid. 15 m.p. = 165-166*C, MS (ei) m/e: M' = 409 Synthesis examples 20 (-)-6-{2-[2-(2,3-(Methylenedioxy)phenyl)-2-methylpropyl]-2-hydroxyoct-3-ynoyl)-4 methyl-2,3-benzoxazin-I -one 1 and (+)-6-{2-[2-(2,3-(methylenedioxy)phenyl)-2 methylpropyl]-2-hydroxyoct-3-ynoyl)-4-methyl-2,3-benzoxazin-I -one 2 H OH O N H 00 N N 0 ~- 0 0 I 0 25 nBuLi (0.7 ml, 1.6M in hexane) was added to a solution of 1-hexyne (0.5 ml) in THF (4 ml) at -78 0 C. The mixture was stirred at -78 0 C for 20 min, 6-[4-(benzo[1,3]dioxol-4 yl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1 -one (192 mg) was added, and the mixture was stirred at -78 0 C for 4 h. Water was then added and the mixture was allowed to reach room temp. Extraction with ethyl acetate, washing with saturated 30 sodium chloride solution, drying over sodium sulphate and purification by column chromatography on silica gel resulted in 82 mg of a white foam which was then converted by preparative chiral HPLC (Chiralpak AD 250 x 10 mm, eluent: 71 WO 2006/136461 PCT/EP2006/006531 acetonitrile/water 55/45 v/v, flow rate 4.7 ml/min, temperature 400C, retention times: 12.2 min (+)-enantiomer, 15.7 min (-)-enantiomer) into the compounds (-)-6-{2-[2-(2,3 (methylenedioxy) phenyl)-2-methylpropyl]-2-hydroxyoct-3-ynoyl}-4-methyl-2,3 benzoxazin-1-one (Example 1) and (+)-6-{2-[2-(2,3-(methylenedioxy)phenyl)-2 5 methylpropyl]-2-hydroxyoct-3-ynoyl}-4-methyl-2,3-benzoxazin-1 -one (Example 2). 1H-NMR (ppm, CDC1 3 , 400 MHz): 0.91 (t, J = 7.2 Hz, 3H, CH3), 1.32 - 1.49 (m, 4H), 1.55 (s, 3H), 1.58 (s, 3H), 2.17 (t, J = 7.2 Hz, 2H), 2.56 (s, 3H, CH3), 2.59 (d, J = 14.4 Hz, 1H), 2.74 (d, J = 14.8 Hz, 1H), 2.80 (s, 1H, OH), 5.94 - 5.96 (m, 2H), 6.46 - 6.49 10 (m, 1H), 6.64 (t, J = 7.8 Hz, 1H), 7.47 - 7.49 (m, 1H), 8.25 - 8.28 (m, 1H), 8.76 (s, 1H, NH). C 28

H

3 oN 2 0 6 (490.6): rac-6-{2-[2-(2-Chloro-5-fluorophenyl)-2-methylpropyl]-2,7-dihydroxyhept-3-ynoyl} 4-methyl-2,3-benzoxazin-1 -one 3 OH H NN OH 0 0 15 F 0 Stage A: Reaction of 5-(tert-butyldimethylsilyloxy)pent-1-yne (531 mg), nBuLi (0.7 ml, 1.6 M in hexane) and 6-[4-(2-chloro-5-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4 methyl-2,3-benzoxazin-1 -one (207 mg) at -78"C as described for Example I gave, after column chromatography on silica gel, a colourless oil (86 mg). 20 Stage B: The resulting oil was stirred in THF (3 ml) at room temp. under argon (3 h). Addition of water, extraction with ethyl acetate and washing with saturated brine were followed by drying with sodium sulphate. Purification by column chromatography on silica gel led to the title compound as a white foam (43 mg). 1H-NMR (ppm, CDCl 3 , 400 MHz): 1.58 (s, 3H, Me), 1.59 (s, 3H, Me), 1.71 - 1.74 (m, 25 2H, CH 2 ), 2.2 - 2.3 (m, 2H), 2.56 (s, 3H, CH 3 ), 2.75 (d, J = 15.2 Hz, 1H, CH), 2.92 (d, J = 14.8 Hz, 1H, CH), 3.26 (s, 1H, OH), 3.74 - 3.78 (m, 2H), 6.67 - 6.78 (m, 1H), 7.09 7.19 (m, 2H), 7.66 - 7.69 (m, 2H), 8.20 - 8.21 (m, 1H), 8.27 - 8.29 (m, 1H), 8.99 (s, 1H, NH). C 26

H

26

CIFN

2 0 5 (501.0): LC-MS: m/z = 501 [M + H*]. 72 WO 2006/136461 PCT/EP2006/006531 rac-6-{2-[2-(2-Chloro-5-fluorophenyl)-2-methylpropyl]-2-hydroxyoct-3-ynoyl)-4 methyl-2,3-benzoxazin-1 -one 4 CI HO N 0 o F 0 Reaction of 1-hexyne (0.6 ml), nBuLi (0.7 ml, 1.6 M in hexane) and 6-[4-(2-chloro-5 5 fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1 -one (207 mg) at -78 0 C as described for Example 1 gave, after column chromatography on silica gel and preparative thin-layer chromatography a viscous oil (12 mg). 1 H-NMR (ppm, CDCl 3 , 400 MHz): 0.90 (t, J = 7.2 Hz, 3H, Me), 1.32 - 1.47 (m, 4H), 1.57 (s, 3H, Me), 1.62 (s, 3H, Me), 2.13 (t, J = 7.2 Hz, CH 2 C=C), 2.56 (s, 3H, Me), 2.81 10 2.95 (m, 3H), 6.68 - 6.71 (m, 1H), 7.11 - 7.17 (m, 2H), 7.56 - 7.58 (m, 1H), 8.21 (d, J = 2.0 Hz, 1H), 8.29 (d, J = 12.6 Hz, 1H), 8.73 (br. s., 1H, NH). C 27

H

28

CIFN

2 0 4 (499.0): LC MS: m/z = 499 [M + H*]. 15 rac-6-{2-[(2-Chlorophenyl)cyclopentyl]methyl-2-hydroxy-4-phenylbut-3-ynoyl amino}-4-methyl-2,3-benzoxazin-1 -one 5 CI H N 16| OH 00 Lithiumphenylacetylide (0.65 ml, 1M in THF) was added to 6-{3-[1-(2-chlorophenyl) cyclopentyl]-2-oxopropionylamino}-4-methyl-2,3-benzoxazin-1 -one (110 mg) at -78 0 C 20 and allowed to reach room temperature under argon during the night. Working up as described for Example 1 and column chromatography on silica gel resulted in the title compound as a foam (54 mg) after oil-pump drying. 1H-NMR (ppm, CDCl 3 , 400 MHz): 1.59 - 1.85 (m, 5H), 2.18 - 2.35 (m, 3H), 2.54 (s, 3H, Me), 2.7 - 3.09 (3H), 6.94 - 7.58 (m, 10H), 8.18 (d, J = 1.1 Hz), 8.25 (d, J = 8.6 Hz, 1H), 8.81 (br. s., 1H, NH). 25 C 31

H

27

CIN

2 0 4 (526.0): HPLCMS: m/z = 526 [M], purity 97%. 73 WO 2006/136461 PCT/EP2006/006531 6-{2-[2-(2,3-Dihydro-7-benzofuranyl)-2-methylpropyl]-2-hydroxy-3 octynoylamino)-4-methyl-2,3-benzoxazin-1 -one 6 O HO H N O O 0 Reaction of 1-hexyne (0.4 ml), nBuLi (0.7 ml, 1.6 M in hexane) and 6-[4-(2,3-dihydro-7 5 benzofuranyl)-4-methyl-2-oxopentanoylamino]-4-methyl-2,3-benzoxazin-1-one (99.5 mg) at -78 0 C in THF (3 ml) as described for Example 1 gave, after column chromatography on silica gel and drying in vacuo, a solidified colourless oil (42 mg). 1H NMR (ppm, CDCI 3 , 400 MHz): 0.89 (t, J =7.2 Hz, 3H, Me), 1.35 - 1.56 (m, 1OH), 2.14 - 2.18 (m, 2H), 2.56 (s, 3H, Me), 2.66 (d, J =14.8 Hz, 1H), 2.73 (d, J = 14.8 Hz, 10 1H), 3.0 -3.2 (m, 2H), 3.27 (s, 1H), 4.57 (t, J = 9.3 Hz, 2H), 6.75 (t, J = 7.5 Hz, 1H), 6.95 (d, J = 6.3 Hz, 1H), 7.05 (d, J = 7.8 Hz, 1H), 7.50 - 7.52 (m, 1H), 8.23 - 8.29 (m, 2H), 8.78 (br. s., NH). C 29

H

32

CIN

2 0 5 (488): LC-MS: m/z = 489 [M + H*]. 15 rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-2-[(4-hydroxyphenyl)ethynyl]-4 methylpentanoylamino)-4-methyl-2,3-benzoxazin-1 -one 7 OH Cl HO/ H N F O O 0 Stage A: a suspension of the compound of Example 10 (57.8 mg), triphenylphosphine 20 (6.8 mg), copper iodide (5 mg), 4-iodophenyl acetate (51 mg), 5 mg of palladium acetate in THF (1 ml) and triethylamine (3 ml) was reacted in an ultrasonic bath under argon for 1 h. Addition of saturated aqueous ammonium chloride solution was followed by extraction with ethyl acetate and washing with water and brine. Drying with sodium sulphate was followed by concentration and purification by column chromatography on 25 silica gel. A white solid (46.7 mg) was obtained. Stage B: A suspension of the compound from stage A (46.7 mg) and sodium bicarbonate (128 mg) in methanol was stirred at room temperature under argon for 6 h. A spatula tip of sodium bicarbonate was then added, and the mixture was stirred overnight. It was diluted with ethyl acetate, 74 WO 2006/136461 PCT/EP2006/006531 water was added, and separation of the phases was followed by extraction with ethyl acetate. Washing of the combined organic phases with brine, drying over sodium sulphate, concentration and column chromatography on silica gel resulted in the title compound as a viscous oil (29 mg). 5 1H-NMR (ppm, CDCI 3 , 400 MHz): 1.63 (s, 3H, Me), 1.69 (s, 3H, Me), 2.56 (s, 3H, Me), 2.94 - 3.01 (m, 3H), 5.48 (br. s, 1 H, OH), 6.74 - 6.77 (m, 2H), 6.84 - 6.93 (m, 2H), 7.21 - 7.25 (m, 2H), 7.43 (dd, J = 9.0, 6.1 Hz, 1H), 7.57 - 7.59 (dd, J = 8.6, 2.3 Hz, 1H), 8.22 - 8.23 (m, 1H), 8.31 (d, J = 8.6 Hz, 1H), 8.80 (br. s, 1H, NH). C 29

H

24 ClFN 2 0s (534.98): LC-MS: m/z = 535 [M + H*]. 10 rac-6-{2-[2-(2-Chloro-4-fluorophenyl)-2-methylpropyl]-2-hydroxydec-3-ynoyl amino}-4-methyl-2,3-benzoxazin-1 -one 8 C1 HO H N F 0 0 0 15 Reaction of 1-octyne (0.4 ml), nBuLi (0.6 ml, 1.6 M in hexane) and 6-[4-(2-chloro-4 fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1 -one (110 mg) in THF (3 ml) at -780C as described for Example 1 gave, after column chromatography on silica gel, a white solid (25 mg). 1 H-NMR (ppm, CDCI 3 , 400 MHz): 0.87 (t, J = 7.0 Hz, 3H), 1.26 - 1.46 (m, 8H), 1.58 (s, 20 3H, Me), 1.63 (s, 3H, Me), 2.12 (t, J = 7.0 Hz, CH 2 C=C), 2.56 (s, 3H, Me)2.79 - 2.91 (m, 3H), 6.92 - 6.95 (m, 2H), 7.40 (dd, J = 8.9, 6.3 Hz, 1H), 7.53 (dd, J = 8.6, 1.9 Hz, 1H), 8.21 (d, J = 1.9 Hz, 1H), 8.30 (d, J = 8.6 Hz, 1H), 8.71 (br. s., 1H, NH); C 29

H

32

CIFN

2 0 4 (527.0): LC-MS: m/z = 527 [M + H*]. 75 WO 2006/136461 PCT/EP2006/006531 rac-6-{2-[2-(2-Chloro-4-fluorophenyl)-2-methylpropyl]-2-hydroxy-5-phenylpent-3 ynoylamino)-4-methyl-2,3-benzoxazin-1 -one 9 CI HO H F / 0 5 Reaction of 3-phenyl-1-propyne (0.17 ml), nBuLi (0.51 ml, 1.6 M in hexane) and 6-[4-(2 chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1 -one (140 mg) in THF (3 ml) at -78 0 C as described for Example 1 gave, after column chromatography on silica gel and drying in vacuo, a white foam (116 mg). 1H-NMR (ppm, CDCl 3 , 400 MHz): 1.59 (s, 3H, Me), 1.61 (s, 3H, Me), 2.55 (s, 3H, Me), 10 2.79 - 2.95 (m, 3H), 3.4 - 3.6 (m, 2H, CH 2 C=C), 6.8 - 6.93 (m, 2H), 7.23 - 7.42 (m, 7H), 8.15 (d, J = 2.3 Hz, IH), 8.27 (d, J = 8.6 Hz, 1H), 8.64 (br. s., 1H, NH).

C

30

H

26

CIFN

2 0 4 (533.0): LC-MS: m/z = 533 [M + H*]. 15 rac-6-{4-(2-Chloro-4-fluorophenyl)-2-ethynyl-2-hydroxy-4-methylpentanoylamino) 4-methyl-2,3-benzoxazin-1 -one 10 C1 HO I/ H 00 F 0 Ethynylmagnesium bromide (2.2 ml, 0.5 M in THF) was added to an ice-cold solution of 20 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin 1-one (208 mg) in THF (4 ml). Under argon, the reaction solution was allowed to reach room temperature over the course of 3 h. Working up as described in Example 1 and column chromatography on silica gel resulted in the title compound as a foam (84 mg) after oil-pump drying. 1H-NMR (ppm, CDCl 3 , 400 MHz): 0.8 - 0.9 (m, 1H), 1-58 (s, 3H, 25 Me), 1.65 (s, 3H, Me), 2.56 - 2.96 (6H), 6.86 - 6.94 (m, 2H), 7.41 (dd, J = 9.0, 6.2 Hz, 1H), 7.56 (dd, J = 8.6, 1.9 Hz, 1H), 8.19 (d, J = 1.9 Hz, 1H), 8.31 (d, J = 8.6 Hz, 1H), 8.63 (br. s., 1H, NH).

C

23

H

20

CIFN

2 0 4 (542.9): LC-MS: m/z = 543 [M + H*]. 76 WO 2006/136461 PCT/EP2006/006531 rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-4-methyl-2-vinyl-pentanoylamino}-4 methyl-2,3-benzoxazin-1 -one 11 C1 HO F 0 5 A vinylmagnesium bromide solution (0.5 ml, 1M in THF) was injected into 6-[4-(2-chloro 4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1-one (103 mg) in THF (3 ml) at -78 0 C, and the mixture was allowed to reach room temp. under argon overnight. Addition of aqueous ammonium chloride solution was followed by extraction 10 with ethyl acetate and washing with sat. sodium chloride solution. Drying with sodium sulphate was followed by concentration in a rotary evaporator and purification by column chromatography on silica gel to result in the title compound as solidified oil (18 mg). 1H-NMR (ppm, CDCl 3 , 400 MHz, selected signals): 1.53 (s, 3H, Me), 1.57 (s, 3H, Me), 2.35 (s, 1H), 2.56 (s, 3H, Me), 2.74 (d, J = 15.3 Hz, 1H), 2.89 (d, J = 15.3 Hz, 15 1H), 5.15 (d, J = 10.5 Hz, 1H), 5.27 (d, J = 17.6 Hz, 1H), 6.10 (dd, J = 17.2, 10.6 Hz, 1 H), 6.81 - 6.86 (m, 1 H), rac-6-{4-(2-Chloro-4-fluorophenyl)-2-hydroxy-2-[(4-methoxyphenyl)ethyny]-4 20 methylpentanoylamino}-4-methyl-2,3-benzoxazin-1 -one 12 0 C HO H NNI F 0 Reaction of 4-methoxyphenylacetylene (0.4 ml), nBuLi (0.6 ml, 1.6 M in hexane) and 25 6-[4-(2-chloro-4-fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin 1-one (110 mg) at -78*C as described for Example 1 gave, after column chromatography on silica gel, the title compound as a white solid (44 mg). 1H-NMR (ppm, CDCl 3 , 400 MHz): 1.63 (s, 3H, Me), 1.69 (s, 3H, Me), 2.91 - 3.01 (m, 3H), 3.81 (s, 3H, Me), 6.81 - 6.94 (m, 3H), 7.25 - 7.29 (m, 3H), 7.43 (dd, J = 8.4, 6.3 77 WO 2006/136461 PCT/EP2006/006531 Hz, 1H), 7.58 (dd, J = 8.6, 2.3 Hz, 1H), 8.24 (d, J = 1.9 Hz, 1H), 8.31 (d, J = 8.6 Hz, 1H), 8.79 (br. s., 1H, NH). C 30

H

26

CIFN

2 0 5 (549.0): LC-MS: m/z = 549 [M + H*]. 5 rac-6-(4-(2-Chloro-4-fluorophenyl)-2-hydroxy-4-methyl-2-(phenylethynyl) pentanoylamino}-4-methyl-2,3-benzoxazin-1 -one 13 N__N - N 00 F 0 Lithium phenylacetylide (0.65 ml, 1M in THF) was added to 6-[4-(2-chloro-4 10 fluorophenyl)-4-methyl-2-oxovaleroylamino]-4-methyl-2,3-benzoxazin-1 -one (136 mg) at -78 0 C and the mixture was stirred at -78*C under argon for 2.5 h. Working up as described for Example 1 and column chromatography on silica gel resulted in the title compound as a white foam (102 mg) after oil-pump drying. 1H-NMR (ppm, CDCl 3 , 400 MHz): 1.64 (s, 3H, Me), 1.70 (s, 3H, Me), 2.57 (s, 3H, Me), 15 2.92 - 3.03 (m, 3H), 6.82 - 6.86 (m, 1 H), 6.91 - 6.93 (m, 1 H), 7.30 - 7.36 (m, 5H), 7.44 (dd, J = 9.0, 6.2 Hz, 1H), 7.59 (dd, J = 8.6, 2.0 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.31 (d, J = 8.2 Hz, 1H), 8.79 (br. s., NH); C 29

H

24

CIFN

2 0 4 (519.0): HPLC-MS: m/z = 518 [M]. The compounds 14 and 15 were prepared in analogy to Example 10 from 6-(4-methyl 20 4-phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1 -one and the alkynyl magnesium halide: rac-6-[2-Ethynyl-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4-methyl-2,3 25 benzoxazin-1-one 14 HO /I H 7, 0 0 1H-NMR (ppm, CDCI 3 , 400 MHz): 1.42 (3H), 1.59 (3H), 2.57 (3H), 2.64 (4H), 7.15 (1H), 7.31 (2H), 7.46 (2H), 7.58 (1H), 8.25 (1H), 8.30 (1H), 8.81 (1H). 30 78 WO 2006/136461 PCT/EP2006/006531 rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-propynylpentanoylamino]-4-methyl-2,3 benzoxazin-1 -one 15 HO H 1 y0 O 5 1H-NMR (ppm, CDCI 3 , 400 MHz): 1.42 (3H), 1.59 (3H), 2.50-2.65 (6H), 7.11 (1H), 7.30 (2H), 7.43 (2H), 7.58 (1H), 8.29 (2H), 8.85 (1H). The compounds 15-28 were prepared in analogy to Example 1 from 6-(4-methyl-4 phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the respective lithium 10 arylacetylide: rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-(phenylethynyl)pentanoylamino]-4-methyl 2,3-benzoxazin-1 -onej 6 15 HO H N N 00 00 1H-NMR (ppm, CDCl 3 , 300 MHz): 1.47 (3H), 1.65 (3H), 2.57 (3H), 2.62-2.78 (3H), 7.15 (1H), 7.27-7.37 (5H), 7.40 (2H), 7.50 (2H), 7.59 (1H), 8.29 (2H), 8.90 (1H). 20 79 WO 2006/136461 PCT/EP2006/006531 (+)-6-[2-Hydroxy-4-methyl-2-[(4-methylphenyl)ethynyl]-4-phenylpentanoylamino] 4-methyl-2,3-benzoxazin-1 -one 17a and (-)-6-[2-Hydroxy-4-methyl-2-[(4-methylphenyl)ethynyl]-4-phenylpentanoylamino] 4-methyl-2,3-benzoxazin-1 -one 1_7b HO H N N 0O 0 5o 1H-NMR (ppm, CDCI 3 , 300 MHz): 1.48 (3H), 1.64 (3H), 2.36 (3H), 2.57 (3H), 2.60-2.80 (3H), 7.08-7.20 (3H), 7.30 (4H), 7.49 (2H), 7.60 (1H), 8.29 (2H), 8.90 (1H). 16a: [a]D 20 : +28.40 (CHCI 3 , 1.03 g/1 00 ml; X=589 nm) 10 16b: [a]D20: -28.6* (CHCI 3 , 1.01 g/100 ml; X=589 nm) rac-6-[2-Hydroxy-2-[(4-methoxyphenyl)ethynyl]-4-methyl-4-phenylpentanoyl amino]-4-methyl-2,3-benzoxazin-1 -one 18 0-~ HO H N_ - N~ 00 15 0 1H-NMR (ppm, CDCI 3 , 300 MHz): 1.47 (3H), 1.63 (3H), 2.56 (3H), 2.60-2.78 (3H), 3.80 (3H), 6.81 (2H), 7.13 (1H), 7.25-7.38 (4H), 7.48 (2H), 7.60 (1H), 8.28 (2H), 8.89 (1H). 20 (+)-6-[2-Hydroxy-2-[(4-methoxyphenyl)ethynyl]-4-methyl-4 phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one j.8a and (-)-6-[2-Hydroxy-2-[(4-methoxyphenyl)ethynyl]-4-methyl-4 phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1-one j18b The racemic mixture which was described in example 18 was separated by preparative 25 chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 18a and 18b. 18a: [a] 20: + 29.30 (CHCI 3 , 1.12 g/100 ml; X=589 nM) 18b : [a] 20: - 30.0* (CHCI 3 , 1.14 g/100 ml; X=589 nM) 80 WO 2006/136461 PCT/EP2006/006531 rac-6-[2-Hydroxy-2-[(4-(N,N-dimethylamino)phenyl)ethynyl]-4-methyl-4-phenyl pentanoylamino]-4-methyl-2,3-benzoxazin-1-one 19 N HO H 00 00 5 1H-NMR (ppm, CDCI 3 , 400 MHz): 1.48 (3H), 1.62 (3H), 2.57 (3H), 2.60-2.75 (3H), 2.98 (6H), 6.58 (2H), 7.12 (1H), 7.23-7.38 (4H), 7.48 (2H); 7.57 (1H), 8.28 (2H), 8.90 (1H). 10 rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-trifluoromethylphenyl)ethynyl] pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 20 F F F HO H 00 15 1H-NMR (ppm, CDC 3 , 400 MHz): 1.48 (3H), 1.63 (3H), 2.57 (3H), 2.64-2.80 (3H), 7.17 (1H), 7.33 (2H), 7.48 (4H), 7.56 (2H), 7.61 (1H), 8.30 (2H), 8.92 (1H). (+)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-trifluormethylphenyl)ethynyl] pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 20a and 20 (-)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-trifluormethylphenyl)ethynyl] pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 20b The racemic mixture which was described in example 20 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 20a and 20b. 20a : [a]D 20 : + 19.90 (CHCl 3 , 1.05 g/100 ml; X=589 nM) 25 20b: [a] 2 0 : - 20.4* (CHCl 3 , 1.01 g/100 ml; X=589 nM) 81 WO 2006/136461 PCT/EP2006/006531 rac-6-[2-[(4-Cyanophenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino] 4-methyl-2,3-benzoxazin-1 -one 21 HO" H N N O 0 5 1H-NMR (ppm, CDCI 3 , 400 MHz): 1.50 (3H), 1.62 (3H), 2.57 (3H), 2.63-2.82 (3H), 7.18 (1H), 7.35 (2H), 7.48 (4H), 7.55-7.68 (2H), 7.62 (1H), 8.30 (2H), 8.94 (1H). 10 (+)-6-[2-[(4-Cyanophenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino] 4-methyl-2,3-benzoxazin-1 -one 21 a and (-)-6-[2-[(4-Cyanophenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4 methyl-2,3-benzoxazin-1 -one 21 b The racemic mixture which was described in example 21 was separated by preparative 15 chiral HPLC (column Chiralpak AD 250x1 0 mm) into the enantiomers 21 a and 21 b. 21a: [C]D 20: + 26.60 (CHCI 3 , 1.12 g/100 ml; X=589 nM) 21b : [a]D20: - 26.8* (CHCI 3 , 1.02 g/100 ml; X=589 nM) 20 rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-phenylphenyl)ethynyl]pentanoylamino] 4-methyl-2,3-benzoxazin-1 -one 22 HO N o 0 0 0 25 1H-NMR (ppm, CDCI 3 , 400 MHz): 1.50 (3H), 1.68 (3H), 2.58 (3H), 2.64-2.81 (3H), 7.18 82 WO 2006/136461 PCT/EP2006/006531 (1 H), 7.30-7.40 (3H), 7.41-7.61 (11 H), 8.30 (2H), 8.92 (1 H). (+)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-phenylphenyl)ethynyl]pentanoylamino] 4-methyl-2,3-benzoxazin-1 -one 22a and 5 (-)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(4-phenylphenyl)ethynyl]pentanoylamino] 4-methyl-2,3-benzoxazin-1 -one 22b, The racemic mixture which was described in example 22 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 22a and 22b. 22a [a]D 20: + 38.4* (CHCl 3 , 1.06 g/100 ml; X=589 nM) 10 22b: [a] 20 : - 30.6* (CHCl 3 , 1.12 g/100 ml; X=589 nM) rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(3-trifluoromethylphenyl)ethynyl] 15 pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 23 F F F HO H N N 0 1H-NMR (ppm, CDCI 3 , 300 MHz): 1.52 (3H), 1.68 (3H), 2.60 (3H), 2.65-2.88 (3H), 7.21 20 (1H), 7.49 (2H), 7.42-7.70 (7H), 8.34 (2H), 8.96 (1H). rac-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(2-trifluoromethylphenyl)ethynyl] pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 24 25 F F F HO H N-N | o 0 0 1H-NMR (ppm, CDCl 3 , 600 MHz): 1.52 (3H), 1.65 (3H), 2.62 (3H), 2.69 (1H), 2.78 (1H), 83 WO 2006/136461 PCT/EP2006/006531 2.91 (1H), 7.11 (1H), 7.32 (3H), 7.51 (3H), 7.57 (2H), 7.70 (1H), 8.20 (1H), 8.45 (1H), 8.75 (1H). (+)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(2-trifluormethylphenyl)ethynyl] 5 pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 24a and (-)-6-[2-Hydroxy-4-methyl-4-phenyl-2-[(2-trifluormethylphenyl)ethynyl] pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 24b The racemic mixture which was described in example 24 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 24a and 24b. 10 24a : [a]D20: + 21.30 (CHCl 3 , 1.00 g/100 ml; X=589 nM) 24b: [C]D 20 : - 19.4' (CHCl 3 , 1.00 g/100 ml; X=589 nM) 15 rac-6-[2-Hydroxy-4-methyl-2-[(4-nitrophenyl)ethynyl]-4-phenylpentanoylamino]-4 methyl-2,3-benzoxazin-1 -one 25

NO

2 HO H 00 | 0 0 20 1H-NMR (ppm, CDCI 3 , 600 MHz): 1.47 (3H), 1.62 (3H), 2.55 (3H), 2.79 (1H), 2.81 (2H), 7.18 (1H), 7.34 (2H), 7.50 (4H), 7.63 (1H), 8.17 (2H), 8.80 (2H), 8.94 (1H). rac-6-[2-[[4-(1,1 -Dimethylethyl)phenyl]ethynyl]-2-hydroxy-4-methyl 25 4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 26 HO H N -N 00 O 0 84 WO 2006/136461 PCT/EP2006/006531 1H-NMR (ppm, CDCl 3 , 300 MHz): 1.32 (9H), 1.51 (3H), 1.68 (3H), 2.62 (3H), 2.65-2.82 (3H), 7.18 (1H), 7.30-7.40 (6H), 7.52 (2H), 7.63 (1H), 8.32 (2H), 8.93 (1H). 5 rac-6-[2-Hydroxy-4-methyl-2-[(3-methylphenyl)ethynyl]-4-phenylpentanoylamino] 4-methyl-2,3-benzoxazin-1 -one 27 HO H N N 0I 0 100 1H-NMR (ppm, CDCI 3 , 400 MHz): 1.47 (3H), 1.63 (3H), 2.30 (3H), 2.58 (3H), 2.62-2.80 (3H), 7.12-7.26 (5H), 7.32 (2H), 7.50 (2H), 7.60 (1 H), 8.30 (2H), 8.90 (1 H). 15 rac-6-[2-Hydroxy-4-methyl-2-[(2-methylphenyl)ethynyl]-4-phenylpentanoylamino] 4-methyl-2,3-benzoxazin-1 -one 28 HO H N N 0 o 0 20 1H-NMR (ppm, CDCl 3 , 300 MHz): 1.47 (3H), 1.65 (3H), 2.38 (3H), 2.58 (3H), 2.62-2.80 (3H), 7.08-7.42 (7H), 7.49 (2H), 7.60 (1H), 8.22-8.36 (2H), 8.90 (1H). rac-6-[2-(3,3-Dimethylbutynyl)-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4 25 methyl-2,3-benzoxazin-1 -one 29 85 WO 2006/136461 PCT/EP2006/006531 HO H N -O 00 00 1H-NMR (ppm, CDCl 3 , 300 MHz): 1.20 (9H), 1.43 (3H), 1.60 (3H), 2.46 (1H), 2.50-2.63 (5H), 7.11 (1H), 7.28 (2H), 7.43 (2H), 7.54 (1H), 8.22 (1H), 8.29 (1H), 8.32 (1H). 5 The following compound was prepared in analogy to Example 7 from the compound described in Example 13 and 4'-iodoacetophenone: 10 rac-6-[2-[(4-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino] 4-methyl-2,3-benzoxazin-1 -one 30 0 HO H N - N 0 O 15 1H-NMR (ppm, CDCl 3 , 300 MHz): 1.48 (3H), 1.63 (3H), 2.56 (3H), 2.60 (3H), 2.63-2.82 (3H), 7.18 (1H), 7.33 (2H), 7.40-7.56 (4H), 7.62 (1H), 7.90 (2H), 8.30 (2H), 8.93 (1H). (+)-6-[2-[(4-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4 methyl-2,3-benzoxazin-1 -one 30a and 20 (-)-6-[2-[(4-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino]-4 methyl-2,3-benzoxazin-1 -one 30b The racemic mixture which was described in example 30 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 30a and 30b. 30a : [a]D 2 0: + 31.3* (CHCl 3 , 1.09 g/1 00 ml; X=589 nM) 25 30b: [a]D 20: - 28.4* (CHCI 3 , 1.09 g/100 ml; X=589 nM) 86 WO 2006/136461 PCT/EP2006/006531 The compounds 30 and 31 were prepared in analogy to Example 1 from 6-[3-[1-(2 fluoro-5-trifluoromethylphenyl)cyclopropyl]-2-oxopropionylamino]-4-methyl-2,3 benzoxazin-1-one 5 rac-6-[2-[(2-Fluoro-5-trifluoromethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4 trifluoromethylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1 -one 31 F F F F HO H 00 00 F F F 10 1H-NMR (ppm, CDCI 3 , 400 MHz): 0.90 (1H), 1.00-1.15 (3H), 2.51 (1H), 2.55 (3H), 2.68 (1H), 3.18 (1H), 7.01 (1H), 7.30 (1H), 7.41 (2H), 7.56 (2H), 7.63 (1H), 7.68 (1H), 8.19 (1H), 8.31 (1H), 8.98 (1H). 15 (+)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4 trifluormethylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1 -one 31a and (-)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4 trifluormethylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1 -one 31 b 20 The racemic mixture which was described in example 31 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 31a and 31b. 31a: [a]D 2 0 : + 2.30 (CHCl 3 , 1.00 g/100 ml; X=589 nM) 31b: [a]D20: - 1.90 (CHCl 3 , 1.00 g/100 ml; X=589 nM) 25 87 WO 2006/136461 PCT/EP2006/006531 rac-6-[2-[(2-Fluoro-5-trifl uoromethyl phenyl)cyclopropylmethyl]-2-hyd roxy-4-(4 methylphenyl)but-3-ynoylamino]-4-methyl-2,3-benzoxazin-1 -one 32 F HO O 0 0 F F F 5 1H-NMR (ppm, CDCI 3 , 400 MHz): 0.88 (1H), 0.98-1.13 (3H), 2.34 (3H), 2.44 (1H), 2.55 (3H), 2.70 (1H), 3.02 (1H), 7.01 (1H), 7.10 (2H), 7.22 (2H), 7.30 (1H), 7.64 (2H), 8.19 (1H), 8.31 (1H), 8.98 (1H). 10 (+)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4 methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1 -one 32a and (-)-6-[2-[(2-Fluor-5-trifluormethylphenyl)cyclopropylmethyl]-2-hydroxy-4-(4 methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1 -one 32b The racemic mixture which was described in example 32 was separated by preparative 15 chiral HPLC (column Chiralpak AD 250x1 0 mm) into the enantiomers 32a and 32b. 32a [a]D20: + 8.6* (CHC13, 1.00 g/1 00 ml; X=589 nM) 32b: [a]D 20 : - 8.7' (CHCl 3 , 1.00 g/100 ml; ?=589 nM) The following compound was prepared in analogy to example 7 from compound which 20 was described in example 14 and 3'-Iodacetophenon: rac-6-[2-[(3-Acetylphenyl)ethynyl]-2-hydroxy-4-methyl-4-phenylpentanoylamino] 4-methyl-2,3-benzoxazin-1 -one 33 0 HO H N N 0 00 0 o 25 1H-NMR (ppm, CDCl 3 , 300 MHz): 1.49 (3H), 1.63 (3H), 2.57 (6H), 2.62-2.81 (3H), 7.16 81 H), 7.28-7.70 (7H), 7.90-8.00 (2H), 8.30 (2H), 8.94 (1 H). 88 WO 2006/136461 PCT/EP2006/006531 Compounds 34 and 35 were prepared in analogy to example 1 from 6-(4-Methyl-4 phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1 -one and the according Lithium arylacetylide. 5 rac-6-[2-[(2,5-Dimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4 phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 34 HO NHN N_, - 1 0 10 1H-NMR (ppm, CDCI 3 , 400 MHz): 1.49 (3H), 1.62 (3H), 2.27 (3H), 2.33 (3H), 2.57 (3H), 2.65-2.78 (3H), 7.03 (2H), 7.13 (2H), 7.30 (2H), 7.50 (2H), 7.61 (1H), 8.22 (1H), 8.30 (1H), 8.89 (1H). 15 rac-6-[2-[(2,4,5-Trimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4 phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 35 HO H N - N 00 O O 0 20 1H-NMR (ppm, CDCl 3 , 400 MHz): 1.47 (3H), 1.64 (3H), 2.18 (3H), 2.21 (3H), 2.30 (3H), 2.56 (3H), 2.65-2.77 (3H), 6.93 (1H), 7.12 (2H), 7.30 (2H), 7.48 (2H), 7.59 (1H), 8.22 (1 H), 8.29 (1 H), 8.90 (1 H). 25 (+)-6-[2-[(2,4,5-Trimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4 phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 35a and (-)-6-[2-[(2,4,5-Trimethylphenyl)ethynyl]-2-hydroxy-4-methyl-4 phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 35b 89 WO 2006/136461 PCT/EP2006/006531 The racemic mixture which was described in example 35 was separated by preparative chiral HPLC (column Chiralpak AD 250x1 0 mm) into the enantiomers 35a and 35b. 35a: [a]D 20: + 30.6* (CHCl 3 , 0.97 g/100 ml; X=589 nM) 35b : [a]D 20 : - 28.0* (CHCl 3 , 0.96 g/100 ml; X=589 nM) 5 The following compound was prepared in analogy to example 9 from 3-Phenyl-1 propine, nBuLi and 6-(4-Methyl-4-phenyl-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin 1-one: 10 rac-6-{2-(2-phenyl)-2-methylpropyl]-2-hydroxy-5-phenylpent-3-inoylamino)-4 methyl-2,3-benzoxazin-1 -one 36 HO\ H O - 0 O 1H-NMR (ppm, CDCI 3 , 400 MHz): 1.42 (3H), 1.53 (3H), 2.55-2.70 (6H), 3.58 (2H), 7.11 15 (1H), 7.20-7.35 (7H), 7.41 (2H), 7.48 (1H), 8.20 (1H), 8.28 (1H), 8.80 (1H). Compounds 37 and 38 were prepared in analogy to example 1 from 6-(4-Methyl-4-(2 chlor-6-fluorphenyl)-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1-one and the 20 according Lithium arylacetylide. rac-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-methylphenyl ethinyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 37 F HO H N N~ N I 00 F 0 0 25 1H-NMR (ppm, CDC 3 , 300 MHz): 1.73 (3H), 1.82 (3H), 2.33 (3H), 2.57 (3H), 2.88-3.02 (3H), 6.75-6.96 (2H), 7.01 (1H), 7.09 (2H), 7.27 (2H), 7.60 (1H), 8.22-8.35 (2H), 8.96 (1 H). 90 WO 2006/136461 PCT/EP2006/006531 (+)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-methylphenyl ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 37a and (-)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-methylphenyl 5 ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 37b The racemic mixture which was described in example 37 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 37a and 37b. 37a: [a]D 2 0: + 21.5* (CHCI 3 , 1.00 g/100 ml; X=589 nM) 37b: (a]D 20 : - 21.0" (CHCl 3 , 1.04 g/100 ml; X=589 nM) 10 rac-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-(trifluormethyl)phenyl ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 38 CF, C HOO 15 F 0 1H-NMR (ppm, CDCI 3 , 400 MHz): 1.60 (3H), 1.93 (3H), 2.36 (1H), 2.56-2.72 (5H), 7.04 (1H), 7.14 (2H), 7.45 (2H), 7.53 (2H), 7.80 (1H), 8.35-8.45 (2H), 8.90 (1H). 20 (+)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-(trifluormethyl)phenyl ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 38a and (-)-6-[2-Hydroxy-4-methyl-4-(2-chlor-6-fluorphenyl)-2-(4-(trifluormethyl)phenyl ethynyl)pentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 38b The racemic mixture which was described in example 38 was separated by preparative 25 chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 38a and 38b. 38a: [a] 20 : + 143.2* (CHC 3 , 1.05 g/1 00 ml; X=589 nM) 38b : [a]D 20 : - 137.8* (CHCl 3 , 1.12 g/100 ml; X=589 nM) 30 Compounds 39 and 40 were prepared in analogy to example 1 from 6-(4-Methyl-4-(2 chlorphenyl)-2-oxovaleroylamino)-4-methyl-2,3-benzoxazin-1 -one and the according Lithium arylacetylide. 91 WO 2006/136461 PCT/EP2006/006531 rac-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylphenyl)but-3 inoylamino]-4-methyl-2,3-benzoxazin-1 -one 3 C HO H N_ - N oI 5 0 1H-NMR (ppm, CDCI 3 , 400 MHz): 0.84 (1H), 1.00 (1H), 1.08-1.22 (2H), 2.36 (3H), 2.53 (3H), 2.90 (1H), 7.03-7.18 (4H), 7.23-7.38 (3H), 7.50 (1H), 7.60 (1H), 8.22 (1H), 8.29 (1H), 8.91 (1H). 10 (+)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylphenyl)but-3 inoylamino]-4-methyl-2,3-benzoxazin-1 -one 39a and (-)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-methylpheny)but-3 inoylamino]-4-methyl-2,3-benzoxazin-1 -one 39b 15 The racemic mixture which was described in example 39 was separated by preparative chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 39a and 39b. 39a: [a]D 2 0: + 30.80 (CHCI 3 , 1.00 g/1 00 ml; X=589 nM) 39b : [a]D 20 : - 28.3* (CHCl 3 , 1.00 g/100 ml; X=589 nM) 20 rac-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluor methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1 -one 40 CF, 'II Ci HO ON a 0 00 25 92 WO 2006/136461 PCT/EP2006/006531 1H-NMR (ppm, CDCl 3 , 300 MHz): 0.91 (1H), 1.02 (1H), 1.08-1.25 (2H), 2.53 (3H), 3.00 (1H), 7.02-7.18 (2H), 7.28 (1H), 7.42-7.54 (3H), 7.55-7.67 (3H), 8.22 (1H), 8.32 (1H), 8.91 (1H). 5 (+)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluor methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1 -one 40a and (-)-6-[2-(2-Chlorphenyl)cyclopropylmethyl]-2-hydroxy-4-(4-trifluor methylphenyl)but-3-inoylamino]-4-methyl-2,3-benzoxazin-1 -one 40b The racemic mixture which was described in example 40 was separated by preparative 10 chiral HPLC (column Chiralpak AD 250x10 mm) into the enantiomers 40a and 40b. 40a : [a]D 2 0: + 20.90 (CHCI 3 , 1.06 g/100 ml; X=589 nM) 40b: [a]D20: - 20.6o (CHCI 3 , 1.05 g/100 ml; X=589 nM) 15 rac-6-[2-[[3-(1 -Hydroxy-1 -methylethyl)phenyl]ethynyl]-2-hydroxy-4-methyl 4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 41 OH HO H 7 0 00 20 59 pl of 3 molar solution of Methylmagnesium chloride was diluted with 1 ml of pure Tetrahydrofurane. The solution was cooled to -70 0 C and a solution of 30 mg of the compound which was described in example 33 in 0,5 ml of pure Tetrahydrofurane was added. After stirring for 2,5 hours at -70 0 C the mixture was given to a saturated solution of ammonium chloride. After extracting the mixture with Ethyl acetate the combined 25 organic phases were washed with saturated sodium chloride and dried over sodium sulphate. After column chromatography 16 mg of the product was obtained. 1 H-NMR (ppm, CDCI 3 , 400 MHz): 1.46 (3H), 1.53 (6H), 1.62 (3H), 1.80 (1H), 2.55 (3H), 2.65-2.90 (3H), 7.12 (1H), 7.30 (3H), 7.40-7.52 (3H), 7.53 (1H), 7.60 (1H), 8.27 (2H), 8.95 (1 H). 30 The following compound was prepared in analogy to example 7 from the compound which was described in example 14 and 4-lodobenzylalcohol: 93 WO 2006/136461 PCT/EP2006/006531 rac-6-[2-[[4-(Hydroxymethyl)phenyl]ethynyl]-2-hydroxy-4-methyl 4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 42 5 OH HO 00 1H-NMR (ppm, CDC 3 , 300 MHz): 1.47 (3H), 1.60 (3H), 1.80 (1H), 2.57 (3H), 2.62-2.83 (3H), 4.68 (2H), 7.13 (1H), 7.25-7.43 (6H), 7.48 (2H), 7.59 (1H), 8.25-8.32 (2H), 8.91 10 (1H). The following compound was prepared in analogy to example 7 from the compound which was described in example 14 and 4-lodobenzylalcohol: rac-6-[2-[[3-(Hydroxymethyl)phenyl]ethinyl]-2-hydroxy-4-methyl 15 4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 43 HO HO H N 0 0 1H-NMR (ppm, CDCl 3 , 400 MHz): 1.48 (3H), 1.62 (3H), 1.79 (1H), 2.57 (3H), 2.62-2.80 20 (3H), 4.68 (2H), 7.15 (1H), 7.25-7.39 (5H), 7.40 (1H), 7.49 (2H), 7.60 (1H), 8.29 (2H), 8.91 (1H). The following compound was prepared in analogy to example 41 from the compound which was described in example 30 and a solution of Methyl magnesium chloride: 25 rac-6-[2-[[4-(1 -Hydroxy-1 -methylethyl)phenyl]ethynyl]-2-hydroxy-4-methyl 4-phenylpentanoylamino]-4-methyl-2,3-benzoxazin-1 -one 44 94 WO 2006/136461 PCT/EP2006/006531 HO HOO 10 0 1H-NMR (ppm, CDCI 3 , 400 MHz): 1.47 (3H), 1.55 (6H), 1.62 (3H), 1.70 (1H), 2.55 (3H), 2.60-2.80 (3H), 7.14 (1H), 7.28-7.40 (4H), 7.41 (2H), 7.48 (2H), 7.60 (1H), 8.25-8.32 5 (2H), 8.90 (1H). 10 15 20 95

Claims (12)

1. Compounds of the general formula I R R 0 5 O R' and R 2 are independently of one another a hydrogen atom, a linear or nonlinear, branched or unbranched C 1 -C 5 -alkyl group, further forming together with the C atom of the chain a ring having a total of 3-7 10 members, R 3 is a radical C=C-Ra, where Ra is a hydrogen or a C 1 -CB-alkyl, C 2 -CB-alkenyl, C 2 -C 8 alkynyl, C 3 -C 1 o-cycloalkyl, heterocycloalkyl optionally substituted one or more times, identically or differently, by 15 K, or an aryl or heteroaryl optionally substituted one or more times, identically or differently by L, K is a cyano, halogen, hydroxy, nitro, -C(O)Rb, CO 2 Rb, -0-R, -S-Rb, SO 2 NRcRd, -C(O)-NRcRd, -OC(O)-NRcRd, -C=NORb -NRcRd or C 3 -C 10 -cyclo 20 alkyl, heterocycloalkyl optionally substituted one or more times, identically or differently, by M, or aryl or heteroaryl optionally substituted one or more times by L, L is C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C 1 -C 6 25 perfluoroalkyl, C 1 -C 6 -perfluoroalkoxy, C 1 -C 6 -alkoxy C 1 -C 6 -alkoxy, (CH 2 )p-C 3 -C 1 o-cycloalkyl, (CH 2 )p heterocycloalkyl, (CH 2 )pCN, (CH 2 )pHal, (CH 2 )pNO 2 , (CH 2 )p-C 6 -C 12 -aryl, (CH 2 )p-heteroaryl, -(CH 2 )pPO 3 (R) 2 , 30 -(CH 2 )pNRcRd, -(CH 2 )pNReCORb, -(CH 2 )pNReCSRb, -(CH 2 )pNReS(O)Rb, -(CH 2 )pNReS(O) 2 Rb, -(CH 2 )pNReCONRcRd, 96 WO 2006/136461 PCT/EP2006/006531 -(CH 2 )pNReCOORb, -(CH 2 )pNReC(NH)NRcRd, -(CH 2 )pNReCSNRcRd, -(CH 2 )pNReS(O)NRcRd, -(CH 2 )pNReS(O) 2 NRcRd, -(CH 2 )pCORb, -(CH 2 )pCSRb, -(CH 2 )pS(O)Rb, 5 -(CH 2 )pS(O)(NH)R , -(CH 2 )pS(O) 2 Rb, -(CH 2 )pS(O) 2 NRcRd, -(CH 2 )pSO 2 ORb, -(CH 2 )pCO 2 Rb, -(CH 2 )pCONRcRd, -(CH 2 )pCSNRcRd, -(CH 2 )pOR , -(CH 2 )pSRb, (CH 2 )pCR (OH)-R*, -(CH 2 )p-C=NOR, 10 -O-(CH 2 )n-O-, -O-(CH 2 )n-CH 2 -, -O-CH=CH- or -(CH 2 )n. 2 -, where n is 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring carbon atoms, M is C 1 -C 6 -alkyl or a group -COR , CO 2 R , -O-R , 15 or -NRcRd, where R b is a hydrogen or a Cl-C 6 -alkyl, C 2 -C 8 alkenyl, C 2 -C 8 -alkynyl, C 3 -Cl 0 cycloalkyl, C 6 -C 12 -aryl or C 1 -C 3 20 perfluoroalkyl and Rc and Rd are independently of one another a hydrogen, Cl-C 6 -alkyl, 0 2 -C 8 -alkenyl, C 2 -C 8 -alkynyl, C 3 -Clo-cycloalkyl, C 6 -C 12 -aryl, C(O)R b or a hydroxy 25 group, where if Rc is a hydroxy group, then R d can only be a hydrogen, a C 1 -C 6 -alkyl, 0 2 -C 8 alkenyl, C 2 -CB-alkynyl, C 3 -Cl 0 cycloalkyl or C 6 -C 12 -aryl and vice 30 versa, and Re is a hydrogen, C 1 -C 6 -alkyl, C 2 -C 8 alkenyl, C 2 -C 8 -alkynyl, C 3 -C10-cyclO alkyl or C 6 -C 12 -aryl, and p can be a number from 0-6, 35 or 97 WO 2006/136461 PCT/EP2006/006531 R 3 is a radical C=C-RgR , where R9 and Rh are independently of one another a hydrogen or a C 1 -C 8 -alkyl, C 2 -C 8 -alkenyl or C 2 -C 8 -alkynyl optionally substituted one or more times, identically 5 or differently, by X, in which X is a cyano, halogen, hydroxy, nitro, -C(O)R , CO 2 Rb, -O-R, -C(O)-NRcRd, -NRcRd with the meanings already mentioned before for Rb, Rc and Rd, and 10 R 4 is a hydrogen atom, a methyl or an ethyl group or a partly or completely fluorinated C,-C 3 -alkyl group, A is a mono- or bicyclic carbocyclic or heterocyclic aromatic ring which may optionally be substituted one or more times by C 1 -C 8 -alkyl, C 2 -C 8 15 alkenyl, C 2 -C 8 -alkynyl, C 1 -C 6 -perfluoroalkyl, C 1 -C 6 -perfluoroalkoxy, C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy-C 1 -C 6 -alkoxy, (CH 2 )p-C 3 -CO cycloalkyl, (CH 2 )p-heterocycloalkyl, (CH 2 )pCN, (CH 2 )pHal, (CH 2 )pNO 2 , (CH 2 )p-C 8 -C 12 -aryl, (CH 2 )p-heteroaryl, -(CH 2 )pPO 3 (Rb) 2 , -(CH 2 )pNRcRd, -(CH 2 )pNReCORb, -(CH 2 )pNReCSRb, 20 -(CH 2 )pNReS(O)Rb, -(CH 2 )pNReS(O) 2 Rb, -(CH 2 )pNReCONRcRd, -(CH 2 )pNReCOORb, -(CH 2 )pNReC(NH)NRcRd, -(CH 2 )pNReCSNRcRd, -(CH 2 )pNReS(O)NRcRd, -(CH 2 )pNReS(O) 2 NRcRd, -(CH 2 )pCORb, -(CH 2 )pCSR , -(CH 2 )p S(O)R, -(CH 2 )pS(O)(NH)R , -(CH 2 )pS(O) 2 Rb, -(CH 2 )pS(O) 2 NRcRd, -(CH 2 )pSO 2 ORb, -(CH 2 )pCO 2 Rb, -(CH 2 )pCONRcRd, 25 -(CH 2 )pCSNRcRd, -(CH 2 )pOR , -(CH 2 )pSR , -(CH 2 )pCR (OH)-Rd, -(CH 2 )p-C=NORb, -O-(CH 2 )n-O-, -O-(CH 2 )n-CH 2 -, -O-CH=CH- or -(CH 2 )n+ 2 -, where n is 1 or 2, and the terminal oxygen atoms and/or carbon atoms are linked to directly adjacent ring carbon atoms, or 30 A is a radical -CO 2 R , C(O)NRcRd, CORb, or A is an alkenyl group -CR 5 =CR R , where 35 R , R and R are identical or different and are independently of one another hydrogen atoms, halogen atoms, aryl 98 WO 2006/136461 PCT/EP2006/006531 radicals or an unsubstituted or partly or completely fluorinated C,-C 5 -alkyl group, or A is an alkynyl group -C=CR , with the meaning stated above for R , and 5 B is a carbonyl or a CH 2 group and their pharmaceutically acceptable salts.

2. Compounds according to Claim 1, in which R' and R 2 are preferably a hydrogen 10 atom, a methyl or ethyl group.

3. Compounds according to Claim 1, in which R' and R 2 preferably form together with the C atom of the chain a ring having a total of 3-7 members. 15 4. Compounds according to Claim 1 to 3, in which R 3 is preferably alkenyl, alkynyl, arylalkynyl, heteroarylalkynyl, cycloalkylalkynyl, heterocycloalkylalkynyl.

5. Compounds according to any of the preceding claims, in which R 3 is preferably a vinyl, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, 20 hydroxypropynyl, hydroxybutynyl, 3-hydroxy-3-methylbutynyl, hydroxypentynyl, carboxypropynyl, t-butylcarboxypropynyl, phenylethynyl, (hydroxyphenyl)ethynyl, (methoxyphenyl)ethynyl, (dimethylaminophenyl)ethynyl, (methylphenyl)ethynyl, (cyanophenyl)ethynyl, (trifluoromethyl)ethynyl, (diphenyl)ethynyl, (nitrophenyl)ethynyl, (tert-butylphenyl)ethynyl, (acetylphenyl)ethynyl, 25 (acetoxyphenyl)ethynyl, (carboxyphenyl)ethynyl or a benzylethynyl group.

6. Compounds according to any of the preceding claims, in which A is preferably an aromatic ring. 30 7. Compounds according to any of the preceding claims, in which A is preferably a phenyl or naphthyl radical.

8. Compounds according to Claim 7, in which A is preferably an unsubstituted or optionally mono- or polysubstituted phenyl radical. 35

9. Compounds according to Claim 8, where the phenyl radical is preferably substituted 99 WO 2006/136461 PCT/EP2006/006531 by one or two halogen atoms or one trifluoromethyl group.

10. Compounds according to Claim 9, in which the halogen atoms are preferably chlorine and/or fluorine. 5

11. Compounds according to Claims 1-8, in which A is preferably a phenyl ring substituted by -O-(CH 2 )n-O- or -O-(CH 2 )n-CH 2 -, where the respectively directly adjacent ring carbon atoms are linked. 10 12. Compounds according to any of the preceding claims, in which R 4 is a hydrogen atom, a methyl or a trifluoromethyl radical.

13. Compounds according to Claim 1 to 5, namely No. Racemic or R3 enantiomer 1 rac R 3 OH 2 7/ H 3 + 0 4 rac 0 5 + 0 6 0 7 rac H 8 + 9 10 rac 11 + 12 13 rac 14 + 15 16 rac 17 + 18 19 rac 20 + 21 22 rac 0 23 + 24 25 rac 26 + 27 28 rac CF, 29 +1 30 _ _ _ _ _ _ _ _ _ 100 WO 2006/136461 PCT/EP2006/006531 31 rac 32 + 33 L 34 rac 35 + 36 37 rac 0 38 + 39 40 rac 41 + 42 43 rac 44 + 45 46 rac 47 + NO, 48 49 rac O 50 + 51 No. Racemic or R3 enantiomer R OH 52 rac ci 53 H N 54 + N 55 rac 0 0 56 + F 0 57 58 rac 59 + 60 61 rac 62 + 63 64 rac 65 + 66 67 rac CF, 68 + 69 70 rac 71+ 72N 73 rac 74 + 75N 76 rac 77 + 78 101 WO 2006/136461 PCT/EP2006/006531 79 rac F, 80 + 81 82 rac N 83 + 84 85 rac 86 + 87 88 rac 89 + 90 91 rac N 92 + 93 94 rac 95 + 96 97 rac NO, 98 + 99 100 rac 191 + 102 103 rac OH 104 + 105 No. Racemic or R3 enantiomer R3 106 rac OH 107 H 108 + N 109 rac 0 0 110 + 0 112 rac H 113 + 114 115 rac 116 + 117 118 rac 119 + 120 121 rac 122 + 123 124 rac I 125 + N 126 102 WO 2006/136461 PCT/EP2006/006531 127 rac * 128 + 129 130 rac 131 + 132 133 rac 134 + 135 136 rac 137 + 138 139 rac 140 + 141 142 rac 143 + 144 145 rac -N 146 + 147 148 rac 149 + 150 151 rac 152 + NO, 153 154 rac 155 + 156 157 rac 158 + 159 160 rac 161 + 162 163 rac 164 + 165 166 rac - 167 + I 168 No. Racemic or R3 enantiomer R 3 169 rac OH 170 H 171 + N 172 rac 0 0 173 + 174 103 WO 2006/136461 PCT/EP2006/006531 175 rac 176 + 177 178 rac 179 + 180 181 rac 182 + 183 184 rac 185 +CF 186 187 rac 188 + 189 190 rac 191 + 192 193 rac 194 + 195 196 rac 197 + 198 199 rac 200 + 201 202 rac 203 + 204 205 rac 206 + 0 207 208 rac N 209 + 210 211 rac 212 + 213 214 rac NO2 215 + 216 217 rac 218 + 219 220 rac 221 + 222 223 rac 224 + 225 104 WO 2006/136461 PCT/EP2006/006531 226 rac 227 + 228 229 rac OH_ 230 + 231 No. Racemic or R3 R O enantiomer OH 232 rac H F 3 233 NN 234 + 0 - 0 235 rac 236 + 237 238 rac 239 + H 240 241 rac 242 + 243 244 rac 245 + 246 247 rac 248 + 249 250 rac 251 + 252N 253 rac 0 254 + 255 256 rac 257 + 258 259 rac CF 260 + 261 262 rac 263 + 264 265 rac 266 + 267 268 rac 269 + 270 271 rac 272 + 12730 105 WO 2006/136461 PCT/EP2006/006531 274 rac 275 + 276 277 rac 278 + NO2 279 280 rac 281 + 282 283 rac CF 284 + 285 286 rac 287 + 288 289 rac 290 + 291 292 rac 293 + 294 No. Racemic or R3 enantiomer R 3 295 rac OH 296 H 297 + N N 298 rac 0 0 299 + F 0 300 301 rac 302 + H 303 304 rac 305 + 306 307 rac 308 + 309 310 rac 311 + CF. 312 313 rac 314 + 315 316 rac 317 + 317 319 rac 320 + 321 1 106 WO 2006/136461 PCT/EP2006/006531 322 rac 323 + 324 325 rac 326 + 327 328 rac 329 + 330 331 rac 332 + 333 334 rac N 335 + N 336 337 rac 338 + 339 340 rac 2 - NOr 343 rac 344 + 345 346 rac CF 347 + 348 349 rac 350 + 351 352 rac 353 + 354 355 rac OH 356 + 357 No. Racemic or R3 enantiomer R 3 358 rac 359 - H 360 + N 361 rac 0 0 362 + 363 364 rac 365 + 366 367 rac 368 + 369 107 WO 2006/136461 PCT/EP2006/006531 370 rac 371 + 372 373 rac CF3 374 + 375 376 rac 377 + . N.. 378 379 rac 380 + 381 382 rac 383 + 384 385 rac F 386 + 387 388 rac 389 + 390 391 rac 392 + 393 394 rac 395 + 396N 397 rac N 398 + N 399 400 rac 401 + 402 403 rac 404 + N 405 406 rac 407 + 408 409 rac CF 410 + 411 412 rac 413 + 414 415 rac 416 + 417 418 rac 419 + 4201 108 WO 2006/136461 PCT/EP2006/006531 No. Racemic or R3 enantiomer 421 rac R 3 422 -R OH 423 + H 424 rac N N 425 + 0 0 426 427 rac 428 + H 429 430 rac 431 + 432 433 rac 434 + 435 436 rac CF 437 + 438 439 rac 440 + 441 442 rac 443 + 4 445 rac 446 + 447 448 rac CF 449 + 450 451 rac 452 + 453 454 rac 455 + 456 457 rac 458 + 459 460 rac N 461 + 462 463 rac 464 + 465 466 rac 467 + NO, 468N 469 rac 4701 471N 109 WO 2006/136461 PCT/EP2006/006531 472 rac CF 473 + 474 475 rac 476 + 477 478 rac 479 + 480 481 rac OH 482 + 483 No. Racemic or R3 enantiomer Ra 484 rac NO 485 H 486 + N N 487 rac 0 0 488 + F 0 489 490 rac 491 + H 492 493 rac 494 + 495 496 rac 497 + 498 499 rac 500 + CF 501 502 rac 503 + 504 505 rac 506 + 507 508 rac 509 + 510 511 rac CF 512 + 513 514 rac 515 + 516 517 rac 518 + 519 -_ 110 WO 2006/136461 PCT/EP2006/006531 520 rac 521 + 522 523 rac N 524 + 525 526 rac 527 + 528 -_-' 529 rac N, 530 + 531 532 rac 533 + 534 535 rac 536 + 537 538 rac 539 + ) 540 541 rac 542 + 543 544 rac 545 + 546 No. Racemic or R3 enantiomer R3 547 rac OH 548 -/FH 549 + CF 3 N I N 550 rac 0 0 551 + 0 552 553 rac H 554 + 555 556 rac 557 + 558 559 rac 560 + 561 562 rac 563 + CF, 564 565 rac 566 + 567N WO 2006/136461 PCT/EP2006/006531 568 rac 569 + 570 571 rac 572 + 573 574 rac 575 + 576 577 rac 578 + 579 | 580 rac 581 + 582 583 rac 584 + 585 586 rac 587 + 588 589 rac 590 + 591 592 rac 0O 593 + 594 595 rac 596 + 597 598 rac 599 + CF 600 601 rac 602 + 603 604 rac 605 + 606 607 rac OH 608 + 609 No. Racemic or R3 enantiomer 610 rac Ra OH 611 6 / H 612 + N 613 rac 0 0 614 + F O O 615 -_CFa 0 112 WO 2006/136461 PCT/EP2006/006531 616 rac 617 + 618 619 rac 620 + 621 622 rac 623 + 624 625 rac 626 + 627 628 rac 629 + N 630 631 rac 632 + 633 634 rac 635 + 636 637 rac F 638 + 639 640 rac 641 + 642 643 rac 644 + 645 646 rac 647 + 648 649 rac N 650 + 651 652 rac 653 + 654N 655 rac 656 +NO

657-N 658 rac 659 + 660 661 rac CF, 662 + 663 664 rac 665 + 666 113 WO 2006/136461 PCT/EP2006/006531 667 rac 668 + 669 670 rac OH 671 + 672 1 No. Racemic or R3 enantiomer Ra3 OH 673 rac F 674 H 675 + N 676 rac 0 0 677 + cF 0 678 679 rac H 680 + 681 682 rac 683 + 684 685 rac 686 + 687 688 rac CF, 689 + 690 691 rac 692 + 693 694 rac 695 + 696 697 rac 698 + 699 700 rac CF 701 + 702 703 rac 704 + 705 706 rac 707 + 708 709 rac 710 + 0 711 712 rac 713 + 714 114 WO 2006/136461 PCT/EP2006/006531 715 rac 716 + 717N 718 rac NO 719 + 720 721 rac 722 + N 723 724 rac CF 725 + 726 727 rac 728 + 729 730 rac 731 + 732 733 rac 734 + OH 735 No. Racemic or R3 enantiomer R 3 736 rac 737 H 738 + N 739 rac 0 0 740 + o 741 742 rac H 743 + 744 745 rac 746 + 747 748 rac 749 + 750 751 rac 752 CF 753 754 rac 755 + - N-.. 756 N 757 rac 0 758 + 759 760 rac 761 + 762 115 WO 2006/136461 PCT/EP2006/006531 763 rac F 764 + 765 -o 766 rac V 767 + 768 769 rac 770 + 771 772 rac O 773 + 774 775 rac N 776 + 777 778 rac 779 + 780 781 rac 782 + NO, 783 784 rac 785 + 786 787 rac 788 + 789 790 rac 791 + 792 793 rac 794 + 795 796 rac 797 + N 798 No. Racemic or R3 R enantiomer OH 799 rac -o 800 N N 801 + | 0 802 rac cI 803 +0 804 805 rac H 806 + 807 808 rac 809 + 810 116 WO 2006/136461 PCT/EP2006/006531 811 rac 812 + 813 814 rac CF, 815 + 816 817 rac 818 + 819 820 rac 821 + o 822 823 rac 824 + 825 826 rac 827 + 828 829 rac 830 + 831 832 rac 833 + 834 835 rac 836 + 837 838 rac N 839 + - N 840 841 rac 842 + 843 844 rac 845 + N 846 847 rac 848 + 849 850 rac 851 + CF, 852 rac 853 rac 854 + 855N 856 rac 857 + 858 859 rac OH 860 + 861 117 WO 2006/136461 PCT/EP2006/006531 No. Racemic or R3 R OH enantiomer H 862 rac N N 863 1 864 + 865 rac F 0 866 + 867 868 rac 869 + 870 871 rac 872 873 N 874 rac 875 + 876 - 877 rac CF, 878 + 879 880 rac 881 + 882N 883 rac 884 + I 885N 886 rac 887 + 888 889 rac CF 890 + 891 892 rac 893 + 894 895 rac 896 + 897 898 rac 899 + 900 901 rac 902 + 903 904 rac 905 + 906N 907 rac N02 908 + 909 910 rac 911 + 118 WO 2006/136461 PCT/EP2006/006531 912 913 rac 914 + 915 916 rac 917 + 918 919 rac 920 + 921 922 rac OH 923 + 924 No. Racemic or R3 enantiomer R 3 OH 925 rac 926 H N 927 + N 928 rac 0 0 929 + F 0 930 931 rac 932 + 933 934 rac 935 + 936 N 937 rac 938 + 939 940 rac C 941 + 942 943 rac 944 + N 945N 946 rac 947 + 948 949 rac 950 + 951 952 rac CF, 953 + 954 955 rac 956 + 957 958 rac 0 959 + 960 119 WO 2006/136461 PCT/EP2006/006531 961 rac os 962 + 963 964 rac 965 + 966 967 rac 968 + 969 970 rac NO, 971 + N 972 973 rac 974 + 975 976 rac 977 + 978 979 rac 980 + 981 982 rac 983 + 984 985 rac OH 986 + 987 No. Racemic or R3 R 3 enantiomer OH 988 rac Br 989 N N 990 + 0 991 rac 992 + F 0 993 994 rac H 995 + 996 997 rac 998 + 999 1000 rac 1001 + 1002 1003 rac CF 1004 + 1005 1006 rac 1007 + N 1008 120 WO 2006/136461 PCT/EP2006/006531 1009 rac 1010 + 1011 1012 rac 1013 + 1014 -_- 1015 rac F 1016 + 1017 1018 rac \ 1019 + 1020 1021 rac 1022 + 1023 1024 rac s 1025 + 1026 1027 rac 1028 + N 1029 1030 rac 1031 + 1032 1033 rac 1034 + N 1035 1036 rac 1037 + 1038 1039 rac 1040 + 1041 1042 rac 1043 + 1044 1045 rac 1046 + 1047 1048 rac 1049 + 1050 No. Racemic or R3 enantiomer R 3 1051 rac OH 1052 H 1053 + / N N 1054 rac C - o 0 1055 + CF0 1056 121 WO 2006/136461 PCT/EP2006/006531 1057 rac 1058 + 1059 1060 rac 1061 + 1062 1063 rac 1064 + 1065 1066 rac CF. 1067 + 1068 1069 rac 1070 + 1071 N 1072 rac 1073 + 1074 1075 rac 1076 + 1077 1078 rac F 1079 + 1080 1081 rac 1082 + 1083 1084 rac 1085 + 1086 1087 rac 0 1088 + 1089 1090 rac N 1091 + N 1092 1093 rac 1094 + 1095 1096 rac NO, 1097 + 1098 1099 rac 1100 + 1101 1102 rac 1103 + 1104 1105 rac 1106 + 1107 122 WO 2006/136461 PCT/EP2006/006531 1108 rac 1109 + 1110 1111 rac 1112 + 1113 No. Racemic or R3 enantiomer R 3 1114 rac OH 1115 - CF 3 H 1116 + N N 1117 rac 1118 + 1119 1120 rac 1121 + 1122 1123 rac 1124 + 1125 1126 rac 1127 + 1128 1129 rac 1130 + 1131 1132 rac 1133 + 1134 1135 rac 1136+ 1137 N 1138 rac 1139 + 1140 1141 rac CF 1142 + 1143 1144 rac \ 1145 + 1146 -6 1147 rac 1148 + 1149 - 1150 rac 1151 + 1152 1153 rac 1154 + 1155 123 WO 2006/136461 PCT/EP2006/006531 1156 rac 1157 + 1158 1159 rac 1160 + 1161 ._-_ 1162 rac 1163 + 1164 1165 rac 1166 + 1167 1168 rac 1169 + 1170 1171 rac 1172 + 1173 1174 rac 1175 + 1176 No. Racemic or R3 enantiomer R 3 1177 rac OH 1178 -CF 3 H 1179 + N N 1180 rac I o 1181 + 1182 1183 rac 1184 + H 1185 1186 rac 1187 + 1188 1189 rac 1190 + 1191 1192 rac 1193 + 1194 1195 rac 1196 + N.. 1197 N 1198 rac 1199 + 1200N 1202 rac 1202 + 1203 124 WO 2006/136461 PCT/EP2006/006531 1204 rac F, 1205 + 1206 1207 rac 1208 + 1209 1210 rac 1211 + 1212 1213 rac Os 1214 + 1215 1216 rac 1217 + 1218 1219 rac 1220 + 1221 1222 rac 1223 + _ NO2 1224 1225 rac 1226 + 1227 1228 rac 1229 + 1230 1231 rac 1232 + 1233 1234 rac 1235 + 1236 1237 rac OH 1238 + 1239 No. Racemic or R3 enantiomer R 3 1240 rac OH 1241 -/CF, H 1242 + N I' N 1243 rac 1244 + F O 1245 1246 rac 1247 + H 1248 1249 rac 1250 +1 1251 N 125 WO 2006/136461 PCT/EP2006/006531 1252 rac 1253 + 1254 1255 rac CF 1256 + 1257 1258 rac 1259 + N 1260 1261 rac 1262 + 1263 1264 rac 1265 + 1266 1267 rac F 1268 + 1269 1270 rac \ 1271 + 1272 1273 rac 1274 + 1275 1276 rac 1277 + 1278 1279 rac 1280 + N 1281 1282 rac 1283 + 1284 1285 rac NO, 1286 + 1287 1288 rac 1289 + 1290 1291 rac 1292 + 1293 1294 rac 1295 + 1296 1297 rac 1298 + 1299 1300 rac 1301 + 1302 -_ 126 WO 2006/136461 PCT/EP2006/006531 No. Racemic or R3 R 3 OH enantiomer c1 1303 rac H 1304 N 1305 + 0 1306 rac F 0 1307 + 1308 1309 rac 1310 + 1311 1312 rac 1313 + 1314 1315 rac 1316 + 1317 1318 rac C 1319 + 1320 1321 rac 1322 + 1323 1324 rac 1325 + N 1326 _______ 1327 rac 1328 + 1329 1330 rac F 1331 + 1332 1333 rac 1334 + 1335 1336 rac 1337 + 1338 1339 rac oN 1340 + 1341 1342 rac 1343 + N 1344 1345 rac 1346 + 1347 N 1348 rac 1349 + N 1350 127 WO 2006/136461 PCT/EP2006/006531 1351 rac 1352 + 1353 1354 rac 1355 + 1356 1357 rac 1358 + 1359 1360 rac 1361 + 1362 1362 rac 1364 + 1365 No. Racemic or R3 enantiomer 1366 rac 1367 - OH 1368 + CF 3 H 1369 rac N N 1370 + 0 o 1371 - F 1372 rac 1373 + 1374 1375 rac 1376 + 1377 1378 rac 1379 + 1380 1381 rac 1382 + 1383 1384 rac 1385 + 1386 1387 rac 0 1388 + 1389 1390 rac 1391 + 1392 1393 rac F 1394 + 1395 -_- 1396 rac 1397 + 1398 128 WO 2006/136461 PCT/EP2006/006531 1399 rac 1400 + 1401 1402 rac Os 1403 + 1404 1405 rac 1406 + N 1407 1408 rac 1409+ 1410N 1411 rac NO, 1412 + 1413 1414 rac 1415 + 1416 1417 rac CF 1418 + 1419 1420 rac 1421 + 1422 1423 rac 1424 + 1425 1426 rac 1427 + 1428 No. Racemic or R3 enantiomer R 3 1429 rac OH 1430 CF 3 H 1431 + N N 1432 rac - O 1433 + 1434 0 1435 rac 1436 + 1437 1438 rac 1439 + 1440 1441 rac 1442 + 1443 1444 rac CF, 1445 + N 1446 - _'' 129 WO 2006/136461 PCT/EP2006/006531 1447 rac 1448 + 144 N 1450 rac 1451 + 1452N 1453 rac 1454 + 1455 1456 rac F 1457 + 1458 1459 rac \ 1460 + 1461 1462 rac 1463 + 1464 1465 rac 1466 + 1467 1468 rac N 1469 + N 1470 1471 rac 1472 + 1473 1474 rac NO, 1475 + 1476 1477 rac 1478 + 1479 1480 rac 1481 + 1482 1483 rac 1484 + 1485 1486 rac 1487 + 1488 1489 rac H 1490 + 1491 130 WO 2006/136461 PCT/EP2006/006531 No. Racemic or R3 enantiomer R 3 1492 rac OH 1493 -c H 1494 + /N N 1495 rac - o 1496 + 1497 1498 rac 1499 + 1500 _ 1501 rac 1502 + 1503 1504 rac 1505 + 1506 1507 rac CFa 1508 + 1509 1510 rac 1511 + 1512 ra 1513 rac 0 1514 + 1515 1516 rac 1517 + 1518 1519 rac CF, 1520 + 1521 1522 rac 1523 + 1524 1525 rac 1526 + 1527 1528 rac 1529 + 1530 - _ 1531 rac 1532 + 1533 1534 rac 1535 + N 1536N 1537 rac NO, 1538 + 1539 1540 rac 1541 + 1542 131 WO 2006/136461 PCT/EP2006/006531 1543 rac 1544 + 1545 1546 rac 1547 + 1548 1549 rac 1550 + 1551 1552 rac O 1553 + 1554 | No. Racemic or R3 enantiomer 1555 rac 1556 R 3 1557 + OH 1558 rac cI H 1559 + N N 1560 -1o o 1561 rac 1562 + H 1563 1564 rac 1565 + 1566 1567 rac 1568 + 1569 1570 rac F, 1571 + 1572 1573 rac 1574 + N 1575 1576 rac 1577 + 1578 1579 rac 1580 + 1581 1582 rac 1583 + 1584 1585 rac 1586 + 1587 1588 rac 1589 + 1590 132 WO 2006/136461 PCT/EP2006/006531 1591 rac os 1592 + 1593 | 1594 rac 1595 + 1596 1597 rac 1598 + 1599 1600 rac 1601 + NO, 1602 1603 rac 1604 + 1605 1606 rac 1607 + 1608 1609 rac 1610 + 1611 1612 rac 1613 + 1614 1615 rac 1616 + 1617 No. Racemic or R3 enantiomer R 3 1618 rac OH 1619 - CF 3 H 1620 + N N 1621 rac 0 o 1622 + 1623 1624 rac 1625 + 1626 1627 rac 1628 + 1629 1630 rac 1631 + 1632 1633 rac CF, 1634 + 1635 1636 rac 1637 + 1638 133 WO 2006/136461 PCT/EP2006/006531 1639 rac 1640 + 1641__ _ _ _ _ _ 1642 rac 1643 + 1644 -_ 1645 rac F 1646 + 1647 1648 rac 1649 + 1650 1651 rac 1652 + 1653 1654 rac 0 1655 + 1656 1657 rac 1658 + 1659 1660 rac 1661 + 1662 1663 rac 1664 + 1665 1666 rac 1667 + 1668 1669 rac 1670 + 1671 1672 rac 1673 + 1674 1675 rac 1676 + 1677 1678 rac 1679 + 1680 No. Racemic or R3 enantiomer 1681 rac R OH 1682 |-o H 1683 + / 0 N N 1684 rac 1685 + 1686 0 134 WO 2006/136461 PCT/EP2006/006531 1687 rac 1688 + 1689 1690 rac 1691 + 1692 1693 rac 1694 + 1695 1696 rac CF, 1697 + 1698 1699 rac 1700 + 1701 1702 rac 1703 + 1704 1705 rac 1706 + 1707 1708 rac 1709 + 1710 1711 rac 1712 + 1713 1714 rac 1715 + 1716 1717 rac 1718 + 1719 1720 rac 1721 + N 1722 1723 rac 1724 + 1725 1726 rac 1727 + NO, 1728 1729 rac 1730 + 1731 1732 rac 1733 +C 1734 1735 rac 1736 + 1737 135 WO 2006/136461 PCT/EP2006/006531 1738 rac 1739 + 1740 1741 rac OH 1742 + 1743 1 No. Racemic or R3 enantiomer 1744 rac 1745 1746 + 1747 rac 1748 + 1749 1750 rac 1751 + 1752 1753 rac 1754 + 1755 1756 rac 1757 + 1758 1759 rac CF, 1760 + 1761 1762 rac 1763 + N 1764 1765 rac 0 1766 + 1767 1768 rac 1769 + 1770 1771 rac CF, 1772 + 1773 1774 rac \ 1775 + 1776 1777 rac 0 1778 + 1779 1780 rac 0 1781 + 1782 1783 rac 1784 + N 1785 136 WO 2006/136461 PCT/EP2006/006531 1786 rac 1787 + 1788 1789 rac 1790 + 1791 1792 rac 1793 + 1794 1795 rac 1796 + ) 1797 1798 rac 1799 + 1800 1801 rac 1802 + 1803 1804 rac OH 1805 + OH 1806 1807 rac 1808 + 1809 1810 rac 1811 + 1812 No. Racemic or R3 enantiomer R3 1813 rac OH 1814 /0 H 1815 + 0 N N 1816 rac - o 1817 + 1818 0 1819 rac 1820 + 1821 1822 rac 1823 + 1824 1825 rac 1826 + 1827 1828 rac c 1829 + 1830 1831 rac 1832 + 1833 N 137 WO 2006/136461 PCT/EP2006/006531 1834 rac 1835 + 1836 . N 1837 rac 1838 + 1839 1840 rac F 1841 + 1842 1843 rac 1844 + 1845 1846 rac 1847 + 1848 1849 rac 1850 + 1851 1852 rac 1853 + N 1854 1855 rac 1856 + 1857 1858 rac NO, 1859 + N 1860 1861 rac 1862 + 1863 1864 rac 1865 + 1866 1867 rac 1868 + 1869 1870 rac 1871 + 1872 1873 rac OH 1874 + 1875 No. Racemic or R3 enantiomer R 3 1876 rac OH 1877 ci H 1878 + N 1879 rac 0 o0 1880 + 1881 | 138 WO 2006/136461 PCT/EP2006/006531 1882 rac 1883 + 1884 1885 rac 1886 + 1887 1888 rac 1889 + 1890 1891 rac CF. 1892 + 1893 1894 rac 1895 + N 1896 1897 rac 1898 + 1899N 1900 rac 1901 + 1902 1903 rac 1904 + 1905 1906 rac 1907 + 1908 1909 rac 1910 + 1911 1912 rac o, 1913 + 1914 1915 rac 1916 + N 1917 1918 rac 1919 + 1920 1921 rac NO 1922 + N 1923 1924 rac 1925 + 1926 1927 rac 1928 + 1929 1930 rac 1931 + 1932 139 WO 2006/136461 PCT/EP2006/006531 |1933 rac 1934 + 1935 1936 rac OH 1937 + 1938 1 No. Racemic or R3 enantiomer R 3 1939 rac OH 1940 H 1941 + N N 1942 rac I 1943 + 1944 1945 rac 1946 + 1947 1948 rac 1949 + 1950 1951 rac 1952 + 1953 1954 rac CF, 1955 + 1956 1957 rac 1958 + N 1959 1960 rac 0 1961+ 1962 1963 rac 1964 + 1965 1966 rac CF 1967 + 1968 1969 rac 1970 + 1971 1972 rac 1973 + 1974 1975 rac 1976 + 1977 1978 rac 1979 + N 1980 - _ 140 WO 2006/136461 PCT/EP2006/006531 1981 rac 1982 + 1983 1984 rac 1985 + 1986 1987 rac 1988 + 1989 1990 rac CF 1991 + 1992 1993 rac 1994 + 1995 1996 rac 1997 + 1998 1999 rac OH 2000 + 2001 No. Racemic or R3 enantiomer 2002 rac OH 2003 C' H 2004 + / N -N 2005 rac 0 o o 2006 + 0 2007 2008 rac 2009 + 2010 2011 rac 2012 + 2013 2014 rac 2015 + 2016 2017 rac F, 2018 + 2019 2020 rac 2021 +N 2022 2023 rac 2024 + 2025 2026 rac 2027 + 2028 141 WO 2006/136461 PCT/EP2006/006531 2029 rac F 2030 + 2031 2032 rac 2033 + 2034 2035 rac 2036 + 2037 2038 rac o 2039 + 2040 2041 rac 2042 + N 2043 | 2044 rac 2045 + 2046 2047 rac No, 2048 + 2049 2050 rac 2051 + 2052 2053 rac 2054 + 2055 2056 rac 2057 + 2058 2059 rac 2060 + 2061 2062 rac OH 2063 + 2064 No. Racemic or R3 enantiomer R 3 2065 rac OH 2066 -_CI H 2067 + N N 2068 rac o 2069 + 2070 2071 rac 2072 + 2073 2074 rac 2075 + 2076 I 142 WO 2006/136461 PCT/EP2006/006531 2077 rac 2078 + 2079 2080 rac CF, 2081 + 2082 2083 rac 2084 + N 2085 2086 rac 2087 + 2088 - _ 2089 rac 2090 + 2091 2092 rac 2093 + 2094 2095 rac 2096 + 2097 2098 rac 2099 + 2100 2101 rac s 2102 + 2103 2104 rac 2105 + 2106 2107 rac 2108 + 2109 2110 rac NO, 2111+ N

2112- 2113 rac 2114 + 2115 _ 2116 rac 2117 + 2118 2119 rac 2120 + 2121 2122 rac 2123 + 2124 2125 rac 2126 + 2127 143 WO 2006/136461 PCT/EP2006/006531 No. Racemic or R3 enantiomer R 3 2128 rac OH 2129 cI H 2130 + N N 2131 rac I o 2132 + F 2133 2134 rac 2135 + 2136 2137 rac 2138 + 2139 2140 rac 2141 + 2142 2143 rac 2144 + 2145 2146 rac 2147 + 2148 2149 rac 2150 + 2151 2152 rac 2153 + 2154 2155 rac CF 2156 + 2157 2158 rac 2159 + 2160 2161 rac 2163 + 2163 2164 rac s 2165 + 2166 2167 rac 2168 + 2169 2170 rac 2171 + 2172 2173 rac 2174 + 2175 2176 rac 2177 + 2178 144 WO 2006/136461 PCT/EP2006/006531 2179 rac 2180 + 2181 2182 rac 2183 + 2184 2185 rac 2186 + 2187 2188 rac 2189 + 2190 No. Racemic or R3 enantiomer 2191 rac OH 2192 -/CF 3 H 2193 + N N 2194 rac 0 o 2195 + F O 2196 2197 rac 2198 + 2199 2200 rac 2201 + 2202 2203 rac 2204 + 2205 2206 rac CF 2207 + 2208 2209 rac 2210 + 2211 2212 rac 0 2213 + 2214 2215 rac 2216 + 2217 2218 rac CFa 2219 + 2220 2221 rac 2222 + 2223 2224 rac 0 2225 + 2226 F-_I_____Z 145 WO 2006/136461 PCT/EP2006/006531 2227 rac Os 2228 + 2229 2230 rac 2231 + 2232 - 2233 rac 2234 + 2235 2236 rac NO, 2237 + 2238 2239 rac 2240 + 2241 2242 rac 2243 + 2244 2245 rac 2246 + 2247 2248 rac 2249 + 2250 2251 rac O 2252 + 2253 1 No. Racemic or R3 enantiomer R 3 2254 rac OH 2255 -0 H 2256 + N N 2257 rac - 0 2258 + 2259 0 2260 rac 2261 + 2262 2263 rac 2264 + 2265 2266 rac 2267 + 2268 2269 rac CF, 2270 + 2271 2272 rac 2273 + 2274 146 WO 2006/136461 PCT/EP2006/006531 2273 rac 2276 + 2277 - ~ 2278 rac 2279 + 2280 2281 rac F 2282 + 2283 2284 rac 2285 + 2286 2287 rac 2288 + 2289 | 2290 rac 2291 + 2292 2293 rac N 2294 + 2295 2296 rac 2297 + 2298 2299 rac NO, 2300 + 2301 2302 rac 2303 + 2304 2305 rac 2306 + 2307 2308 rac 2309 + 2310 2311 rac 2312 + 2313 2314 rac OH 2315 + 2316 No. Racemic or R3 enantiomer R 3 2317 rac OH 2318 H 2319 + N N 2320 rac 0 o 2321 + 2322 0 147 WO 2006/136461 PCT/EP2006/006531 2323 rac 2324 + H 2325 2326 rac 2327 + 2328 2329 rac 2330 + 2331 2332 rac - CF. 2333 + 2334 2335 rac 2336 + N 2337 2338 rac 2339 + 2340 2341 rac 2342 + 2343 2344 rac CF, 2345 + 2346 2347 rac 2348 + 2349 2350 rac 2351 + 2652 2353 rac 2354 + 2355 2356 rac 2357 + N 2358 2359 rac 2360 + 2361 2362 rac 2363 + N 2364 2365 rac 2366 + 2367 2368 rac 2369 + 2370 2371 rac 2372 + 2373 148 WO 2006/136461 PCT/EP2006/006531 2374 rac 2375 + 2376 2377 rac OH 2378 + 2379 1-__ No. Racemic or R3 enantiomer R 3 2380 rac OH 2381 0 H 2382 + N N 2383 rac o 2384 + 0 2385 2386 rac 2387 + 2388 2389 rac 2390 + 2391 2392 rac 2393 + 2394 2395 rac CF, 2396 + 2397 2398 rac 2399 + N 2400 2401 rac 2402 + 2403 2404 rac 2405 + 2406 2407 rac CF 2408 + 2409 2410 rac 2411 + 2412 2413 rac 2414 + 2415 2416 rac 2417 + 2418 2419 rac 2420 + 2421 - _--' 149 WO 2006/136461 PCT/EP2006/006531 2422 rac 2423 + 2424 2425 rac NO, 2426 + 2427 2428 rac 2429 + 2430 2431 rac 2432 + 2433 2434 rac 2435 + 2436 2437 rac 2438 + 2439 2440 rac OH 2441 + 2442 No. Racemic or Structure enantiomer 2443 rac 2444 2445 + 2446 rac 2447 + 2448 2449 rac 2450 + 2451 2452 rac 2453 + 2454 2455 rac 2456 + 2457 2458 rac 2459 + 2460 2461 rac 2462 + 2463 2464 rac 2465 + 2466 2467 rac 150 WO 2006/136461 PCT/EP2006/006531 2468 + 2469 2470 rac 2471 + 2472 2473 rac 2474 + 2475 2476 rac 2477 + 2478 151 WO 2006/136461 PCT/EP2006/006531 14. Pharmaceutical composition comprising at least one compound of the general formula I according to any of Claims 1 to 13 and, where appropriate, at least one further active ingredient together with pharmaceutically suitable excipients and/or 5 carriers. 15. Pharmaceutical composition according to Claim 14, where the further active ingredient is a SERM (selective estrogen receptor modulator), an aromatase inhibitor, an antiestrogen or a prostaglandin. 10 16. Pharmaceutical composition according to Claim 14, where the active ingredient may be tamoxifen, 5-(4-{5-[(RS)-(4,4,5,5,5-pentafluoropentyl)sulphinyl]pentyloxy}phenyl) 6-phenyl-8,9-dihydro-7H-benzocyclohepten-2-ol, ICI 182 780 (7alpha-[9-(4,4,5,5 pentafluoropentylsulphinyl)nonyl]estra-1,3,5(10)-triene-3,17beta-diol), 11beta-fluoro 15 7alpha-[5-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulphanyl] propyl)amino)pentyl]estra-1,3,5(10)-triene-3,17beta-diol, 11beta-fluoro-7alpha-{5 [methyl(7,7,8,8,9,9,10,10,1 0-nonafluorodecyl)amino]pentyl}estra-1,3,5(1 0)-triene 3,17beta-diol, 11beta-fluoro-17alpha-methyl-7alpha-{5-[methyl(8,8,9,9,9 pentafluorononyl)amino]pentyl)estra-1,3,5(10)-triene-3,17beta-diol, clomifen, 20 raloxifen, fadrozole, formestane, letrozole, anastrozole or atamestane. 17. Use of compounds according to any of Claims 1 to 13 for producing a medicament. 18. Use of compounds according to Claim 17 for producing a medicament for the 25 therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea. 19. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of hormone-dependent tumours. 30 20. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of breast carcinomas. 21. Use of compounds according to Claim 17 for producing a medicament for the 35 therapy and prophylaxis of endometrial carcinoma. 152 WO 2006/136461 PCT/EP2006/006531 22. Use of compounds according to Claim 17 for producing a medicament for the therapy and prophylaxis of ovarian carcinomas. 23. Use of compounds according to Claim 17 for producing a medicament for the 5 therapy and prophylaxis of prostate carcinomas. 24. Use of compounds according to Claim 17 for producing a medicament for female hormone replacement therapy. 10 25. Use of compounds according to Claim 17 for female fertility control. 26. Process for the selective addition of lithium alkynyl and magnesium haloalkynyl compounds onto a keto amide. 153