TW200835498A - Non-steroidal progesterone receptor modulators - Google Patents

Abstract

The present invention relates to non-steroidal progesterone receptor modulators of the general formula I, the use of the progesterone receptor modulators for the manufacture of medicaments, and pharmaceutical compositions which comprise these compounds. The compounds according to the invention are suitable for the therapy and prophylaxis of gynaecological disorders such as endometriosis, leiomyomas of the uterus, dysfunctional bleeding and dysmenorrhoea, and for the therapy and prophylaxis of hormone-dependent tumours and for use for female fertility control and for hormone replacement therapy.

Description

200835498 IX. The invention relates to a non-steroidal luteinizing hormone receptor modulator, a preparation method thereof, a use of the progesterone receptor modulator in the manufacture of a medicament, and a compound containing the same Pharmaceutical composition. [Prior Art]

Steroid progesterone controls the reproductive process in a decisive manner in the female body. Luteinizing hormone is secreted in large amounts by the ovaries and placenta, individually during this cycle and during pregnancy. Luteinizing hormone, which works in conjunction with estrogen, produces a cyclical change in the uterine mucosa (endometrium) during the menstrual cycle. The increased luteinizing hormone content after typography affects the uterine mucosa and transforms it into a state in which the fetus (blast cell) is allowed to be implanted. 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 hyperplasia by suppressing mitosis mediated by estrogen in uterine tissue (K ChwaUsz, RM), υ· Fuhrmann, H. Hess-stumpp, w. E丨ger, Steroids 65, 2, 741 751). It is also known that the luteinizing hormone and the progesterone receptor system play a significant part in the pathophysiology process. The progesterone receptor has been detected in the lesions of the endometrial tissue ectopic, and in the uterus, breast and (10) tumors. Uterine flat is further known; osteomyeloma grows in a luteinizing hormone-dependent manner. The role of phylogenetic hormones in the tissues of reproductive organs and in other tissues is through interaction with the luteinizing hormone receptor responsible for cellular action. ^ Luteinizing hormone receptor modulators are either pure agonists, or partially or completely 127094 200835498. Therefore, the material 剤, part of the mobilization of the south lr, the burial w * buffalo is deprecated as pure urging le d (k selective phytohormone receptor antagonist. f and body dying agent = SPRM) and The ability of pure vapor hormonal fork body regulators, these compounds have considerable playful role in gynecological fish swollen hurricane, &#, 曰力 as a therapeutic agent for = oncology signs and obstetrics and fertility control use. ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, It has the ability to resist the middle end of the endometrium of the endometrium, and the manor cover 11 Dunsu in the child into the λ 丄 (four) 70 king to shrink. Therefore, it is particularly suitable for female reproductive processes 'such as after ovulation' to prevent bed of fertilized cells, to increase the uterus response to prostaglandins or oxytocin during pregnancy' or to achieve the opening and softening of the cervix ("mature"), and the agility that causes the contraction of the myometrium. It is expected that the beneficial effects on pathological events are in the uterus (four) tissue ectopically formed lesions' and in the tumor tissue tissue, which is loaded with the progesterone receptor after administration of the pure luteinizing hormone receptor antagonist. If typographic inhibition can be achieved by a luteinizing hormone receptor antagonist, there may be a specific benefit for affecting the pathological state, such as endometrial tissue ectopic formation or uterine leiomyoma. Ovulation inhibition also exempts a portion of ovarian hormone production, and is therefore a pathologically altered tissue derived from the stimulating effect of this ratio. The first progesterone receptor antagonist, RU 486 (also known as mifepristone), has been described as followed by a very large number of analogs with different concentrations of progesterone receptor antagonistic activity. Synthesis and feature characterization. Although RU 486 showed anti-corticoid action in addition to the luteinizing hormone receptor-antagonism, the compound synthesized later was particularly significantly more selective as a luteinizing hormone receptor antagonist. In addition to steroid compounds such as onapristone or Hlopristone, it is worth noting that compared to RU 486, it provides progesterone receptor antagonism and anti-cortisol The role of better dissociation, also known from the literature for a variety of non-steroid structures, its antagonism of the progesterone receptor is being studied [see, for example, SA Leonhardt and D. R Edwards, Exp. Biol. Med. 227 : 969-980 (2002) and Winnerker, A. Fensome, JE Wrobel, Z. Zhang, P. Zhang, Symposium on Reproductive Medicine, Vol. 23: 46-57 (2005)]. However, the non-steroidal compounds disclosed so far have only moderate antagonistic activity compared to the activity of known steroid structures. The most effective non-steroidal compounds have been reported to have a living activity of 10% of the activity of RU 486. In the case where the inhibition of the progesterone receptor is at the forefront of the therapy, the anti-cortisol activity is detrimental to the therapeutic use. Anti-cortisol activity can cause unwanted side effects at the doses necessary for therapy. This may interfere with the administration of a therapeutically matched dose or may result in a discontinuation of treatment. Therefore, partial or complete reduction in the properties of anti-corticosteroids is an important prerequisite for the use of treatments for luteinizing hormone receptor antagonists, especially for indications that require weeks or months of treatment. In contrast to pure antagonists, a partial progesterone receptor agonist (SPRM) exhibits residual catabolic properties which can vary in intensity. This causes these substances to show a stimulant effect on the progesterone receptor in certain organ systems (D. DeManno, W. Eiger, R. Garg? R. Lee, B. Schneider, H. Hess-Stumpp, G . 127094 200835498

Schuber, Κ·Chwalisz, Steroids 68, 2003, 1019-1032). The role of such organs in dissociation and dissociation may have therapeutic benefit for the indications described. SUMMARY OF THE INVENTION Accordingly, one item of the present invention is to provide other non-steroidal luteinizing hormone dimer modulators. These compounds are intended to have a reduced anti-cortisol action and are therefore useful for the treatment and prevention of gynecological conditions such as ectopic formation of the endometrial tissue, leiomyomas of the uterus, dysfunction and menstrual difficulties. The compounds according to the invention are additionally intended to be useful in the treatment and prophylaxis of aggressive-dependent tumors, such as the breast, endometrium, ie nest and prostate cancer. The compound is intended to be further applicable to female fertility control and female hormone replacement therapy. This item is achieved in accordance with the present invention by providing a non-steroid compound of the formula

Λ is wind, CrCr base, dilute base, C2-C8i base, which is the same or differently substituted by 2 or _, or C3_Ci〇 cycloalkyl or M2-membered heterocycloalkyl, The same or different conditions are singly or multi-substituted, or Z itself, wherein z is defined as follows: cyano, halogen, hydroxyl, nitro, _c(〇)Rb, c〇2Rb, 127094 200835498 -0-Rb , -S-Rb, S02NRcRd, -C(0)-NRcRd, -OC(0)-NRcRd, -C=NORb, -NRcRd, _P〇3(Rb)2, NReCORb, -NReCSRb, -NReS(0) Rb, -NReS(0)2Rb, _NReCONRcRd, -NReCOORb, -NReC(NH)NRcRd, -NReCSNRcRd, _NReS(0)NRcRd, -NReS(0)2NRcRd ' -S(0)Rb, -S(0)NRcRd , -S(0)2Rb, -S020Rb, -CSNRcRd '-CRb(〇H)-Rb, or C3-C1G-cycloalkyl or heterocycloalkyl, which are the same or different depending on the case - Or polysubstituted, and Μ is ci alkyl or _c〇Rb, C02Rb, -〇-Rb or -NReRd, wherein R is gas or Ci-C6-alkyl, C2_C8-alkenyl, c2-C8_alkynyl, C3 -C1 (r cycloalkyl, C6-C12-aryl or partially or fully fluorinated Ci-Cy alkyl, and RC and hydrazine are each independently hydrogen, Ci_c6_alkyl, c2_C8-alkenyl, crc8_block a C3_Ci〇_cycloalkyl or aryl group, a C(〇)Rb group, wherein Rb is as defined above or a hydroxy group, wherein when RC is a thiol group, Rd may be only hydrogen, CAi group, phenyl group a c2-cv alkynyl group, a C3_Ci〇-cycloalkane group or a C6<:12-aryl group, and vice versa, and

Re is hydrogen, Ci-Q-alkyl, c2-cv group, C2_q_alkynyl, C3-C10-cycloalkyl or cvCi2_aryl, 127094 -10. 200835498 R1 and R2 R3 f

K and each independently is an unbranched or branched Ci_alkyl group, or together with the carbon atom of the chain, forms a ring having a total of 3-7 members, wherein when A is hydrogen, R1 and R2 cannot both be 曱a group, which is hydrogen or (ν(:8-alkyl, c2_c8-alkenyl, C2_C8-alkynyl, C3-C1G-cycloalkyl, 3-12-membered heterocycloalkyl, which are the same or different depending on the case) K-mono- or poly-substituted, or mono- or bicyclic Q-Cn-aryl or 3-12-membered heteroaryl, which is optionally or differently substituted by L単- or poly, and is cyanide Base, halogen, hydroxy, nitro, -q〇) Rb, C02Rb ^ -〇-Rb . .s.Rb Λ S〇2NRcRd >-C(0>NRcRd,_0C(0)-NRcRd, _c=N〇 Rb, -nrcrcI or cycloalkyl, 3-12-membered heterocycloalkyl, which are, as the case may be, mono- or polysubstituted, or c6_Ci2_aryl or 3-12-membered heteroaryl, Depending on the case, it may be mono- or polysubstituted, having the definition of Μ specified in A, and is 4-(:8-alkyl, c2-C8-alkenyl, C2-C8-alkynyl, partially or completely Fluorinated Cl _c6_alkyl, partially or fully characterized Ci-cv alkoxy, Ci-Q-alkoxy-CrC6_alkyl, Cl_c6_alkoxy &l t; 1 <: 6-alkoxy, mono- or bicyclic (CH2) p-C3_C1G-cycloalkyl 'mono- or bicyclic 3-12-membered (CH2) p-heterocycloalkyl, ( CH2)pCN, 127094 • 11 - 200835498 (CH2)pHal, (CH2)pN02, mono- or bicyclic (CH2) p-C6-C12-aryl, mono- or bicyclic 3-12-member (CH2) ) p-heteroaryl, or -(CH2)pP03(Rb)2, -(CH2)pNRcRd, _(CH2)pNReCORb, -(CH2)pNReCSRb, -(CH2)pNReS(0)Rb, -(CH2) pNReS(0)2Rb, -(CH2)pNReCONRcRd, -(CH2)pNReCOORb, _(CH2)pNReC(_NRcRd, -(CH2)pNReCSNRcRd, _(CH2)pNReS(0)NRcRd, -(CH2)pNReS(0) 2NRcRd, -(CH2)pCORb, -(CH2)pCSRb, -(CH2)PS(0)Rb, -(CH2)pS(0)(NH)Rb, -(CH2)pS(0)2Rb, -(CH2 ) pS(0)2NRcRd, -(CH2)pS020Rb, -(CH2)pC02Rb, -(CH2)pCONRcRd, -(CH2)pCSNRcRd, -(CH2)pORb, -(CH2)pSRb, -(CH2)pCRb(OH )-Rb , -(CH2 )pC=NORb , -CKCH2)n-0·,-0-(CH2)n-CH2-,-0-CH=CH- or -(CH2)n + 2-, and the end An oxygen atom and/or a carbon atom is bonded to a directly adjacent ring carbon atom, and η is 1 or 2, and ρ is 0, 1, 2, 3, 4, 5 or 6, and X is an oxygen atom or Two hydrogenogens Sub, Υ is (CH2)m, -CEC- or -CH=CH-, wherein m = 0 or 1, and R4 is an aromatic or heteroaromatic 3- to 12-membered mono- or bicyclic ring, which is 127094 -12- 200835498 Unsubstituted, or as appropriate, substituted by 1 to 3 groups mentioned in L or one of the following groups mentioned in B or C: B: 6-member/6-member ring system:

C · 6-贝/5-贝ί 糸 糸 ·

R5 is hydrogen or alkyl or partially or fully fluorinated C! -C4 -alkyl group R6a and R6b are each independently hydrogen, Ci-C4_alkyl or partially or finished 127094 -13- 200835498 C-alkyl, or together with a ring carbon atom to form a 3- to 6-membered ring, and a pharmaceutically acceptable salt thereof. The compound of the formula 1 according to the present invention may exist as a stereoisomer due to the presence of an asymmetric center. Both the racemate and the individual stereoisomers are attributable to the subject matter of the present invention. The invention further comprises a novel compound as an active pharmaceutical ingredient, a therapeutic use thereof, and a pharmaceutical dosage form comprising the novel substance. The compound of the formula (1) or the pharmaceutically acceptable salt thereof of the invention of the root age can be used for the manufacture of an agent, in particular for the treatment and prevention of gynecological diseases, such as ectopic formation of endometrial tissue, leiomyomas of the uterus, function Obstruction bleeding and menstrual difficulties. The compounds according to the invention can be used in the treatment and prevention of hormone-dependent tumors, e.g. for breast, prostate and endometrial cancers. The compound of the formula 1 according to the present invention or a pharmaceutically acceptable salt thereof is also suitable for use in female fertility control or female hormone replacement therapy. The non-steroid compound of the formula 1 according to the present invention has a strong antagonistic effect against a progesterone receptor or a strong partial agonist, and has high efficacy. Regarding its binding strength to the luteinizing hormone receptor and to the corticosteroid receptor, it shows a strong dissociation effect. Although known luteinizing hormone receptor antagonists, such as mifepristone (RU 486), in addition to the high binding affinity for the progesterone receptor, also show high affinity for corticosteroid receptors. , : The compounds according to the invention are notable for the very low cortical glycoside binding, accompanied by the high luteinizing hormone receptor affinity. The compound of the formula j according to the present invention, the substituent defined as a group may have the following meanings in each case of 127094 - 14 · 200835498: q CV, Cl-cv, Cl_C6· and Ci<8-alkyl Unbranched or as appropriate

The condition is a branched alkyl group. Its example A member is listed as methyl, ethyl, n-propyl, isopropyl,

Positive-, iso-, tri-butyl, n-methyl, 2,2-dimethylpropyl, 3-methylbutyl, hexyl, heptyl or octyl. In the sense of R1, R2 and R3, a methyl group, an ethyl group, a n-propyl group or a n-butyl group and a n-pentyl group are preferred.

According to the invention, it is preferred for R5

It is a thiol methyl or ethyl group, and R6 a and r6 b are hydrogen. , alkenyl means unbranched or, as the case may be, a branched thin base. c^c(4), meaning, examples, in the context of the present invention are the following: vinyl, fluorenyl, 3_:al-1-yl or 2,3-dimethyl-2-propenyl. When the aromatic group in the middle is substituted by a Q-C8-alkenyl group, it is preferably a vinyl group. An alkynyl group means unbranched or, as the case may be, a branched alkynyl group. The q-alkynyl group is intended to be, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl and octynyl, but is preferably ethynyl or propynyl.

Possible examples of Cl_C6-alkoxy-Cl-Cp alkoxy are methoxymethoxy, ethoxymethoxy or 2-methoxyethoxy. For the purposes of the present invention, the group ORF is hydroxy, methoxy, ethoxy, n-propoxy, isopropoxy, n-'iso-t-butoxy or n-pentyloxy, 2, 2_ Dimethylpropoxy or 3-methylbutoxy. Hydroxy, methoxy and ethoxy groups are preferred. Suitable partially or fully fluorinated Cl-C4_alkyl groups are especially trifluoromethyl or pentafluoroethyl. 127094 -15- 200835498 Good Halogen atoms can be fluorine, chlorine, desert or iodine atoms. Fluorine, chlorine or fills here should be understood that 3- to 12-membered cycloalkyl and heterocyclic alkyl groups mean both monocyclic disc-like groups. ^ X &, Society. In the meaning of hydrazine, examples of the monocyclic Mo-cycloalkyl group are exemplified by bad propane, cyclobutane, cyclopentane and cyclohexane. Preferably, cyclopropyl, cyclopentyl and hexyl are preferred. When W and R2 and the carbon atoms of the chain are formed together to have a total of 3-7 members, this is a ring composed of a total of 3-7 carbon atoms. When A is simultaneously hydrogen, the most preferred ones are cyclopentyl and cyclohexyl. In the sense of R3 or Rb, R'R'Re and ..., the mono- or bicyclic c6-c12-aryl group is, for example, a phenyl group or a fluorenyl group, preferably a phenyl group. In the sense of R3, K and L, an example of a 3-12-membered heteroaryl is 2, 3- or 4: dimethyl, 2- or 3-mercapto, 2 or phenyl, ... Or 5-imidazolyl, pyridinyl, '4_ or 5-pyridinyl or 3- or 4-indole. i is in the meaning of A, Z, K, R3 or R4, single. For example, the money of the 3_10-bee heterocyclic group in the form of I is as follows: Ρ福Ρ林, tetrachloropyrene., 丄俨王” ^ acridine, tetrahydropyrrole, ethylene oxide, % oxygen Propane, aziridine, -盏彳a, dioxin, n-furan, pyran, P-pyrene, imipenem, pyridinium, pyridinium, pyrimidine, sorghum, argon, pyridin, thiazole , slogan, main TO, can be bitten, dihydroanthracene, oxazoline, triazole, at: atomic position of any chemically possible isomer. ^ This (four) can be pointed out that the example is (4) L forest and According to the present invention, with respect to R4, a preferred system of the ring system is known. The double ring of 127094 -16-200835498, the number of (CH2)P groups is 〇, 1, 2, 3 , 4, 5 or 6, preferably

Or, according to the invention, a group, means all of the functional groups mentioned in relation to (Ch2) in R1. P In the case where the compound of the formula 1 is in the form of a salt, it may, for example, be a hydrochloride, a sulfate, a nitric acid, or a pure acid, a sulphate, a sulphate, a succinimide In the form of a diacid salt, succinate or benzoate. If the compound according to the invention is in the form of a racemic mixture, it can be separated into pure optically active H by a method known to the skilled person as a racemate. For example, a racemic mixture can be used in: As an optically active support material (CHIRALPAKAD8), it was separated into pure isomers by chromatography. It is also possible for the optically active acid to liberate the free hydroxy group in the racemic compound of the formula 及 and to diastereoisomers formed by fractional crystallization or chromatographic separation, and in each case It is intended to hydrolyze into a purely isomer. As the optically active acid, for example, phenylglycolic acid, camphoric acid or tartaric acid can be used. Preferred compounds of the formula 1 according to the present invention are those in which A.s., and R4R2 and the carbon atom of the chain form a ring composed of 3 to 7 carbon atoms, or

A is ^-^-alkyl or ^cyclo[cycloalkyl], however "and each is methyl, or Μ and its prerequisite is γ is ΤξΟ or -CH=CH·, R3 is Cl-Cs-alkyl , mono- or bicyclic Q-Cn-aryl or 3_12_membered heteroaryl, or "127094 -17- 200835498 when Y is (CH2)m, R3 is a mono- or bicyclic CVCu-aryl or 3-12-membered heteroaryl, and R4 may be mono- or di-substituted mono- or bicyclic aromatic, or one of the B groups having a chain at position 6 as mentioned in R4, Or one of the C groups having a link at position 5 as mentioned in R4.

Among these, the following lines are preferred in order:

%6b

Further, R5 R6 PL is preferably a methyl group or an ethyl group, and the gas is '0', 1 or 2, and is a Ci-C8-alkyl group, a C2-C8-mercapto group, a C2-C8-alkynyl group, Partially or completely vaporized (^1-(116-alkyl, -((11112)0〇]^, ((1;112)011&1

(ch2) pN02, (CH2)p-C6-Ci 2 -aryl, -(ch2)p-heteroaryl, -(CH2)pNRcRd, -(CH2)pNReCORb, -(CH2)pNReS(0)2Rb, -(CH2)pNReCONRcRd, -(CH2)pNReS(0)NRcRd, -(CH2)p NRe S(0)2 NRC Rd, -(CH2)p CORb, -(CH2)p S(0)Rb, -( CH2) pS(0)2Rb, -(CH2)pS(0)2NRcRd, -(CH2)pC02Rb, -(CH2)pC0NRcRd, -(CH2)p0Rb, -(CH2)pCRb(0H)-Rb, and Z is Cyano, halogen, hydroxy, nitro, -C(0)Rb, C02Rb, -0-Rb, S02NRcRd, -C(0)-NRcRd, -NRcRd, -NReC0Rb, _NReS(0)Rb, -NReS(0 2Rb, NReC0NRcRd, -S(0)Rb, 127094 200835498 S(0)NRcRd, -S(0)2Rb, -CRb(OH)-Rb, or C3-C10-cycloalkyl or heterocycloalkyl, depending on The situation is the same or differently replaced by M- or more.

The compounds mentioned hereinafter and their use are preferably according to the invention: number racemic or palmomerisomer -Y-R1 1 racemic oxime, 2 + 3 - 4 racemic 5 + 6 - 7 racemic 8 + 9 - 10 racemic 11 + 12 - 13 racemic JJ 14 + 15 - 16 racemic 17 + 18 - 19 racemic 20 + 21 - 22 racemic 23 + 24 - 127094 -19- 200835498

No. Racemic or palmar isomer - Y-R1 25 Racemic 〆〆26 + 27 - 28 Racemic 29 + 30 - 31 Racemic 32 + 33 - 34 Racemic 35 + 36 - 37 Racemic X) 38 + 39 - 40 racemic 41 + 42 - 43 racemic 44 + 45 - 46 racemic 47 + 48 -

No. Racemic or palmar isomer -Y-R1 49 Racemic 〆, 50 + 51 -

127094 -20- 200835498

52 racemic 53 + 54 - 55 racemic 56 + 57 - 58 racemic 59 + 60 - 61 racemic X) 62 + 63 - 64 racemic 65 + 66 - 67 racemic 68 + 69 - 70 racemic 71 + 72 - number racemic or palmomer isomer -Y-R1 73 racemic oxime, 74 + 75 - 76 racemic 77 + 78 - 79 racemic 80 + 81 - 127094 - 21 - 200835498

82 racemic 83 + 84 - 85 racemic X) 86 + 87 - 88 racemic 89 + 90 - 91 racemic 92 + 93 - 94 racemic 95 + 96 - number racemic or palm STRUCTURE - Y-R1 97 racemic oxime 98 + 99 - 100 racemic 101 + 102 - 103 racemic 104 + 105 - 106 racemic 107 + 108 - 109 racemic X) 110 + 111 - 127094 -22- 200835498 112 racemic 113 + 114 - 115 racemic 116 + 117 - 118 racemic jXr 119 + 120 - number racemic or palmomerisomer -Y-R1 121 racemic oxime, 122 + 123 - 124 racemic 125 + 126 - 127 racemic 128 + 129 - 130 racemic 131 + 132 - 133 racemic X) 134 + 135 - 136 racemic 137 + 138 - 139旋140 + 141 - ch3o 127094 -23- 200835498

142 racemic 143 + 144 雠 number racemic or palmomer isomer Y-R1 145 racemic 〆, 146 + 147 - 148 racemic 149 + 150 - 151 racemic 152 + 153 - 154 Race 155 + 156 - 157 racemic J 158 + 159 - 160 racemic 161 + 162 - 163 racemic 164 + 165 - 166 racemic 167 + 168 - 127094 -24- 200835498 number racemic or pair Palmomer isomer-Y-R1 169 racemic oxime, 170 + 171 - 172 racemic 173 + 174 - 175 racemic 176 + 177 - 178 racemic 179 + 180 - 181 racemic X) 182 + 183 - 184 racemic 185 + 186 187 racemic 188 + 189 - 190 racemic 191 + 192 -

No. rac or palm toomer -Y-R1 193 racemic 194 + 195 -

127094 -25 - 200835498

196 racemic 197 + 198 cycles 199 racemic 200 + 201 a 202 racemic 203 + 204 - 205 racemic X) 206 + 207 - 208 racemic 209 + 210 - 211 racemic 212 + 213 - 214 racemic 215 + 216 - 3 tiger racemic or palmomer isomer - Y-R1 217 racemic oxime, 218 + 219 - 220 racemic 221 + 222 - 127094 -26- 200835498

223 racemic 224 + 225 - 226 racemic 227 + 228 - 229 racemic J 230 + 231 - 232 racemic 233 + 234 - 235 racemic 236 + 237 雠 238 racemic 239 + 240 - No. Racemic or palmomer isomer-Y-R1 241 racemic oxime, 242 + 243 - 244 racemic 245 + 246 - 247 racemic 248 + 249 - 250 racemic 251 + 252 - 127094 - 27- 200835498

253 racemic AJ 254 + 255 - 256 racemic 257 + 258 - 259 racemic 260 + 261 - 262 racemic 263 + 264 - number racemic or palmomerisomer - Y-R1 265 Cyclo 266 + 267 - 268 racemic 269 + 270 - 271 racemic 272 + 273 - 274 racemic 275 + 276 - 277 racemic Λ) 278 + 279 - 280 racemic p 281 + 282

127094 -28- 200835498

No. Racemic or palmar isomer - Y-R1 289 racemic oxime, 290 + 291 - 292 racemic ^0 293 + 294 - 295 racemic 296 + 297 - 298 racemic 299 + 300 - 301 racemate J 302 + 303 - 304 racemic r° 305 + 306 - 307 racemic jXX 308 + 309 - 310 racemic 311 + 312 -

127094 -29- 200835498 r % number racemic or palmomer isomer-Y-R1 313 racemic 314 + 315 - 316 racemic 317 + 318 - 319 racemic 320 + 321 - 322 racemic 323 + 324 - 325 racemic X) 326 + 327 - 328 racemic 329 + 330 - 331 racemic fK 332 + 333 - 334 racemic 335 + 336 - R1

O

No. rac or palm toomer -Y-R1 337 racemic 338 + 339 -

127094 -30· 200835498

340 racemic 341 + 342 343 racemic 344 + 345 346 racemic 347 + 348 - 349 racemic X) 350 + 351 - 352 racemic 353 + 354 - 355 racemic 356 + 357 _ 358 Racer 359 + 360 - / number racemic or palmomerisomer - Y-R1 361 racemic 362 + 363 - 364 racemic 365 + 366 - 367 racemic 368 + 369 -

127094 -31 - 200835498

370 racemic 371 + 372 - 373 racemic J 374 + 375 - 376 racemic 377 + 378 - 379 racemic 380 + 381 - 382 racemic 383 + 384 - number racemic or palm STRUCTURE - Y-R1 385 racemic oxime, 386 + 387 - 388 racemic 389 + 390 - 391 racemic 392 + 393 - 394 racemic 395 + 396 - 397 racemic X) 398 + 399 - 〇h3〇127094 -32- 200835498 400 racemic 401 + 402 - 403 racemic 404 + 405 - 406 racemic 407 + 408 - number racemic or palmomerisomer -Y-R1 409 racemic 〆, 410 + 411 - 412 racemic ^0 413 + 414 - 415 racemic 416 + 417 - 418 racemic 419 + 420 - 421 racemic X) 422 + 423 - 424 racemic 425 + 426 - 427 racemic fK 428 + 429 - h2n 127094 -33 - 200835498

430 racemic 431 + 432 - number racemic or palmomer isomer - Y-R1 433 racemic 〆, 434 + 435 - 436 racemic 437 + 438 - 439 racemic 440 + 441 - 442 Racemic 443 + 444 - 445 racemic J 446 + 447 448 racemic 449 + 450 - 451 racemic 452 + 453 - 454 racemic 455 + 456 - 127094 -34- 200835498 \ number racemic or Opposite-Y-R1 457 racemic oxime, 458 + 459 - 460 racemic 461 + 462 - 463 racemic 464 + 465 biliary 466 racemic ^cr 467 + 468 - 469 racemic X ) 470 + 471 - 472 racemic 473 + 474 - 475 racemic 476 + 477 - 478 racemic 479 + 480 -

No. rac or palm toomer -Y-R1 481 racemic 482 + 483 -

127094 -35- 200835498

484 racemic 485 + 486 - 487 racemic 488 + 489 - 490 racemic 491 + 492 sun 493 racemic 494 + 495 - 496 racemic 497 + 498 - 499 racemic fK 599 + 501 - 502 Racemic 503 + 504 - number racemic or palmomer toomer - Y-R1 505 racemic oxime, 506 + 507 - 508 racemic 509 + 510 - 511 racemic 512 + 513 - 127094 -36 - 200835498

514 racemic 515 + 516 - 517 racemic X) 518 + 519 520 racemic 521 + 522 - 523 racemic 524 + 525 - 526 racemic 527 + 528 number racemic or palmomer -Y-R1 529 Racemic 〆〆530 + 531 - 532 Racemic 533 + 534 - 535 Racemic 536 + 537 - 538 Racemic 539 + 540 - 541 Racemic. Human J 542 + 543 - 127094 -37- 200835498 544 racemic 545 + 546 - 547 racemic 548 + 549 - 550 racemic 551 + 552 - number racemic or palmomerisomer - Y-R1 553 racemic, 554 + 555 - 556 racemic 557 + 558 - 559 racemic 560 + 561 - 562 racemic 563 + 564 - 565 racemic X) 566 + 567 - 568 racemic 569 + 570 - 571 racemic 572 + 573 - 127094 -38- 200835498

574 racemic 575 + 576 - number racemic or palmomer isomer - Y-R1 577 racemic oxime, 578 + 579 - 580 racemic ^0 581 + 582 - 583 racemic 584 + 585 - 586 racemic 587 + 588 - 589 racemic J 590 + 591 - 592 racemic 593 + 594 - 595 racemic 596 + 597 雠 598 racemic 599 + 600 - 127094 -39- 200835498 Spin or palmomer isomer-Y-R1 601 racemic oxime, 602 + 603 - 604 racemic 605 + 606 607 racemic 608 + 609 - 610 racemic 611 + 612 - 613 racemic oxime 0 614 + 615 - 616 racemic 617 + 618 - 619 racemic 620 + 621 - 622 racemic 623 + 624 - 5 tiger racemic or -Y-R1 to palm isomer 625 racemic 626 + 627 sleep 127094 -40- 200835498 628 racemic 629 + 630 - dr 631 racemic 632 + 633 - 634 racemic 635 + 636 - 637 racemic 638 + zO 639 - 640 racemic 641 + f° 642 643 racemic 644 + 645 - 646 racemic 647 + 648 - numbered racemic or palmomer Y-R1 649 racemic oxime, 650 + 651 - 652 racemic 653 + 654 - 655 racemic 656 + 657 - ch3o 127094 -41 - 200835498 658 racemic 659 + 660 - 661 racemic X) 662 + 663 664 racemic 665 + 666 - 667 racemic 668 + 669 - 670 racemic 671 + 672 - number racemic or palmomer isomer - Y-R1 673 racemic, 674 + 675 - 676 racemic 677 + 678 - 679 racemic 680 + 681 - 682 racemic 683 + 684 - 685 racemic 686 + 687 - h2n 127094 -42- 200835498 688 racemic 689 + 690 - 691 racemic 692 + 693 - 694 racemic 695 + 696 - number racemic or palmomer isomer - Y-R1 697 racemic, 698 + 699 - 700 racemic 701 + 702 - 703 racemic 704 + 705 - 706 racemic 707 + 708 - 709 racemic 710 + 〆0 711 - 712 racemic 713 + r° 714 - 715 racemic 716 + 717 - 127094 -43 - 200835498

718 racemic 719 + 720 - number racemic or palmomerisomer - Y-R1 721 racemic oxime, 722 + 723 - 724 racemic 725 + 726 - 727 racemic 728 + 729 - 730 Racemic 731 + 732 - 733 racemic AJ 734 + 735 - 736 racemic 737 + 738 - 739 racemic 740 + 741 _ 742 racemic 743 + 744 - 127094 -44- 200835498 number racemic or pair Palmomer isomer-Y-R1 745 racemic oxime, 746 + 747 - 748 racemic 749 + 750 - 751 racemic 752 + 753 - 754 racemic 755 + 756 - 757 racemic 〆 0 758 759 - 760 racemic 761 + 762 - 763 racemic 764 + 765 - 766 racemic 767 + 768 -

Number racemic or palmomerisomer -Y-R1 769 racemic 770 + 771 -

127094 -45- 200835498

772 racemic 773 + 774 - 775 racemic 776 + 111 - 778 racemic: sound 779 + 780 - 781 racemic 782 + 783 - 784 racemic 785 + 786 - 787 racemic 788 + 789 - 790 racemic 791 + 792 - number racemic or palmomerisomer - Y-R1 793 racemic 794 + 795 - 796 racemic 797 + 798 - 799 racemic 800 + 801 127094 -46 - 200835498 802 racemic 803 + 804 - 805 racemic X) 806 + 807 - 808 racemic 809 + 810 - 811 racemic fK 812 + 813 雠814 racemic 815 + 816 - number racemic or Pair of palm isomers - Y-R1 817 racemic oxime, 818 + 819 - 820 racemic 821 + 822 - 823 racemic 824 + 825 - 826 racemic 827 + 828 - 829 racemic AJ 830 + 831 - 127094 -47- 200835498 832 racemic 833 + 834 - 835 racemic 836 + 837 - 838 racemic 839 + 840 雠 number racemic or palmomerisomer - Y-R1 841 racemic 〆 , 842 + 843 - 844 race 845 + 846 - 847 race 848 + 849 - 850 racemic 851 + 852 - 853 racemic person J 854 + 855 - 856 racemic 857 + 858 - 859 racemic 860 + 861 - 127094 -48- 200835498

862 racemic 863 + 864 - number racemic or palmomer isomer - Y-R1 865 racemic oxime, 866 + 867 - 868 racemic ^0 869 + 870 - 871 racemic 872 + 873 - 874 racemic 875 + 876 - 877 racemic • X) 878 + 879 880 racemic r° 881 + 882 - 883 racemic 884 + 885 - 886 racemic 887 + 888 - 127094 -49- 200835498 Racemic or para-isomeromer - Y-R1 889 racemic oxime, 890 + 891 - 892 racemic 893 + 894 - 895 racemic 896 + 897 - 898 racemic 899 + 900 - 901 Spin X) 902 + 903 - 904 racemic p 905 + 906 - 907 racemic fk 908 + 909 - 910 racemic 911 + 912 -

/ \ %

Cf3 CN number racemic or -Y-R1 to palm isomer 913 racemic 914 + 915 - 127094 -50- 200835498 916 racemic 917 + 918 - 919 racemic 920 + 921 - 922 racemic % 923 + 924 - 925 racemic AJ 926 + 927 - 928 racemic 929 + 930 - 931 racemic 932 + 933 - 934 racemic 935 + 936 - number racemic or palmomerisomer -Y -R1 937 racemic 〆〆938 + 939 940 racemic 941 + 942 - 943 racemic 944 + 945 - h2n 127094 -51 - 200835498

946 racemic 947 + 948 - 949 racemic AJ 950 + 951 - 952 racemic 953 + 954 - 955 racemic 956 + 957 958 racemic 959 + 960 - number racemic or palmomerisomer -Y-R1 961 racemic 962 + 963 - 964 racemic 965 + 966 - 967 racemic 968 + 969 970 racemic 971 + 972 973 racemic man 974 + 975 - 127094 -52- 200835498

976 racemic 977 + 978 - 979 racemic 980 + 981 - 982 racemic 983 + 984 - number racemic or palmomerisomer - Y-R1 985 racemic 〆〆986 + 987 988 Spin 989 + 990 - 991 racemic 992 + 993 994 racemic 995 + 996 999 997 racemate J 998 + 999 - 1000 racemic 1001 + 1002 - 1003 racemic 1004 + 1005 - 127094 -53 - 200835498

1006 racemic 1007 + 1008 - number racemic or palmomerisomer - Y-R1 1009 racemic oxime, 1010 + 1011 - 1012 racemic 1013 + 1014 - 1015 racemic 1016 + 1017 - 1018 Racem 1019 + 1020 - 1021 racemic AJ 1022 + 1023 - 1024 racemic 1025 + 1026 - 1027 racemic 1028 + 1029 - 1030 racemic 1031 + 1032 - 127094 • 54- 200835498 number racemic or pair Palmeromer-Y-R1 1033 racemic 1034 + 1035 雠1036 racemic 1037 + 1038 - 1039 racemic 1040 + 1041 - 1042 racemic 1043 + 1044 - 1045 racemic · / 0 1046 + 1047 - 1048 racemic 1049 + 1050 - 1051 racemic 1052 + 1053 - 1054 racemic 1055 + 1056

Number racemic or palmomerisomer -Y-R1 1057 racemic 1058 + 1059 嶋

127094 -55 - 200835498

1060 racemic 1061 + 1062 - 1063 racemic 1064 + 1065 - 1066 racemic 1067 + 1068 - 1069 racemic 1070 + 〆 0 1071 - 1072 racemic 1073 + 1074 雠 1075 racemic 1076 + 1077 - 1078 racemic 1079 + 1080 雠 number racemic or palmomerisomer - Y-R1 1081 racemic oxime 1082 1083 - 1084 racemic 1085 + 1086 draped 1087 racemic 1088 + 1089 127094 -56- 200835498

1090 racemic 1091 + 1092 - 1093 racemic oxime 0 1094 + 1095 - 1096 racemic 1097 + 1098 1099 racemic 1100 + 1101 - 1102 racemic 1103 + 1104 - % number racemic or palm Structure-Y-R1 1105 Racemic 〆〆1106 + 1107 Face 1108 Racemic 1109 + 1110 - 1111 Racemic 1112 + 1113 - 1114 Racemic 1115 + Sound 1116 - 1117 Racemic 1118 + 〆0 1119 -

127094 •57- 200835498

1150 racemic 1151 + 1152 - number racemic or palmomer isomer -Y-R1 1153 racemic oxime, 1154 + 1155 - 1156 racemic 1157 + 1158 - 1159 racemic 1160 + 1161 - 1162 Racemic ^cr 1163 + 1164 - 1165 racemic X) 1166 + 1167 1168 racemic 1169 + 1170 - 1171 racemic fx. 1172 + 1173 - 1174 racemic 1175 + 1176 - 127094 • 59- 200835498

1120 racemic 1121 + 1122 - 1123 racemic 1124 + 1125 - 1126 racemic 1127 + 1128 - number racemic or palmomerisomer -Y-R1 1129 racemic oxime, 1130 + 1131 - 1132 Racem 1133 + 1134 - 1135 racemic 1136 + 1137 - 1138 racemic 1139 + 1140 - 1141 racemic 乂 J 1142 + 1143 - 1144 racemic 1145 + 1146 - 1147 racemic 1148 + 1149 - 127094 - 58-200835498 No. Racemic or palmar isomer-Y-R1 1177 Racemic oxime, 1178 + 1179 - 1180 Racemic 1181 + 1182 - 1183 Racemic 1184 + 1185 - 1186 rac. 1187 + 1188 1189 racemic X) 1190 + 1191 - 1192 racemic 1193 + 1194 - 1195 racemic 1196 + 1197 1198 racemic 1199 + 1200 - ch30 number racemic or palmomerisomer - Y-R1 1201 Racem 1202 + 1203 - h2n 127094 -60- 200835498

1204 racemic 1205 + 1206 - 1207 racemic 1208 + 1209 - 1210 racemic 1211 + 1212 - 1213 racemic 〆 0 1214 + 1215 - 1216 racemic 1217 + 1218 1219 racemic 1220 + 1221 - 1222 Racemic 1223 + 1224 - number racemic or palmomerisomer - Y-R1 1225 racemic oxime 1226 + 1227 - 1228 racemic 1229 + 1230 bed 1231 racemic 1232 + 1233 - 127094 -61 - 200835498

1234 racemic 1235 + 1236 - 1237 racemic X) 1238 + 1239 - 1240 racemic P 1241 + 1242 1243 racemic 1244 + 1245 - 1246 racemic 1247 + 1248 - number racemic or palm Constituting -Y-R1 1249 racemic oxime, 1250 + 1251 - 1252 racemic 1253 + 1254 - 1255 racemic 1256 + 1257 - Jr 1258 racemic 1259 + acoustic 1260 - 1261 racemic 1262 + 〆0 1263 127094 -62- 200835498

1264 racemic 1265 + 1266 - 1267 racemic 1268 + 1269 - 1270 racemic 1271 + 1272 - number racemic or palmomerisomer - Y-R1 1273 racemic 〆〆 1274 + 1275 - 1276 Racem 1277 + 1278 - 1279 racemic 1280 + 1281 - 1282 racemic 1283 + 1284 - 1285 racemic X) 1286 + 1287 - 1288 racemic 1289 + 1290 - 1291 racemic 1292 + 1293 - 127094 - 63- 200835498

No. Racemic or palmar isomer -Y-R1 1297 Racemic 〆, 1298 + 1299 - 1300 Racem 1301 + 1302 - 1303 Racemic 1304 + 1305 - 1306 Racemic. ' 1307 + 1308 - 1309 racemic Μ 1310 + 1311 - 1312 racemic 1313 + 1314 - 1315 racemic 1316 + 1317 sleep 1318 racemic 1319 + 1320 - biological characterization of compounds according to the invention

1294 Racemic 1295 + 1296 - Luteinizing hormone receptor modulators can be confirmed by simple methods and test procedures known to the skilled person. For this project, for example, compounds to be tested 127094-64-200835498 and progestogens can be cultured in a test system for progesterone receptor ligands and examined by luteinizing hormone. The effect, whether in this test system, was changed in the presence of a regulator. The substance of the general formula I according to the present invention is tested in the following mode: Lutein hormone is measured by the binding affinity of the hip binding test receptor. · The total affinity of the body is specifically labeled by the 3沁-labeled hormone (tracer) And the compound to be tested is measured for competitive binding to the cell of the organ to be automatically labeled. The goal in this case is receptor saturation and reaction equilibrium. The tracer and the increasing concentration of the test compound (competitor) were co-cultured with the cytosol fraction containing the receptor for 18 hours at 〇-4t:. After removing the unbound tracer with a carbon-dextran suspension, the tracer content of the receptor binding is measured as per-concentration and IC5. The system is determined from the concentration series. The relative molar concentration binding affinity (RBA) is calculated as the ratio of the reference substance to the IC5 enthalpy of the compound to be tested (χ 1〇〇%) (milk of reference material = 100%). The following culture conditions are selected for the type of receptor: Luteinizing hormone receptor: Estradiol-induced uterine cytosol in rabbits, in TED buffer with 250 1111^ 蔑 sugar (20 mM Tris/HC1, ρΗ7·4; 1 Homogenization in diamine tetraacetic acid, 2 mM dithiothreitol; stored under _3 。. Tracer: 3H_ORG2〇58,5nM; reference substance: progesterone. Corticosteroid-like receptor: 127094 -65- 200835498 The thymocyte solute from the thymus of the adrenalectomy rat, stored under C; buffer: TED. Tracer: dexamethasone, 20 nM; reference substance · dexamethasone. The competition factor (CF value) of the compound of the general formula (I) according to the invention for the luteinizing hormone receptor is between 〇·2 and 35, relative to the progestin. The CF value for cortisol-like styles is in the range of 3 to 35 relative to dexamethasone. The compounds according to the invention therefore have a high affinity for the progesterone receptor' but only a low affinity for the corticosteroid receptor. Antagonism of the progesterone receptor PR The detection of transfer activation was carried out as described in WO 02/054064. The IC5 threshold is in the range of 0.1 to 15 〇 ηΜ. The detection of transfer activation of the xanthine receptor PR is carried out as described in Fuhrmarm et al. (Fuhrmann U. 5 Hess-Stump H.? Cleve A, Neef G.? Schwede W, Hoffmann J Fritzemeier K. -H" Chwalisz K., Journal of Medicinal Chemistry, 43, 26, 2, 5010_5016. EC50 values in the range of 0.01 to i5 〇 nM. Dosage of the progesterone receptor modulator for use according to the invention In addition, it can be administered orally, enterally, parenterally or transdermally. When the dosage of the sputum covers the range of 1 microgram to 1000 mg of the compound according to the invention, the treatment of the indication mentioned above is mentioned. In general, satisfactory results are expected, with regard to gynaecological indications, such as treatment of ectopic endometrial tissue formation, uterine leiomyoma and dysfunctional bleeding, and for use in fertility control and hormone replacement therapy. Oncology indications are to be administered daily according to the compounds of the invention at doses ranging from 1 microgram to 200 milligrams per day. Compounds according to the invention are used in humans for therapeutic purposes. Ectopic formation of endometrial tissue, leiomyomas and dysfunctional uterine bleeding, and appropriate doses for fertility control and hormone replacement therapy are 5 〇 to 5 〇〇 per day, depending on the age and physique of the patient Alternatively, the daily dose may be administered by single or multiple administration. The dose of the compound according to the invention for the treatment of breast cancer ranges from 1 mg to 2 mg per day. The basic pharmaceutical product is formulated in a manner known per se, via a substance, a binder, a moisturizer, a lubricant, an absorbent, which disintegrates the active ingredient into a carrier material which is used in medical technology. The diluent 'masking flavors, colorants, etc. are processed and converted into the desired form of administration. For this, reference should be made to Remingt〇n's Pharmaceuticals, 15th Edition, Mack Publishing Company, East Pennsylvania (1980). For oral administration, especially tablets, film coated tablets, sugar coated tablets, capsules, pills, powders, granules, lozenges, suspensions, emulsions or solutions Formulations for injection and infusion may be administered parenterally. Appropriately prepared crystalline suspensions may be used for intra-articular injections. t. In aqueous and oily solutions or suspensions and corresponding storage formulations, may be used Intramuscular injection. For rectal administration, the novel compounds can be used in the form of suppositories, capsules, solutions (for example in the form of an enemas) and ointments for both systemic and topical therapy. Compositions of 127094-67-200835498 As a formulation, the drug 'which can be aerosolized and inhaled' can also be referred to for use in the vaginal use of the pulmonary compound in the form of the novel compound. Adhesives are available for transdermal administration, and are formulated as gels, ointments, fat ointments, whey, granules, powders, lotions, and granules for topical application. Formula = The dose in these preparations should be %_ listened to achieve a proper effect. The corresponding tablets can be obtained, for example, by mixing the active ingredient with known excipients such as an inert diluent such as dextrose, sugar, flower, alcohol, polytetraethyltetrahydro (tetra), disintegrant Such as corn starch or alginic acid' binders, such as w gelatin, lubricants, such as stearic acid or talc, and / or devices that achieve storage, such as polymethyl compounds, methine cellulose, fiber Acetic acid vinegar or polyvinyl acetate vinegar. Tablets can also contain many layers. Correspondingly, the coated tablet can be coated with a tablet-like composition via a composition which is usually used in a coating of a tablet, such as polyvinyltetrahydropyrrolidone or shellac, gum arabic, talc, titanium dioxide or sugar. Made into a core. The lunar covering may also contain more than one in this case, and the excipients mentioned above for the tablets may be used. The solution or suspension of the compound of the formula I according to the invention may additionally comprise a taste improver such as saccharin, cyclohexylamine lysine or sugar, and for example a scenting agent such as vanillin or an orange extract. It may additionally comprise suspending excipients, such as sodium methicone, or preservatives, such as p-benzoic acid. Capsules comprising a compound of formula 1 can be prepared, for example, by carcinating a compound of formula I with an inert 127094-68.200835498 sexual carrier such as lactose or phytosterol and coating it in gelatin. The appropriate suppository can be prepared, for example, by mixing with a carrier to be used in the present invention, such as a neutral fat or polyethylene glycol or a derivative thereof. The compound of the formula 1 or a pharmaceutically acceptable salt thereof according to the present invention, because of its antagonistic or partial stimulating activity, can be used for the manufacture of a medicament, in particular for the treatment and prevention of gynecological disorders, such as ectopic formation of endometrial tissue. , leiomyomas of the uterus, dysfunctional bleeding and menstrual difficulties. It can further be used to neutralize hormonal irregularities, to induce menstruation, and to use either prostaglandin and/or oxytocin alone or in combination to induce labor. The compound of the formula 1 according to the present invention or a pharmaceutically acceptable salt thereof is further suitable for the manufacture of a product for contraception in women (see also w〇 93/23〇2〇, 93/21927). The compound according to the present invention or a pharmaceutically acceptable salt thereof may be additionally used alone or in combination with a selective estrogen receptor modulator (SERM) for use in female hormone replacement therapy. Furthermore, the compound has an anti-proliferative effect in hormone-dependent tumors. Therefore, it is suitable for use in the treatment of hormone-dependent cancer, such as breast, prostate and endometrial cancer. The compounds according to the invention, or pharmaceutically acceptable salts thereof, can be used in the treatment of hormone-dependent cancers, both in first-line treatment and in second-line treatments, especially after failure of tamoxifen . a compound of the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention having antagonistic or partial stimulating activity, or a compound having an antiestrogenic activity (estrogen receptor antagonist or aromatase inhibitor) or selection The sex estrogen receptor 127094-69-200835498 modulator (SERM) is used in combination to make a pharmaceutical product for the treatment of hormone-dependent tumors. The compounds according to the invention may likewise be used in combination with a SERM or an anti-estrogen agent (although a hormone receptor antagonist or an aromatase inhibitor) for the treatment of ectopic tissue formation or leiomyomas of the uterus. Suitable for use in combination with a non-steroidal luteinizing hormone receptor modulator according to the invention 'in this connection, for example, the following anti-estrogen agent (estrogen receptor antagonist or aromatase inhibitor) or SERM: tamoxifen , 5-(4-{5-[(118)-(4,4,5,5,5-pentenylpentyl)sulfinyl]pentyloxy}phenyl)_6_phenyl-8,9 -Dihydro-7H-benzocyclohepten-2-ol (WO 00/03979), ICI 182 780 (7 α-[9_(4,4,5,5-pentafluoropentylsulfinyl)壬基]Estragen-1,3,5(10)•Triene_3,17/3-diol), 11 fluorocarbon _7α-[5-(methyl{3-[(4,4,5) ,5,5-pentafluoropentyl)thio]propyl}amino)pentyl]-estra-1,3,5(10)·triene_3,17/3_diol (WO 98/ 07740), 11 fluoroyl-7 [methyl (7,7,8,8,9,9,10,10,10-nonafluoroindolyl)amino]pentyl}-est-1,3,5 ( 10)-Triene _3,17-diol (WO 99/33855), 11/3-fluoro-based hydrazine; _methyl-7 α-{5-[methyl (8,8,9, 9,9-pentafluoroindenyl)amino]pentyl}estr_1,3,5(10)-triene-3,17/5-diol (|〇03/045972), clomiphene (〇1〇11^61^), raloxifene, and other antiestrogenic activities And aromatase inhibitors, such as fadrozole, formestane, letrozole, anastrozole or atamestane . Finally, the invention also relates to the use of a compound of formula I, where appropriate, with an antiestrogen or SERM, in the manufacture of a medicament. The invention further relates to a pharmaceutical composition comprising at least one compound according to the invention, suitably in the form of a pharmaceutically/pharmaceutically acceptable salt 127094-70-200835498. These medicinal groups may be intended for oral, rectal, vaginal, subcutaneous, intradermal or intramuscular administration. In addition to conventional carriers and/or diluents, it comprises at least one compound according to the invention. The medicament of the present invention is manufactured by a conventional solid or liquid carrier or diluent, and an excipient which is usually used in a pharmaceutical technique and is suitable for the mode of administration to be administered, in a known manner. Preferred formulations include those suitable for oral administration

The dosage form of the medicine. Examples of such dosage forms are tablets, film coated tablets, sugar coated H capsules, pills, powders, solutions or suspensions, where appropriate, in the form of a reservoir. A pharmaceutical composition comprising at least one compound according to the invention is preferably administered orally.

Also suitable are parenteral preparations such as solutions for injection. Other formulations which may also be mentioned are, for example, suppositories, and compositions for vaginal use. Preparation of the compounds of the invention:

y\/ Η H Grignard or organic compound addition

VIII Scheme 1 127094 -71 - 200835498 The compound of formula i can be synthesized, for example, as shown in the scheme 丨. From the type 〗 〖 aldehydes Key growth can be achieved, for example, by the Horner-Wittig reaction. The reduction of the double bond', e.g., by hydrogenation in the presence of a suitable catalyst, results in a compound of formula IV which is oxidized to a ketone by the acylation followed by oxidation of the formed alcohol to a ketone. For the preparation of the α-hydroxylation of the compound of the formula v, various methods known in the literature can be used, for example, 2-dimercaptooxyziridine, by the method described by Davis et al. (j. 〇$. f 1984, do, 3241). Oxidation to the compound of formula VI can then be accomplished by known standard methods. The hydrazines of the formula VIII are produced, for example, by the formation of ruthenium chloride and subsequent reaction with the corresponding amines. Alternatively, for this project, other methods of forming guanamine may also be utilized depending on the amine to be introduced. Then, the compound of the formula I is prepared from a compound of the formula νπι oxime by repeated addition of a Grignard or an organolithium compound. Nonetheless, step 1_7 can also be performed in the order of change. In many cases, intermediate compounds of formula III-VII are also commercially available. Substituents A, X, Y, Ri, R2, R3 and R4 may be further modified after they have been introduced, as appropriate. For this project, possible reactions include, for example, oxidation, reduction, alkane a coupling reaction by catalysis, deuteration, nucleophilic addition or transition metal catalysis. The functional group in the compound of the formula II-VIII is optionally in the middle, and then in the appropriate stage. The following examples are provided to illustrate the subject matter of the present invention in detail without intending to limit it thereto. Aminomethyl 2,3_benzoxanthene + ketone The preparation is described in w〇127094-72-200835498 199854159 6_(4,4-dimethyl-2-ketopentylamino)·4-methyl_2,3_benzopyrene p well- Preparation of 1-ketone:

4,4-Dimethyl-2-ketodecanoic acid (75 g) was dissolved in 10 ml of N,N-didecylacetamide. At -10 ° C, 460 μl of sulfinium dichloride dichloride was added, and the mixture was left to stand at -10 ° C for one hour. Then, 1.28 g of 6-amino-4- was added in portions. Methyl-2,3-benzo-4 p small ketone. Then, the mixture was further mixed for 3 hours (-l 〇 ° C to 0 ° C.) Then, the reaction mixture was poured onto ice water. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography eluting with hexane/ethyl acetate. 1.41 g of product was obtained. 1H NMR (ppm, CDC13, 300 MHz): 1.08 (9H)5 2.60 (3H), 2.93 (2H)? 7.84 (1H),8·31 (1H), 8.38 (1H); 18 (1H). Example 1: Racemic 6-[2(2,2-dimethylpropyl)-2-hydroxypent-3-ynylamino)]methanol-2,3-benzene And the loss of v well-1-阙

Add 1-propynylmagnesium bromide (2.65 ml, 0.5 M in tetrahydrofuran) to 6·(4,4-dimethyl-2-ketopentylamino)-4-methyl-2 , 3-benzoxanthone 127094-73-200835498 (200 mg) in THF (5 mL) which was cooled to -70 °C. The reaction solution was allowed to come to room temperature under argon gas for 3 hours, and then stirred for another 16 hours. The reaction mixture was then poured onto an ice-cold saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution and dried over sodium sulfate. The resulting crude product was chromatographed on silica gel. 168 mg of product was obtained. 1H NMR (ppm5 CDC13 5 400 MHz): 1.08 (9H)5 1.99 (3H), 2.07 (2H)? 2.58 (3H),2·90 (1H),7·70 (1H), 7.83 (1H), 8.40 (1H), 9·10 (1H)· Example 2: Racemic-6-[2(2,2-dimethylpropyl)_2-pyridyl-4-phenylbut-3-ylideneguanamine 4-methyl-2,3_benzoindole-i-ketone

To a solution of 145 microliters of phenylacetylene in tetrahydrofuran, n-butyllithium (830 microliters, 1.6 liters in hexane) was added at -78 °C. The mixture was left to stir at this temperature for 30 minutes, and then 6-(4,4-dimethyl-2-03⁄4ylpentyl)-4-methyl-2,3-benzoquinone p was added dropwise. - A solution of Ι-g with (200 mg) in 5 ml of tetrahydrofuran. Next, the mixture was brought to 23 ° C for about 3 hours and then stirred for 10 hours. Next, the reaction mixture was poured onto an ice-cold saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution and dried over sodium sulfate. The crude product was chromatographed on silica gel. 199 mg of product was obtained. 127094 • 74- 200835498 1H NMR (ppm, CDC13, 400 MHz): 1.14 (9H), 2.15-2.25 (2H), 2.58 (3H), 3·20 (1H), 7.27-7.49 (3H), 7.43 (2H), 7·22 (1H), 8·34 (1H), 8.40 (1H), 9.18 (1H). Examples 2a and 2b: (+)-6-[2(2,2_dimethylpropane) ))-2-yl-4-phenylbutyrate _3· fast-branched amino group]_4_methyl-2,3_benzoxanthine-1·one 2a and (_)-6-[2( 2,2·dimethylpropyl)_2_transcarbyl-4-phenylbutanyl fluorenylamine] ice methyl-2,3-benzopyrene-1-one 2b

Preparatory palmar HPLC

Examples 3 and 4 were synthesized as in Example 2: Example 3: The racemic mixture obtained in Example 2 was borrowed (tube, 曰 2a 2b)

•3·block ugly 127094 -75- 200835498

1H NMR (ppm, CDC13, 400 MHz): 1·13 (9H), 2.12-2.25 (2H), 2.32 (3H), 2.56 (3H), 3.39 (1H)5 7.10 (2H), 7.30 (2H)? 7.73 (1H)5 8.31 (1H), 8.38 (1H)5 9.22 (1H). Examples 3a and 3b: (+)-6-[2(2,2-dimethylpropyl)·2_carboxy-4_ (4-methylphenyl) butyl each fluorenylamino]-4_methyl-2,3-benzopyrene-1-1-one 3a and (+6·[2(2,2-dimethyl) Propyl)·2-hydroxy-4-(4-methylphenyl)butynynylamino]]_4_methyl·2,3_benzopyrene 3b

The racemic mixture obtained in Example 3 was prepared by the preparation of the palmitic isomers 3a and 3b. Into = 589 nm) λ 489 nm) (column: Chimlpak AD 250 χ 10 mm), separated into pairs of palms 3a: [〇:] D2〇: +24.8° (CHC13, 11.2 mg/; [ml; 3b: [ a]D2〇: _192〇(CHCl3,5 !mg A ml; Example 4: racemic·6-[2(2,2-dimethylpropyl)-2-hydroxy_4_(4_three gas^ ^ ^ 虱methylphenyl) butyl-3 fast-branched amino group]_4_mercapto-2,3-benzopyrene +_ 127094 -76- 200835498

1H NMR (ppm, CDC13, 400 MHz): 1.16 (9H), 2·16·2·28 (2H), 2.59 (3H), 3·21 (1H), 7.50-7.62 (4H), 7·76 ( 1H), 8·35 (1H), 8.40 (1H), 9·17 (1H). Examples 4a and 4b: (10)-6-[2(2,2-dimethylpropyl)·2·hydroxy-4 -(4-trifluoromethylphenyl)buty-3-alkynylamino]-4-methyl-2,3_benzoindole small ketone 4a and (a)-6_[2(2,2-a Methylpropyl)_2_transyl-4-(4·trismethylphenyl)butan-3-furanylamino]4-methyl-2-,3_benzo-1^ ·嗣4b

The racemic mixture obtained in Example 4 was separated from the palmar isomer by means of a preparatory pair of Ηρα (column: Chimlpak AD 250 x 10 mm). Such as: [af 20 : +13.r (CHCl3, 11.8 mg 毫升 ml; input = 589 nm) Servant: [af 20 : _13.3 〇 (ChC13, 10.1 mg 毫升 ml; input = 589 nm) Example 5 : racemic-6-[4,4-dimethyl-2-hydroxy-2-phenylpentanylamino]bendenyl 2,3_benzoindole-1 ketone 127094 -77 - 200835498

A 1 molar solution (1·32 ml) of phenyl > stinky town in tetrahydrofuran was diluted with 2 ml of anhydrous tetrahydrofuran. The mixture was cooled to _7 〇ι, then 200 mg of 6-(4,4-dimethylbutanylpentylamino) glacial thiol 2,3_benzo-4 ketamine was added at 5 liters. A solution in tetrahydrofuran. Next, the mixture was left to stir at -70 C for 3.5 hours. Then, the reaction mixture was poured onto an ice-cold saturated chlorinated solution. It was extracted with ethyl acetate. Washed with saturated sodium chloride solution. The organic phase was dried over sodium sulfate and the crude material was purified eluted eluted eluted eluted eluted eluted eluted with 2.59 (3Η), 2.77 (1Η), 2.97 (1Η), 7.30-7.45 (3Η), 7.68-7.79 (3Η), 8.30 (1Η), 8·34 (1Η), 9·32 (1H). Example 6: C racemic dimethyl-2-hydroxyl-2-(phenylmethyl)pentanylamino]methanol-2,3-benzopyrene

A 2 molar solution of benzylmagnesium hydride in tetrahydrofuran (665 microliters) was diluted with 2 ml of anhydrous tetrahydrofuran. The mixture was cooled to _70 ° C, then 200 mg of 6-(4,4-dimethyl-2-ketopentylamino) glacial methyl 2,3-benzene 127094 -78-200835498 was added and A solution of cultivating 1-ketone in 5 ml of tetrahydrofuran. Next, the mixture was left to stir at -70 ° C for 1.5 hours. Then, the reaction mixture was poured onto an ice-cold saturated ammonium chloride solution. It was extracted with ethyl acetate. The combined organic phases were washed with a saturated sodium chloride solution and dried over sodium sulfate. The crude product was chromatographed on silica gel. Obtained 116 mg of product. 1H NMR (ppm, CDC13, 300 MHz): 1·〇〇(9H), 1.64 (1H), 2·26 (1H), 2·35 (1Η), 2.59 (3Η), 2.78 (1Η), 2· 31 (1Η), 7.18 (2Η), 7·22_7·32 (3Η), 7.59 (1Η), 8.19 (lH), 8.28 (1H)? 8.87 (1H). Examples 6a and 6b: (+)_6_[4 , 4_dimercapto-2-yl-based 2-(phenylindenyl)pentanylamino]-indoleyl 2,3_benzoindole-1-one 6a and (-)-6_[4, 4-_Dimethyl-2-yl-2-(phenylmethyl)pentanylamino]_4_methyl-2,3_benzoindole 6b

The racemic mixture obtained in Example 6 was separated from the palmar isomers 6a and 6b by preparative palmarity (column: Chiralpak AD 250 x 10 mm). 6a : [a]D20 : +142.0o (CHC13, 10.1 mg / 1 ml; again = 589 nm) 6b : [a]D20 : -133.8 〇 (CHCl3, 10.2 mg / 1 ml; again = 589 nm) Preparation of Examples 7 and 8 as starting materials for 6-(4-[1,3]dioxoin-2-yl-4-methyl-2-ketopentylamino)-4-methyl Preparation of -2,3-benzopyrene p--1-one: a) 3 ((tert-butyldiphenylphosphonyloxy)-2,2-dimethylpropane + alcohol 127094 -79- 200835498

In a suspension of NaH (3.99 g) in anhydrous tetrahydrofuran, add 1 〇2,2·dimethylpropane in the underarm, and 3-diol in (10) ml of anhydrous tetrachloroethylene. Solution. The mixture was stirred and left to stand for 45 minutes, followed by the addition of 26 liters of a solution of butyl butyl phenyl sulfonate in 3 liters of anhydrous tetrazolium. The mixture was left to stand at 23t: for 15 hours. Then, the reaction mixture was poured onto a saturated aqueous solution of sodium hydrogencarbonate. The mixture was re-synthesized for 1 minute' and then transferred to B. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The resulting crude product (35 g) was used directly in the next stage.

b) 3_(Third-butyldiphenylphosphonyloxy)·2,2_two

The compound (35 g) described in a) was dissolved in 5 mL of dichloromethane. With gentle cooling, 7 ml of triethylamine and 25 ml of dimethyl sulfoxide were added, and the mixture was further stirred for 3 minutes. Then, 4 g of sulfuric anhydride was added to the pyridine complex. The mixture was left to stir at 23 ° C for 2 hours. Then, the reaction mixture was poured onto a saturated aqueous solution of ammonium chloride. The mixture was again left to stir for 30 knives and then extracted with di-methane. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The crude product formed (34 g) was used in the next stage without purification. Di-butyl(2-[1,3]-oxo-indol-2-yl-2-methylpropoxy)diphenyl sinter 127094 -80- 200835498

The crude product obtained in b) was dissolved in 300 ml of benzene. 80 ml of ethylene glycol and 2.5 g of p-toluenesulfonic acid were added, and the mixture was placed on a water separator and boiled for 5 hours. Next, the reaction mixture was poured onto saturated sodium bicarbonate water / broth. The mixture was extracted with ethyl acetate. Then, the organic phase was washed with a saturated aqueous solution of sodium sulfate, dried over sodium sulfate and evaporated. The resulting crude product was chromatographed on silica gel. 28 g of product were obtained. lU NMR (ppm? CDC13 5 300 MHz): 0.95 (6H)? 1.05 (9H), 3.51 (2H)5 3.80-3.93 (2H)5 4.82 (1H), 7.32-7.48 (6H), 7.65-7.73 (4H d) 2_[1,3] Dioxol-2-yloxamethylpropanol The product obtained in c) (28 g) was dissolved in tetrahydrofuran. Tetrabutylammonium fluoride was added, and the mixture was left to stir at 4 ° C for 2.5 hours. Then, the reaction mixture was poured onto a saturated aqueous solution of sodium hydrogencarbonate. The mixture was stirred for a further 15 minutes and then extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The resulting crude product was chromatographed on silica gel. 8.88 g of product were obtained. 4 NMR (ppm, CDC13, 400 MHz): 0.94 (6H), 2·56 (1H), 3·47 (2H) 3.83-4.00 (4H)? 4.11 (1H). e) 2-[l,3] Dioxin-2-yl winter methyl propionaldehyde

127094 -81 - 200835498 A method similar to that described in b), wherein the product obtained in d) (8·88 g) is precipitated as a sulphuric anhydride 4, dimethyl hydrazine, triethylamine in a gas smoldering Oxidation. The resulting crude product was chromatographed on silica gel. 6.2 g of product was obtained. 4 NMR (ppm, CDC13, 400 MHz): Ul (6Η), 3.85-4·00 (4Η), 4.83 (1Η), 9.65 (1Η). f) 4-Π,3]—Oxygen 圜 - Ethyl 2-methyl-4-methylpent-2-enoate in a suspension of sodium hydride (2.58 g) in 30 ml of dimethoxyethane. Under 〇C, slowly add 12.91 ml 2- A solution of (diethoxyphosphonio)ethyl acetate in 40 ml of dimethoxyethane. The mixture was further stirred and stirred for 1 hour, followed by the addition of 6.2 g of a solution of the material described in e) in 40 ml of dimethoxyethane. Then, the mixture was brought to 23 ° C and stirred at this temperature for 2.5 hours. Next, the reaction mixture was poured onto a saturated aqueous solution of ammonium chloride. The mixture was left to stand for further 15 minutes and then extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The resulting crude product was chromatographed on silica gel. 8.67 g of product was obtained. !H NMR (ppm, CDC135 400 MHz): 1.09 (6H)5 1.28 (3H)5 3.80-3.97 (4H)? 4·18 (2H),4·63 (1H),5·84 (1H),7_00 (1H). g) 4-[l,3]Ethoxy-2-oxo-4-methylpentanoate

A solution of the material described in f) (8.67 g) in a mixture of ethanol and tetrahydroanthracene 1 liter 127094 -82 - 200835498 1:1, hydrogenated in the presence of palladium-carbon at standard pressure . After filtration with suction and concentration, 8·25 g of crude material was obtained, which was used in the next stage without further purification. h) 4-[1,3]dioxoindol-2-yl-2-hydroxyl_4_indolyl valerate

To a solution of 2 g of the compound prepared in g) in 2 ml of anhydrous tetrahydrofuran, add 26.15 ml of hexamethyldisulfonium hexoxide in toluene in a solution of 5 mol concentration in toluene at -70 °C. . The mixture was placed at _7 Torr. The mixture was stirred for a further 3 sec., and then a solution of 3.4 g of 2-phenylsulfonyl phenyl oxyziridine in 35 ml of anhydrous tetrahydrofuran was slowly added. Next, the mixture was further stirred at -7 (rc) for one hour, and then poured onto a saturated aqueous solution of ammonium sulphate. The mixture was further stirred and stirred for 30 minutes, followed by extraction with ethyl acetate. The phases were dehydrated and dried over sodium sulfate. The crude product formed was extracted by stirring with a mixture of diisopropyl ether and hexane. Then, the mixture was filtered with suction, crystals were discarded, and the mother liquid was concentrated under reduced pressure. The crude product formed was chromatographed on silica gel to give 192 g of product. lH NMR (ppm5 CDC13 5 300 MHz): 1.00 (3H)? 1.03 (3H)? 1.29 (3H)? 1.65-1.85 (2H), 3· 44 (1H), 3.81-4.02 (4H), 4.20 (2H), 4.32 (1H), 4.61 (1H)· i) 4-[l,3]dioxoindol-2-yl-4-methyl- Ethyl 2-ketopentanoate

Add 100 ml of 1,1-dihydro-1,1,1-triethoxycarbonyl-1,2-benzene to a solution of 8 g of the compound described in h) in 1 mL of dichloromethane. And dioxin 圜 127094 • 83 - 200835498 ene-3(1H)-one (Dess-Martin periodinane) in a 35 molar concentration bath in dichloromethane. The mixture was left at 23 C for another 14 hours. Then, it was diluted with 500 ml of methyl tert-butyl ether, and then poured into a 1 liter aqueous solution of 34 g of sodium hydrogencarbonate and 100 g of sodium thiosulfate. The mixture was left to disturb for 30 minutes, then the liquid phase was separated and the aqueous phase was extracted with decyl-tert-butyl ether. The combined organic phases were washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous sodium chloride and dried over sodium sulfate. The crude product formed (7 7 g) was used in the next stage without further purification. j) 4-[1,3]-oxo-indole-2-yl-4-methyl-2-ketovaleric acid

A solution of 13.5 g of sodium hydroxide in 115 ml of water was added to a solution of the compound (7.7 g) in 1) in 230 ml of ethanol. The mixture was left to stir at 23 ° C for 14 hours, then diluted with water and extracted with ethyl acetate. Subsequently, the aqueous phase was acidified with a second concentration of hydrochloric acid (pH). Then, it was extracted with ethyl acetate, and the organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate, and concentrated under reduced pressure. The crude product formed (4 〇 5 g) was used in the next stage without purification. k) 6 (4-[1,3]- oxyoxazol-2-yl ice methyl-2-ketopentanyl Amino)_4_mercapto-2,3-benzoin

4.05 g of the carboxylic acid described in j) was dissolved in 1 ml of N N dimethylacetamide. At -10 ° C, 1 - 53 ml of di-sulfurized sulphur sulfoxide was added, and the mixture 127094 - 84 - 200835498 was further left to stand at -10 ° C for one hour. Next, 4.59 g of 6-amino-4-methyl-2,3-benzoindole-1-one was added in portions. Then, the mixture was left to stir for 3 hours (-10 ° C to 〇 ° C). Next, the reaction mixture was poured onto ice water. This was extracted with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The crude product was chromatographed on silica gel eluting with hexane / ethyl acetate. 2.52 g of product was obtained. lH NMR (ppm5 CDC135 300 MHz): 1.12 (6H)5 2.59 (3H)5 2.92 (2H)? 3.75-3.90 (4H), 4.59 (1H)? 7.88 (1H)5 8.30 (1H)? 8.38 (1H) , 9.15 (1H). Example 7: Racemic-6-[4,4-dimethyl-2,5-dihydroxy-2-phenylpentanylamino-4-bromo-2,3- Benzopyrene

a) racemic each [4-[1,3]dioxoindol-2-yl-2-hydroxy-4-indolyl-2-phenylpentanylamino]-4-methyl-2, 3_Benzene slogan ρ well-1-ketone

Similar to Example 5, 6-(4-[1,3]dioxoindol-2-yl-4-methyl-2-ketopentylamino)-4-methyl-2,3-benzene The hydrazine-i-ketone (5 mg) was reacted with phenylmagnesium bromide in tetrahydrofuran. After column chromatography, 317 mg of product was obtained. 1 H NMR (ppm, CDC13, 400 MHz): 0·95 (3Η), 1·08 (3Η), 2.25 (1Η), 2.56 (3H)? 2.71 (1H)? 3.92-4.15 (4H), 4.50 ( 1H), 6.70 (1H), 7.28 (1H)? 7.36 (2H), 127094 -85- 200835498 7·68 (1Η), 7·73 (2H), 8.28 (2H), 9·54 (1H)· b Racemic-6-[4,4-dimercapto-2,5-di-propyl-2-phenylpentylamino]methyl-2,3-stupid $ _ _1_酉The product obtained in 7a) (317 mg) was dissolved in 10 ml of acetone. 1 ml of 2 equivalents of hydrochloric acid was added, and the reaction mixture was allowed to stand for 14 hours under reflux. Next, the mixture was poured onto a saturated aqueous solution of sodium hydrogencarbonate and extracted with dioxane. The combined organic phases were washed with aq. The resulting crude product was dissolved in 5 mL of dimethoxyethane. The mixture was allowed to cool to 〇〇c. Then 22 mg of sodium borohydride was added. Then slowly add 250 μl of methanol. The mixture was left to stir at 0 ° C for 1.5 hours, and then the reaction mixture was poured onto a saturated aqueous solution of ammonium chloride. The mixture was then extracted with ethyl acetate. The combined organic phases were washed with a saturated aqueous solution of sodium sulfate, dried over sodium sulfate and evaporated. The resulting crude product was purified by column chromatography on silica gel. 78 mg of product was obtained. 1H NMR (ppm, CDC13, 400 MHz): 0·79 (3H), 1.04 (3H), 2·20 (1H), 2.53 (3H), 2·70 (1H), 3.50 (2H), 7.26 (1H ),7·35 (2H),7·68 (1H),7·77 (2H),8·23 (1Η),8·30 (1Η),9·60 (1Η)· Example 8: Racemic -6·[4,4-Dimethyl-2,5-dihydroxy-2-(phenylmethyl)pentanylamino H_methyl·2,3-benzopyrene ketone 127094 -86- 200835498

a) racemic-6_[2·benzyl-4-[l,3]dioxosyl-2-yl-2-hydroxy-2-hydroxyindoleylamino]-4-mercaptobenzopyran _ 酉同

Similar to Example 6, 6-(4-[1,3]dioxosylylene-based sulfonyl-2-ketopentylamino) ylmethyl-2,3-benzopyrene·丨· The ketone (5 mg) was reacted with mercapto magnesium chloride in tetrahydrofuran. After column chromatography, 39 mg of product was obtained. 1H NMR (ppm, CDC13, 300 MHz) ······························································· , 3.75-3.95 (4H)? 4.46 (1H)5 6.14 (1H)5 7.12-7.25 (5H)? 7.50 (1H)? 8.09 (1H)5 8.24 (1H)5 9.10 (1H). b) Racemic Each [4,4-dimethyl-2,5-dihydroxy-2-(phenylmethyl)pentanylamino]-4-methyl-2,3-benzoindole is similar to 7) The process described in the 'transformation of the compounds described in 8a). After column chromatography on the gum, 58 mg of product was obtained. 1H NMR (ppm, CDC13, 400 MHz): 0.99 (6H), 1·81 (1H), 2·50-2·58 (4H), 2.86 (1Η), 3.11 (1Η), 3·40_3·50 ( 2Η), 7.10-7.25 (5Η), 7_48 (1Η), 8·02 (1Η), 8.20 (1Η), 9.01 (1H). For the preparation of Examples 9, 10, 11 and 12 as starting materials 6-( Preparation of 3-cyclohexyl ketopropylamino)-4-methyl-2,3-benzopyrene ketone: 127094 -87- 200835498 1) 2-2-3-4-yl-3-cyclohexylpropanoate Purpose

To a solution of ethyl 3-cyclohexylpropionate (〇·4 Magic in tetrahydrofuran (7 ml), add potassium hexamethyldiazane solution at -70 ° C (5·6 mL, _, at The mixture was stirred at _7 (rc for 3 Torr, followed by the addition of 3-phenyl-2-phenylsulfonyloxyaziridine (〇·5 g) in tetrahydrofuran) The solution was left to stand under _7 ° 1 and stirred for one hour. Then, the reaction mixture was poured onto a saturated aqueous solution of ammonium sulphate. The mixture was stirred for another 30 minutes, and the liquid phase was separated. The organic phase was washed with a saturated aqueous solution of sodium chloride. Dehydrated and dried over sodium sulfate, and concentrated under reduced pressure. The crude product was chromatographed on silica gel to give 0.3 g of product. NMR (ppm, CDC13, 400 MHz): 0·89-1·01 ( 2Η), 1.10.1-2.25 (2Η), 1.30 (3H), 1.48-1.73 (8H), 1.84 (1H), 4.20-4.26 (3H). m) 2_keto-_3-cyclohexylpropionic acid ester

The product obtained in 1) (0.3 g) was oxidized in a manner similar to that described in i). The resulting crude product was chromatographed on silica gel. 0.22 g of product was obtained. 4 NMR (ppm, CDC13, 400 MHz): 0·98 (2H), 1.HM.29 (2H), 1.36 (3H) 1.58-1.71 (6H),1·89 (1H), 2.70 (2H), 4.31 (2H). η) 2-keto-3-cyclohexylpropionic acid

The product obtained in m) (1 g) was prepared in a manner similar to that described in j). The crude product (0.88 g) formed from 127094 - 88 - 200835498 was used in the next stage without purification. 〇) 6-(3-Cyclohexyl-2-ketopropenylamino)-4·methyl-2,3-benzoxanth-1-one

The crude product obtained in η) is produced by a method similar to k). The resulting crude product was chromatographed on silica gel. 1.3 g of product were obtained. lU NMR (ppm5 CDC13, 400 MHz): 1.04-1.34 (4H)5 1.58-1.77 (6H)5 1.92-2.02 (1H), 2.61 (3H), 2.91 (2H), 4.31 (2H), 7·86 ( 1H),8·34 (1H), 8.39 (1H), 9.17 (1H). Example 9: racemic _6-[3-cyclohexyl-2-ylidene-2-(phenylmethyl)propanthene Amino group]-4-mercapto-2,3·benzoxene depletion p--1-嗣

Similar to Example 6, 6-(3-cyclohexyl-2-ketopropylamino)-4-mercapto-2,3-benzoindole (150 mg) and benzylmagnesium chloride in tetrahydrofuran reaction. After column chromatography, 62 mg of product was obtained. 4 NMR (ppm, CDC13, 400 MHz): 0.97-1.26 (4H), 1.46-1.69 (7H), 1.77 (1H)5 2.10 (1H)5 2.24 (1H)5 2.59 (3H)5 2.91 (1H)5 3.35 (1H)? 7.18-7.31 (5H)5 7.60 (1H),8·23 (1H), 8.29 (1H), 8.85 (1H). Examples 9a and 9b: (+)-6_[3-ring Hexyl-2-yl-2-(phenylmethyl)propylamino]-4-methyl-2,3·benzene 127094 -89- 200835498 呤 呤 _1 ketone 9a and (-)-6 -[3·cyclohexyl_2_hydroxy_2_(phenylmethyl)propanylamino]_4_methyl-2,3_benzopyrene_-1,9b

The racemic mixture obtained in Example 9 was prepared by preparative palmarity (column: Chiralpak AD 250 x 10 mm), separated into palmar isomers such as %. % : [<20 : +l18.0〇 (CHCl3, 9.5 mg A ml; λ = 589 nm) Outside: [<20 : -112.8 «(CHC13, 9.2 mg 毫升 ml; input = 589 nm) Example 10: Racemic-6-[3-cyclohexyl-2_hydroxy_2·phenylpropanylamino]_4_methyl-2,3-benzopyrene

Similar to Example 5, 6-(3-cyclohexyl-2-ketopropenylamino)-4-methyl-2,3-benzoindole (150 mg) was combined with phenylmagnesium bromide. Reaction in tetrahydrofuran. After column chromatography, 76 mg of product was obtained. ]H NMR (ppm5 CDC135 400 MHz): 1.01-1.22 (4H), 1.50-1.76 (7H)? 2.11 (1H)5 2.42 (1H)5 2.55 (3H), 2.80 (1H)? 7.29-7.42 (3H) 5 7.65-7.70 (3H)? 8.29 (1H), 8.32 (1H), 9·19 (1H)· 127094 -90- 200835498 Example 11: Racemic-6-[3_cyclohexyl-2-hydroxy·2 -(phenylethynyl)propanylamino]methanol methyl-2,3-benzopyrene-1-one

Similar to Example 2, 6-(3-cyclohexyl-2-ketopropionylamino)-4-methyl-2,3-benzopyrene (150 mg) with phenylacetylene and positive- Butyllithium is reacted in tetrahydrofuran. After column chromatography, 120 mg of product was obtained. !H NMR (ppm5 CDC13 ? 400 MHz) : 1.06-1.33 (5H), 1.67-1.99 (6H)? 2.04 (1H), 2·13 (1H), 2·59 (3H), 3·23 (1H) , 7.29-7.37 (3H), 7·45 (2H), 7.73 (1H), 8·35 (1Η), 8.40 (1Η), 9·09 (1Η)· Examples 11a and lib : (+)- 6-[3_cyclohexyl-2-yl-2-(phenylethyl)pyridylamino]methanol methyl-2,3_benzoindole-1_one 11a and (-)-6- [3-cyclohexyl-2_hydroxy-2-(phenylethynyl)propanylamine-based 4-yl-2,3_ benzo- 〃 〃 嗣 lib

The racemic mixture obtained in Example 11 was prepared by preparative palmitic hpLC (column · Chimlpak AD 250 x 10 mm), separated into palmomerisomers lla and 127094 • 91 - 200835498 lla : [<20 : eO.iYCHCls, 9.8 mg 毫升 ml; λ = 589 nm) 11b: [a]D20: -21.4 〇 (CHCl3, 10.2 mg 71 ml;; 1 = 589 nm Example 12: racemic · 6-[3 -cyclohexyl-2-hydroxy-2-((4-methylphenyl)ethynyl)propanylamino]-4-methyl-2,3-benzopyrene

Similar Example 2 '6-(3-Cyclohexyl-2-ketopropenylamino)-4-indolyl-2-benzene-benzo-l-one (150 mg) with 4-methylphenyl Acetylene and n-butyllithium are reacted in tetrahydrofuran. After column chromatography, 170 mg of product was obtained. !H NMR (ppm, CDC13 5 400 MHz): 1.05-1.33 (5H), 1.67-1.98 (7H), 2.12 (1H), 2.35 (3H), 2·59 (3H), 3·24 (1H), 7·13 (2H), 7·34 (2H), 7.73 (1H), 8.35 (1Η), 8.39 (1Η), 9·09 (1Η). 127094 92-

Claims (1)

200835498 X. Patent application scope: 1. A compound of formula I Wherein A is a mouse, a Ci-Cg-alkyl group, a C2-Cg-fine group, a C2-Cg-fast group, or a Z-mono- or poly-substituted, or a C3-C10-cycloalkyl group, as the case may be. Or a 3-12-membered heterocycloalkyl group which may be mono- or polysubstituted by the same or different conditions, or Z itself, wherein the Z system is defined as follows: cyano group, halogen, hydroxyl group, nitro group, -C (0) Rb, C02Rb, -0-Rb, -S-Rb, S02NRcRd, -C(0)-NRcRd, -0C(0)-NRcRd, -C=NORb, -NRcRd, -P03(Rb)2 -NReCORb, -NReCSRb, -NReS(0)Rb, -NReS(0)2Rb, -NReCONRcRd, -NReCOORb, -NReC(丽)NRcRd, NReCSNRcRd, -NReS(0)NRcRd, -NReS(0)2NRcRd ' - S(0)Rb, -S(0)NRcRd, -S(0)2Rb, -S020Rb, -CSNRcRd, -CRb(OH)-Rb, or C3-C1()-cycloalkyl or 3-12 a cycloalkyl group which is mono- or polysubstituted by the same or different conditions, and Μ is q -C6-alkyl or -CORb, C02Rb, -0-Rb or -NReRd, wherein Rb is nitrogen or Ci - C6 -alkyl, C2 -Cg - dilute, C2 -Cg 127094 200835498 alkynyl, C3_C1G-cycloalkyl, c6_Ci2_aryl or partially or fully fluorinated Ci-7-alkyl, and π and Rd each Independently hydrogen, Cl_C6·alkyl, C2<v dilute, C2-C8-fast radical, c3_CiG_cycloalkyl, C6_Cir aryl; C(〇)Rb, wherein Rb is as defined above, or via, wherein when RC is In the case of a hydroxyl group, Rd may be only hydrogen, Ci-c6-alkyl, <^2-0:8-alkenyl, (]2-0:8_fast radical, (3)<:1()-naphthene Or a C6_C12-aryl group, and vice versa, and Re is hydrogen, C1_C6_alkyl, c2-c8-alkenyl, c2_c8_alkynyl, c3-c1 (r cycloalkyl 4c6_Ci2_aryl, and R1 and R2 Each independently is an unbranched or branched Cl_C5_alkyl group, or together with the carbon atom of the chain, forms a ring having a total of 3-7 members, wherein when R3 A is hydrogen, R1 and R2 cannot both be Methyl, is hydrazine or Q-C8-alkyl, c2-c8-thinyl, c2_C8-alkynyl, c3_Ci decyl, 3-12-membered heterocycloalkyl, which are the same or different - or polysubstituted, or mono- or bicyclic C6_c^-aryl or 3-12-membered heteroaryl, which are optionally mono- or polysubstituted by the same or different, and K-clamp is cyano , halogen, hydroxy, nitro, -c(0)Rb, C02Rb ^ -〇.Rb , .s.Rb Λ s〇2NRcRd > _C(0)-N RcRd 127094, -0C(0)-NRcRd, -C=NORb, -NRcRd or C3-C10-cycloalkyl, 3-12-membered heterocycloalkyl, which are singly- or as appropriate Multi-substituted, or C6-C12-aryl or 3-12-membered heteroaryl, which is optionally mono- or polysubstituted by L, has the enthalpy definition specified in A, and is C!-Cg-alkyl , C2 - Cg - dilute, C2 - Cg - fast radical, partially or fully fluorinated Ci-c6-alkyl, partially or fully fluorinated CVCV alkoxy, CVCV alkoxy-Ci-C6 - Alkyl, Ci-C6-sintered-based-Ci-C^-in-milk, mono- or bicyclic (CH2)p-c3-c1G-cycloalkyl, single or double cyclic 3-12-member ( CH2) p-heterocycloalkyl, (CH2)pCN, (CH2)pHal, (CH2)pN02, mono- or bicyclic (CH2)p-C6-C12-aryl, mono- or bicyclic 3- 12-membered (CH2)p-heteroaryl, or -(CH2)pP03(Rb)2, -(CH2)pNRcRd, -(CH2)pNReCORb, -(CH2)pNReCSRb, -(CH2)pNReS(0)Rb -(CH2)pNReS(0)2Rb, -(CH2)pNReCONRcRd, -(CH2)p NRe COORb, -(CH2)p NRe C(NH)NRC Rd ^ -(CH2 )p NRe CSNRC Rd > -( CH2)pNReS(0)NRcRd > -(CH2)p NRe S(0)2 NRC Rd , -(CH2)pCORb, -(CH2)pCSRb, -( CH2)pS(0)Rb, -(CH2)pS(0)(NH)Rb, -(CH2)p S(0)2 Rb, -(CH2)pS(0)2NRcRd, -(CH2)p S02 0Rb , 200835498 -(CH2)pC02Rb, -(CH2)pCONRcRd, -(CH2)pCSNReRd, -(CH2)pORb, _(CH2)pSRb, -(CH2)p CRb (OH)_Rb, -(CH2 )p -C =NORb, -0-(CH2)n-〇-, -〇_(CH2)n-CH2-, -〇-CH=CH- or -(CH2)n + 2-, and terminal oxygen atom and/or carbon The atomic system is bonded to a directly adjacent ring carbon atom, and / n is 1 or 2, and Ρ is 〇, 1, 2, 3, 4, 5 or 6, and is an oxygen atom and two hydrogen atoms, Υ Is (CH2)m, -CeC- or -CH=CH-, wherein m = 0 or 1, and R4 is an aromatic or heteroaromatic 3_ to 12-membered mono- or bicyclic ring which is unsubstituted, Or, as the case may be, one of the three groups mentioned in L or one of the following groups mentioned in B4C: 127094 200835498 R5 is hydrogen or a Q-ar alkyl group or a partially or fully fluorinated Ci-C4-alkyl group and a "single" are each independently hydrogen, Cl-C4_alkyl or partially or fully fluorinated q- a C4.alkyl group, or a 3- to 6-membered ring together with a ring carbon atom, and a pharmaceutically acceptable salt thereof. 2. A compound of claim 1, wherein A is the same or differently substituted by z Ci Cs -alkyl group' or C3_C10-cycloalkyl group which is the same or differently substituted by % or more, and B and "each as defined in the claim. 3. The compound of claim 2, wherein the octyl group is a cyano group or a c3_c "cycloalkyl group, however, R1 and R2 are each a methyl group. A compound according to claim 1, wherein A is hydrogen, and R1 and R2 together with the carbon atom of the chain form a ring consisting of 3 to 7 carbon atoms. 5. The compound of claim 4 wherein Rl#R2_ is a cyclopentyl or cyclohexyl 127094 200835498 ring. 6. If the compound of the claim ,, i ^ ', R is Ci_c8-alkyl, mono- or bicyclic 16 7 12, aryl or > 12 • member. ^ ^ t Heteroaryl, prerequisites Is a compound of -Cs C- or -ΓΉζζζηττ ^ ^ 7.3, wherein R 3 is a mono- or bicyclic ring & aryl or H aryl ', with the proviso that Y is (CH 2 ) m. r 8· such as the compound of ', where ^ is a mono- or di-substituted mono- or bicyclic aspect, or about the request item! R4 is specified to have one of the groups at the position 6 or the one having the C group at the position 5. 9. The compound of claim 8 wherein R4 has one of the following definitions: The compound of claim 1, wherein R5 is methyl or ethyl. 11. A compound according to claim 1, wherein R6 is hydrazine. 12. The compound of claim 1 wherein p is 〇, 1 or 2. 13. As requested in the compound, where [is. %·alkyl, C2_C8-alkenyl, c2-c8•alkynyl, partially or fully fluorinated Ci_C6_alkyl, _(CH2)pCN, (CH2)pHa(CH2)pN02, (CH2)p_C6_C12- Aryl, -(CH2)p-heteroaryl, -(CH2)pNRCRd, -(CH2)pNReCORb, -(CH2)p NRe S(0)2 Rb, -(CH2)pNReCONRcRd > -(CH2)p NRe S(0)NRc Rd ^ -(CH2 )p NRe S(0)2-NRcRd, _(CH2)pCORb, -(CH2)pS(0)Rb, -(CH2)pS(0)2Rb, -( CH2) pS(0)2NRcRd, -(CH2)pC02Rb, -(CH2)p CONRc Rd, -(CH2)p〇Rb, _(CH2)pCRb(OH)-Rb, where Rb, rc, Rd and Re Definition 127094 200835498 is specified in request 1. 14. The compound of claim 1, wherein z is cyano, halogen, hydroxy, nitro, -C(0)Rb, C〇2Rb ... 〇_Rb, _s〇2NRCRd, _c(〇)_NRCRd, _NRCRd, - NReCORb . -NReS(0)Rb ^ -NReS(0)2Rb ^ -NReCONRcRd ' -S(〇)Rb Λ -S(0)NRc: Rd, -S(〇)2 Rb, _CRb (〇H>Rb, Or & ^ 〇 _ cycloalkyl or heterocycloalkyl as 'same or different M is mono- or polysubstituted, wherein Rb & R, R and Μ are defined in claim 1. , & Rabbit ^! Month is a,, is To the palm 127094 200835498 19 racemic 20 + 21 晦22 racemic 23 + 24 - number racemic or palmomerisomer -Y-R1 25 racemic oxime, 26 + 27 - 28 racemic 29 + 30 - 31 Racemic 32 + 33 - 34 racemic ^cr 35 + 36 - 37 racemic X) 38 + 39 - 40 racemic 41 + 42 - 43 racemic 44 + 45 - 46 racemic jXX 47 + 48 - 127094 200835498 No. Racemic or palmomere-Y-R1 49 Racemic 〆〆50 + 51 - 52 Racemic 53 + 54 - 55 Racemic 56 + 57 - 58 Racemic 59 + 60 - 61 racemic X) 62 + 63 - 64 racemic 65 + 66 - 67 racemic 68 + 69 雠70 racemic 71 + 72 Number racemic or palmomerisomer -Y-R1 73 racemic 74 + 75 - 127094 200835498 76 racemic 77 + 78 - 79 racemic 80 + 81 - 82 racemic 83 + 84 - 85 racemic X) 86 + 87 - 88 racemic 89 + 90 - 91 racemic 92 + 93 - 94 racemic 95 + 96 - number racemic or palmomerisomer - Y-R1 97 racemic oxime 98 + 99 - 100 racemic 101 + 102 - 103 racemic 104 + 105 - 127094 -10- 200835498 106 racemic 107 + 108 - 109 racemic X) 110 + 111 - 112 racemic 113 + 114 115 racemic fK 116 + 117 - 118 racemic 119 + 120 - number racemic or palm STRUCTURE - Y-R1 121 Racemic 〆〆122 + 123 - 124 Racemic ^0 125 + 126 - 127 Racemic 128 + 129 130 Racemic 131 + 132 133 Racemic X) 134 + 135 - 127094 -11 - 200835498 136 racemic 137 + 138 - 139 racemic 140 + 141 - 142 racemic 143 + 144 - number racemic or palmomerisomer - Y-R1 145 racemic enthalpy, 146 + 147 - 148 racemic 149 + 150 - 151 racemic 152 + 153 - 154 racemic 155 + 156 bribe 157 racemic AJ 158 + 159 - 160 racemic 161 + 162 - 163 racemic 164 + 165 - h2n 127094 •12- 200835498 166 racemic 167 + 168 - number racemic or palmomerisomer - Y-R1 169 racemic oxime, 170 + 171 - 172 racemic 173 + 174 - 175 racemic 176 + 177 face 178 outside Racemic 179 + 180 - 181 racemic 182 + 183 - 184 racemic 185 + 186 - 187 racemic 188 + 189 - 190 racemic 191 + 192 - 127094 -13 - 200835498 number racemic or palm Isomer-Y-R1 193 racemic oxime, 194 + 195 - 196 racemic 197 + 198 - 199 racemic 200 + 201 - 202 racemic 203 + 204 - 205 racemic AJ 206 + 207 - 208 racemic 209 + 210 - 211 racemic 212 + 213 - 214 racemic 215 + 216 - Number racemic or palmomerisomer -Y-R1 217 racemic 〆, 218 + 219 - 127094 -14- 200835498 220 racemic 221 + 222 - 223 racemic 224 + 225 - 226 racemic 227 + 228 - 229 racemic X) 230 + 231 - 232 racemic 233 + 234 - 235 racemic f)^ 236 + 237 - 238 racemic 239 + 240 - number racemic or palmomerisomer - Y-R1 241 racemic oxime, 242 + 243 - 244 racemic 245 + 246 - 247 racemic 248 + 249 - 127094 -15- 200835498 250 racemic 251 + 252 - 253 racemic 254 + X) 255 - 256 racemic 257 + 258 - 259 racemic 260 + 261 - 262 racemic 263 + 264 - number racemic or palm STRUCTURE - Y-R1 265 racemic oxime, 266 + 267 - 268 racemic 269 + 270 - 271 racemic 272 + 273 - 274 racemic 275 + 276 - 277 racemic X) 278 + 279 - 127094 -16- 200835498 280 racemic 281 + 282 - 283 racemic 284 + 285 - 286 racemic 287 + 288 - number racemic or palmomerisomer - Y-R1 289 racemic enthalpy, 290 + 291 - 292 Racemic 293 + 294 - 295 racemic 296 + 297 - 298 racemic 299 + 300 - 301 racemic oxime 0 302 + 303 - 304 racemic 305 + 306 - 307 racemic 308 + 309 - 127094 - 17- 200835498 310 racemic 311 + 312 - number racemic or palmomer isomer - Y-R1 313 racemic 〆〆 314 + 315 - 316 racemic 317 + 318 - 319 racemic 320 + 321 - 322 Racemic 323 + 324 - 325 racemic X) 326 + 327 - 328 racemic 329 + 330 - 331 racemic 332 + 333 - 334 racemic 335 + 336 - 127094 -18- 200835498 No. Racemic or palmar isomer - Y-R1 337 racemic oxime, 338 + 339 - 340 racemic 341 + 342 - 343 racemic 344 + 345 - 346 racemic 347 + 348 - 349 Racem X) 350 + 351 - 352 racemic 353 + 354 - 355 racemic fK 356 + 357 - 358 racemic 359 + 360 - No. Racemic or palmar isomer -Y-R1 361 Racemic 〆, 362 + 363 127094 -19- 200835498 364 racemic 365 + 366 - 367 racemic 368 + 369 - 370 racemic 371 + 372 - 373 racemic 374 + 375 - 376 racemic 377 + ρ 378 - 379 racemic 380 + 381 - 382 racemic 383 + 384 - number racemic or palmomerisomer - Y-R1 385 racemic 〆〆 386 + 387 - 388 racemic ^0 389 + 390 - 391 racemic 392 + 393 - ch3〇127094 -20- 200835498 394 racemic 395 + 396 - 397 racemic X) 398 + 399 - 400 racemic 401 + , 402 - 403 racemic fK 404 + 405 - 406 Spin 407 + 408 - number racemic or palmomerisomer - Y-R1 409 racemic 410 + 411 - 412 racemic 413 + 414 - 415 racemic 416 + 417 - 418 racemic 419 + 420 - 421 racemic AJ 422 + 423 雠h2n 127094 -21 - 200835498 424 racemic 425 + 426 - 427 racemic 428 + 429 - 430 racemic 431 + 432 - number racemic or palmomer isomer - Y-R1 433 racemic, 434 + 435 - 436 Racemic 437 + 438 - 439 racemic 440 + 441 - 442 racemic 443 + 444 - 445 racemic X) 446 + 447 - 448 racemic 449 + 450 - 451 racemic 452 + 453 face 127094 - 22- 200835498 454 racemic 455 + 456 - number racemic or palmomer isomer - Y-R1 457 racemic oxime, 458 + 459 - 460 racemic 461 + 462 - 463 racemic 464 + 465 - 466 Racemic 467 + 468 - 469 racemic 〆 0 470 + 471 472 racemic 473 + 474 - 475 racemic 476 + 477 - 478 racemic 479 + 480 - 127094 -23- 200835498 \ number racemic or Opposite-Y-R1 481 racemic oxime, 482 + 483 - 484 racemic 485 + 486 - 487 racemic 488 + 489 - 490 racemic 491 + 492 - 493 racemic 494 + 495 - 496 racemic 497 + 498 - 499 racemic fx. 599 + 501 - 502 racemic 503 + 504 - No. rac or palm toomer -Y-R1 505 racemic 〆, 506 + 507 - 127094 -24- 200835498 508 racemic ^0 509 + 510 - 511 racemic 512 + 513 - 514 racemic 515 + 516 - 517 racemic X) 518 + 519 - 520 racemic 521 + 522 - 523 Racemic 524 + 525 - 526 racemic 527 + 528 - No. rac or palm toomer -Y-R1 529 racemic 530 + 531 - 532 racemic 533 + 534 - 535 racemic 536 + 537 - 127094 -25- 200835498 538 racemic ^cr 539 + 540 - 541 racemic X) 542 + 543 - 544 racemic 545 + 546 - 547 racemic fK 548 + 549 - 550 racemic 551 + 552 - \ Number racemic or palmar isomer - Y-R1 553 racemic 〆〆 554 + 555 - 556 racemic 557 + 558 559 racemic 560 + 561 - 562 racemic 563 + 564 - 565 Racem X) 566 + 567 - 127094 -26- 200835498 568 racemic 569 + 570 - 571 racemic 572 + 573 - 574 racemic 575 + 576 - number racemic or palmomerisomer - Y-R1 577 racemic 〆〆 578 + 579 580 racemic 581 + 582 - 583 racemic 584 + 585 - 586 racemic 587 + 588 589 racemic X) 590 + 591 - 592 racemic 593 + 594 - 595 racemic fK 596 + 597 - 127094 -27- 200835498 598 racemic 599 + 600 number racemic or palmomerisomer - Y-R1 601 racemic 602 + 603 - 604 racemic 605 + 606 607 racemic 608 + 609 - 610 racemic 611 + 612 - 613 racemic X) 614 + 615 - 616 racemic 617 + 618 - 619 racemic fK 620 + 621 - 622 racemic 623 + 624 - 127094 -28- 200835498 number racemic or palm STRUCTURE - Y-R1 625 racemic 626 + 〆〆627 - 628 racemic 629 + 630 - 631 racemic 632 + 633 - 634 racemic 635 + 636 - 637 racemic J 638 + 639 - 640 racemic 641 + 642 - 643 racemic 644 + 645 - 646 racemic 647 + 648 No. Racemic or palmomerisomer -Y-R1 649 racemic 〆, 650 + 651 - 127094 -29-200835498 652 racemic 653 + 654 - 655 racemic 656 + 657 - 658 racemic 659 + 660 - 661 racemic AJ 662 + 663 - 664 racemic 665 + 666 - 667 racemic 668 + 669 - 670 racemic 671 + 672 - number racemic or palmomer isomer - Y-R1 673 racemic, 674 + 675 - 676 racemic 677 + 678 - 679 racemic 680 + 681 - 682 racemic h2n 127094 -30- 200835498 683 + 684 685 racemic AJ 686 + 687 - 688 racemic 689 + 690 - 691 racemic 692 + 693 - 694 racemic Λ 695 + 696 - number racemic or palmomerisomer -Y -R1 697 racemic oxime, 698 + 699 - 700 racemic 701 + 702 - 703 racemic 704 + 705 - 706 racemic 707 + 708 - 709 racemic 710 + 〆0 711 - 127094 31 · 200835498 712 racemic 713 + 714 - 715 racemic 716 + 717 - 718 racemic 719 + 720 - number racemic or palmomer isomer - Y-R1 721 racemic 722 + 723 - 724 racemic 725 + 726 - 727 racemic 728 + 729 - 730 racemic 731 + sound 732 - 733 racemic • JU 734 + 735 - 736 racemic 737 + X) 738 - τ 739 racemic 740 + 741 - 127094 -32- 200835498 742 racemic 743 + 744 - number racemic or palmomer isomer - Y-R1 745 racemic 746 + 747 - 748 racemic 749 + 750 - 751 racemic 752 + 753 - 754 racemic 755 + 756 - 757 racemic X) 758 + 759 - 760 racemic r° 761 + 762 - 763 racemic 764 + 765 - 766 racemic 767 + 768 - 127094 -33 - 200835498 number racemic or Pair of palm isomers - Y-R1 769 Racemic 〆〆770 + 771 772 Racemic 773 + 774 - 775 Racemic 776 + 111 - 778 Racemic 779 + 780 - 781 Racemic J 782 + 783 - 784 racemic 785 + 786 - 787 racemic 788 + 789 - 790 racemic 791 + 792 - No. rac or palm toomer -Y-R1 793 racemic 794 + 795 - 127094 -34- 200835498 796 racemic 797 + 798 - 799 racemic 800 + 801 - 802 racemic 803 + 804 - 805 racemic 806 + 807 - 808 racemic 809 + 810 sleep 811 racemic 812 + 813 - 814 Racemic 815 + 816 number racemic or palmomerisomer - Y-R1 817 racemic oxime, 818 + 819 - 820 racemic 821 + 822 - 823 racemic 824 + 825 - 127094 -35- 200835498 826 racemic 827 + 828 - 829 racemic AJ 830 + 831 - 832 racemic 833 + 834 - 835 racemic 836 + 837 - 838 racemic 839 + 840 - number racemic or palmomer -Y-R1 841 racemic 842 + 843 - 844 racemic 845 + 846 - 847 racemic 848 + 849 - 850 racemic 851 + 852 853 racemic AJ 854 + 855 - 127094 -36- 200835498 856 racemic 857 + 858 - 859 racemic 860 + 861 - 862 racemic 863 + 864 - number racemic or palmomerisomer - Y-R1 865 racemic, 866 + 867 868 Cyclone 869 + 870 - 871 racemic 872 + 873 - 874 racemic 875 + 876 - 877 racemic AJ 878 + 879 - 880 racemic 881 + 882 - 883 racemic 884 + 885 - 127094 -37- 200835498 886 Racemic 887 + 888 - No. Racemic or palmar isomer - Y-R1 889 racemic 890 + 891 - 892 racemic 893 + 894 - 895 racemic 896 + 897 - 898 racemic 899 + 900 - 901 racemic AJ 902 + 903 - 904 racemic 905 + 906 - 907 racemic 908 + 909 - 910 racemic 911 + 912 - 127094 -38- 200835498 \ No. Racemic or palmar isomer - Y-R1 913 Racemic 〆, 914 + 915 - 916 Racemic 917 + 918 - 919 Racemic 920 + 921 - 922 Racemic Acoustic ' 923 + 924 - 925 racemic Μ 926 + 927 928 racemic 929 + 930 - 931 racemic 932 + 933 934 racemic 935 + 936 - Number racemic or palmomerisomer -Y-R1 937 racemic 938 + 939 - 127094 -39- 200835498 940 racemic 941 + 942 - 943 racemic 944 + 945 dr 946 racemic 947 + 948 - 949 racemic 950 + 〆0 951 952 racemic 953 + 954 - 955 racemic 956 + 957 - 958 Racemic 959 + 960 - number racemic or palmomer toomer - Y-R1 961 racemic oxime, 962 + 963 - 964 racemic 965 + 966 967 racemic 968 + 969 - 127094 -40- 200835498 I 970 racemic ^cr 971 + 972 - 973 racemic AJ 974 + 975 - 976 racemic 977 + 978 - 979 racemic 980 + 981 - 982 racemic 983 + 984 - number racemic or palm Isomer-Y-R1 985 racemic oxime, 986 + 987 - 988 racemic 989 + 990 - 991 racemic 992 + 993 - 994 racemic 995 + 996 - 997 racemic X) 998 + 999 127094 -41 - 200835498 1000 racemic 1001 + 1002 - 1003 racemic 1004 + 1005 - 1006 racemic 1007 + 1008 \ Number racemic or palmomerisomer -Y-R1 1009 racemic oxime, 1010 + 1011 - 1012 racemic 1013 + 1014 - 1015 racemic 1016 + 1017 - 1018 racemic 1019 + 1020 - 1021 Racemic 〆 0 1022 + 1023 - 1024 racemic 1025 + 1026 - 1027 racemic 1028 + 1029 127094 -42- 200835498 1030 racemic 1031 + 1032 - number racemic or palmomerisomer -Y-R1 1033 racemic oxime, 1034 + 1035 - 1036 racemic 1037 + 1038 1039 racemic 1040 + 1041 - 1042 Cyclone 1043 + 1044 1045 racemic X) 1046 + 1047 - 1048 racemic 1049 + 1050 - 1051 racemic fK 1052 + 1053 - 1054 racemic 1055 + 1056 - 127094 -43- 200835498 number racemic or pair Palmomeric isomer-Y-R1 1057 racemic oxime, 1058 + 1059 - 1060 racemic 1061 + 1062 - 1063 racemic 1064 + 1065 - 1066 racemic 1067 + 1068 - 1069 racemic X) 1070 + 1071 - 1072 racemic 1073 + 1074 - 1075 racemic fK 1076 + 1077 - 1078 racemic 1079 + 1080 - Number racemic or palmomerisomer Y-R1 1081 racemic 1082 + 1083 noodles 127094 -44- 200835498 1084 racemic 1085 + 1086 - 1087 racemic 1088 + 1089 - 1090 racemic 1091 + 1092 - 1093 racemic X) 1094 + 1095 - 1096 racemic 1097 + P 1098 - 1099 Racem 1100 + 1101 - 1102 racemic 1103 + 1104 - i number racemic or palmomerisomer -Y-R1 1105 racemic oxime, 1106 + 1107 - 1108 racemic 1109 + 1110 - 1111旋1112 + 1113 - 127094 -45- 200835498 1114 racemic 1115 + 1116 - 1117 racemic J 1118 + 1119 - 1120 racemic 1121 + 1122 - 1123 racemic 1124 + 1125 - 1126 racemic 1127 + 1128 - number racemic or palm Construction - Y-R1 1129 racemic 1130 + 1131 - 1132 racemic 1133 + 1134 - 1135 racemic 1136 + 1137 - 1138 racemic 1139 + 1140 - 1141 racemic X) 1142 + 1143 - 127094 - 46- 200835498 1144 racemic 1145 + 1146 - 1147 racemic 1148 + 1149 - 1150 racemic 1151 + 1152 - number racemic or palmomer isomer - Y-R1 1153 racemic, 1154 + 1155 - 1156 Racem 1157 + 1158 - 1159 racemic 1160 + 1161 - 1162 racemic 1163 + 1164 sleep 1165 racemic 1166 + 1167 - 1168 racemic 1169 + 1170 - 1171 racemic 1172 + 1173 - 127094 -47- 200835498 1174 Racemic 1175 + 1176 - number racemic or palmomerisomer -Y-R1 1177 racemic oxime, 1178 + 1179 - 1180 racemic 1181 + 1182 - 1183 racemic 1184 + 1185 - 1186 Racemic 1187 + 1188 - 1189 racemic 1190 + 1191 - 1192 racemic 1193 + 1194 - 1195 racemic 1196 + 1197 - 1198 racemic 1199 + 1200 ch3o 127094 -48- 200835498 number racemic or pair Palmeromer-Y-R1 1201 racemic oxime, 1202 + 1203 - 1204 racemic 1205 + 1206 - 1207 racemic 1208 + 1209 - 1210 racemic 1211 + 1212 - 1213 racemic AJ 1214 + 1215 - 1216 Racemic r° 1217 + 1218 - 1219 racemic 1220 + 1221 - 1222 racemic 1223 + 1224 - No. rac or palm toomer -Y-R1 1225 racemic 1226 + 1227 - 127094 49- 200835498 1228 racemic 1229 + 1230 - 1231 racemic 1232 + 1233 - 1234 racemic 1235 + 1236 - 1237 racemic 〆 0 1238 + 1239 - 1240 racemic 1241 + 1242 - 1243 racemic 1244 + 1245 - 1246 race 1247 + 1248 - Number racemic or palmomerisomer -Y-R1 1249 racemic 1250 + 1251 - 1252 racemic 1253 + 1254 1255 racemic 1256 + 1257 - 127094 -50- 200835498 1258 racemic 1259 + 1260 - 1261 racemic X) 1262 + 1263 - 1264 racemic 1265 + 1266 - 1267 racemic 1268 + 1269 - 1270 racemic 1271 + 1272 - number racemic or palm STRUCTURE - Y-R1 1273 racemic oxime, 1274 + 1275 - 1276 racemic 1277 + 1278 - 1279 racemic 1280 + 1281 - 1282 racemic 1283 + 1284 - 1285 racemic 1286 + 〆0 1287 - 127094 -51 - 200835498 1288 racemic r° 1289 + 1290 - 1291 racemic 1292 + 1293 - 1294 racemic 1295 + 1296 - f number racemic or palmomerisomer -Y-R1 1297 racemic 〆, 1298 + 1299 - 1300 racemic 1301 + 1302 - 1303 racemic 1304 + 1305 - 1306 racemic ^cr 1307 + 1308 - 1309 racemic X) 1310 + 1311 - 1312 racemic 1313 + 1314 - 1315 racemic 1316 + 1317 - 127094 -52- 200835498 1318 racemic 1319 + 1320 - 16 - a pharmaceutical composition comprising at least one of the compounds of formula I, as in any one of the items 1 to 15, and, where appropriate, A further active ingredient is accompanied by a pharmaceutically suitable excipient and/or a planting agent. 17. The pharmaceutical composition according to claim 16, wherein the other active ingredients of the scorpion, the snail, and the acne are SERM (selective estrogen receptor modulator), aromatic salted eternal inhibitor, antiestrogens Agent Or prostaglandin. 18. The pharmaceutical composition of claim 1, wherein the other (four) component is tamoxifen, W-dSH4, 4,5,5,5-pentafluoropentyl)sulfinyl]pentaoxy Benzyl}phenyl>6-phenyl-8,9-dihydro-7H-p-cycloheptenyl alcohol, ια 182 780 (7-corrected 9-(4,4,5,5-pentafluoropentyl) Sulfosyl) sulfhydryl] ruthenium _1, 3 -3, guanidine diol), η wind based _7 noisy (methyl {h(4,4,5) five gas base ^ thiol]- Propyl}amino)pentyl]est-1,3,5(10)-triene_3,17 bed diol, η fluoroyl 7 α-{5-[methyl (7,7,8, 8,9,9,10,10,10-nonafluoroindolyl)amino]pentyl}est-1,3,5(1〇)_triene_3,17/5·diol, u-fluoride基_17〇;•Methyl_7 Corrective 5_[Methyl (8,8,9,9,9-penta-1inyl)amino]pentyl} Female·1,3,5(10)-III Alkene-3,17 stone-diol, clomifene, ral〇xifene, fadrozole, f〇rmestane, letrozole (ietr〇z〇k), Anasta (anastrozole) or Atamistan (atamestane). 19. A compound according to any one of items 1 to 14, which is for use in the manufacture of a medicament. 2. Use of a compound according to any one of claims 1 to 15 for the manufacture of a medicament for the treatment and/or prevention of a gynecological condition, such as ectopic formation of the endometrium, leiomyomas of the uterus, Dysfunctional dysfunction and menstrual sleep 127094 -53- 200835498 Difficult. 21_: The use of a compound according to any one of claims 1 to 15 for the manufacture of a medicament for the treatment and/or prevention of a hormone-dependent tumor. 22. The use of a compound according to any one of claims 1 to 15 for the manufacture of a medicament for treating and/or preventing breast cancer. a,:: The use of a compound according to any one of items 1 to 15 for the manufacture of a medicament for the treatment and/or prevention of endometrial cancer. r 24·: The compound of any one of claims 1 to 15 for use in the manufacture of a medicament, or a treatment for and/or prevention of an ovarian cancer. A compound according to any one of the items i to 15, which is for the treatment and/or prevention of prostate cancer. Use of a compound according to any one of items 1 to 15 for the manufacture of a medicament / a hybrid system for use in a female hormone replacement therapy. Uses: Ask for the compound of the 1st to 15th for the female fertility control 127094 -54- 200835498 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The components of the representative figure Brief description of the symbol: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: 127094