阅读说明：本技术 作为17-hsd1抑制剂的在位置16(17)具有缩合的吡唑环的雌甾-1,3,5(10)-三烯化合物 (Estra-1, 3,5(10) -trienes having a condensed pyrazole ring in position 16(17) as 17-HSD1 inhibitors ) 是由 莉娜·赫维莱 马乔·哈科拉 泰罗·林纳南 帕西·科斯基米 卡米拉·斯特杰伦桑茨 于 2019-12-05 设计创作，主要内容包括：本发明涉及式(I)的化合物及其药学上可接受的盐,其中R1至R4如权利要求中所定义。本发明进一步涉及它们作为17β-HSD1抑制剂和治疗或预防类固醇激素依赖性疾病或病症的用途,例如需要抑制17β-HSD1酶和/或需要降低内源性雌二醇浓度的类固醇激素依赖性疾病或病症。本发明还涉及上述化合物的制备和包含一种或更多种上述化合物或其药学上可接受的盐作为活性成分的药物组合物。(The present invention relates to compounds of formula (I) wherein R1 to R4 are as defined in the claims, and pharmaceutically acceptable salts thereof. The invention further relates to their use as 17 beta-HSD 1 inhibitors and for the treatment or prevention of steroid hormone dependent diseases or disorders, e.g. requiring the inhibition of 17 beta-HSD 1 enzyme and/orSteroid hormone dependent diseases or conditions that require a reduction in endogenous estradiol concentrations. The invention also relates to the preparation of the above compounds and to pharmaceutical compositions comprising one or more of the above compounds or pharmaceutically acceptable salts thereof as active ingredient.)

1. A compound of formula (I)

Wherein

R1 and R2 are each independently selected from H and halogen;

(i) r3 is selected from H and C1-4 alkyl, and

r4 is selected from

-C1-6-alkyl optionally substituted with OH;

--(CH₂)_n-R5, wherein n is 1 to 3 and R5 is a 3-to 7-membered alicyclic ring;

-a 4-to 7-membered unsubstituted saturated alicyclic ring or a 4-to 7-membered unsubstituted heterocyclic ring containing one heteroatom selected from nitrogen, sulfur and oxygen;

-a 5-membered partially unsaturated or aromatic heterocycle comprising 1 to 3 heteroatoms selected from nitrogen and oxygen, and optionally substituted with one or two heteroatoms selected from halogen, CN, C1-4-alkyl, C1-3- (per) haloalkyl, OH, C1-3-alkoxy, C (o) N (C1-3-alkyl) and a 6-membered saturated heterocycle₂Said 6-membered saturated heterocyclic ring comprising 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted with one or two substituents independently selected from halogen, CN, C1-4-alkyl, C1-3- (per) haloalkyl, OH, and C1-3-alkoxy;

-a 5-membered unsubstituted unsaturated or aromatic heterocyclic ring comprising 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen;

-a 5-membered unsaturated or aromatic heterocyclic ring and a 6-membered saturated heterocyclic ring, said 5-membered unsaturated or aromatic heterocyclic ring comprising 1 to 3 heteroatoms independently selected from nitrogen and oxygen, and optionally substituted with one or two heteroatoms independently selected from halogen, CN, C1-4-alkyl, C1-3- (per) haloalkyl, OH, C1-3-alkoxy, C (o) N (C1-3-alkyl)₂Said 6-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur and optionally substituted with one or two substituents independently selected from halogen, CN, C1-4-alkyl, C1-3- (per) haloalkyl, OH and C1-3-alkoxy;

-phenyl, 6-membered unsaturated or aromatic heterocycle and 6-membered saturated heterocycle, said 6-membered saturated heterocycleThe unsaturated or aromatic heterocycle contains 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen, and is optionally substituted with 1 to 5 heteroatoms independently selected from halogen, CN, C1-4-alkyl, C1-3- (per) haloalkyl, OH, oxo, C1-3-alkoxy, morpholino, C (O) N (C1-3-alkyl)₂Said 6-membered saturated heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, optionally substituted with C1-4-alkyl; and

-a 6-membered saturated heterocyclic ring comprising 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur and optionally substituted with 1 to 3 substituents independently selected from halogen, CN, C1-4-alkyl, C1-3- (per) haloalkyl, OH, oxo and C1-3-alkoxy, or two adjacent substituents may form a 5-or 6-membered saturated fused ring;

or

(ii) R3 and R4 form together with the nitrogen atom to which they are attached a group selected from: a 4-to 7-membered saturated heterocyclic ring comprising the nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur, including sulfonyl, and optionally substituted with a substituent selected from: halogen, CN, methyl, C1-3- (per) haloalkyl, OH, oxo, C1-3-alkoxy, and a 4-to 7-membered alicyclic ring or a 4-to 7-membered saturated heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, optionally substituted with C1-4-alkyl;

or

(iii) R3 and R4 form together with the nitrogen atom to which they are attached a group selected from: a 4-to 7-membered saturated heterocyclic ring containing the nitrogen atom, and the saturated heterocyclic ring forms a fused ring or a spiro ring with a saturated or unsaturated 4-to 7-membered alicyclic ring or a 4-to 7-membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur;

if only hydrogen H is present at the same time¹And H²One of (1), hydrogen H¹And H²The position of the double bond in the pyrazole ring attached being based on hydrogen H¹And H²Which one exists to determine

Or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein the compound has formula (Ia)

Wherein R1, R2, R3, R4 and R5 of formula (Ia) are as defined in claim 1,

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 or 2, wherein

-R1 is selected from H, F and Cl,

-R2 is selected from H, F and Cl, and

-R3, R4 and R5 are as defined in claim 1,

or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3, wherein

-R1 is selected from H, F and Cl,

-R2 is H or F, and

-R3, R4 and R5 are as defined in claim 1,

or a pharmaceutically acceptable salt thereof.

5. The compound according to any one of claims 1 to 4, wherein

-R1 is H

-R2 is F, and

-R3, R4 and R5 are as defined in claim 1,

or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of claims 1 to 5, wherein

-R3 is H,

-R4 is a 6-membered unsaturated or aromatic heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or two heteroatoms selected from CN, C1-4-alkyl, C1-3-alkoxy, halogen and C (o) N (C1-3-alkyl)₂Substituted by a substituent ofOr

-R4 is

Or a pharmaceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 5, wherein

1 to 3 heteroatoms of the 5-membered unsubstituted unsaturated or aromatic heterocyclic ring are independently selected from nitrogen and oxygen,

1 to 3 heteroatoms of the 5-membered unsubstituted unsaturated or aromatic heterocycle are independently selected from 2 nitrogens and 1 sulfur, or

1 to 3 heteroatoms of the 5-membered unsubstituted unsaturated or aromatic heterocyclic ring are independently selected from 2 nitrogens and 1 oxygen,

or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1 to 5, wherein

-R3 is H,

-R4 is a 5-membered unsaturated or aromatic heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen and oxygen, optionally substituted by one or two heteroatoms selected from CN, C1-4-alkyl, C1-3-alkoxy, halogen and C (o) N (C1-3-alkyl)₂The substituent (b) of (a) is substituted,

or a pharmaceutically acceptable salt thereof.

9. A compound according to any one of claims 1 to 3, wherein

-R1 is H, Cl or F,

-R2 is H, Cl or F,

-R3 is H,

-R4 is a 6-membered aromatic heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or two heteroatoms selected from CN, C1-4-alkyl, C1-3-alkoxy, halogen and C (o) N (C1-3-alkyl)₂Is substituted by a substituent of (a), or

-R4 is

Or a pharmaceutically acceptable salt thereof.

10. A compound according to any one of claims 1 to 4 or 9, wherein

-R1 is H or F,

-R2 is H or F,

-R3 is H,

-R4 is a 6-membered aromatic heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or two heteroatoms selected from CN, C1-4-alkyl, C1-3-alkoxy, halogen and C (o) N (C1-3-alkyl)₂Is substituted by a substituent of (a), or

-R4 is

Or a pharmaceutically acceptable salt thereof.

11. A compound according to any one of claims 1 to 4 or claims 9 to 10, wherein

-R1 is H,

-R2 is H or F,

-R3 is H,

-R4 is a 6-membered aromatic heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or two heteroatoms selected from CN, C1-4-alkyl, C1-3-alkoxy, halogen and C (o) N (C1-3-alkyl)₂The substituent (b) of (a) is substituted,

or a pharmaceutically acceptable salt thereof.

12. A compound according to any one of claims 1 to 6 or claims 9 to 10, wherein

-R1 is H,

-R2 is F,

-R3 is H,

-R4 is a 6-membered aromatic heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted by one or two heteroatoms selected from CN, methyl, methoxy, F and c (o) N (methyl)₂Is substituted by a substituent of (a), or

-R4 is

Or a pharmaceutically acceptable salt thereof.

13. The compound according to any one of claims 1 to 12, wherein the compound is selected from the group consisting of:

-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (6-methoxypyridazin-3-yl) -propionamide,

-N- (5-cyanopyridin-2-yl) -3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide,

-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (4-fluoropyridin-2-yl) propanamide,

-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5-methoxypyridin-2-yl) propanamide,

-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (4-methylpyridin-2-yl) propanamide,

-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [ [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (2-oxo-1, 2,5,6,7, 8-hexahydroquinolin-3-yl) propionamide,

-6- (3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamido) -N, N-dimethylnicotinamide,

-N- (6-methoxypyridazin-3-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide,

-N, N-dimethyl-6- (3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamido) nicotinamide,

-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (1-methyl-1H-pyrazol-3-yl) -propionamide,

-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (1-methyl-1H-pyrazol-4-yl) -propionamide,

-N- (5- (tert-butyl) isoxazol-3-yl) -3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propionamide,

-N- (5-fluoropyridin-2-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide,

-N- (4-fluoropyridin-2-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide, and

-3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazole

-12-yl) -N- (1-methyl-1H-pyrazol-3-yl) propanamide,

or a pharmaceutically acceptable salt thereof.

14. A process for the preparation of a compound of formula (I) as defined in any one of claims 1 to 13,

comprising reacting a compound of formula (II)

Wherein R1, R2, R3, R4 and R5 of formula (II) are as defined in claim 1,

with hydrazine hydrate to give a compound of formula (I); and optionally converting the compound of formula (I) into a pharmaceutically acceptable salt thereof.

15. A compound of formula (II)

Wherein R1, R2, R3, R4 and R5 of formula (II) are as defined in claim 1.

16. A compound according to any one of claims 1 to 13 for use as a medicament.

17. A compound according to any one of claims 1 to 13 for use in the treatment or prevention of a disease selected from breast cancer, prostate cancer, ovarian cancer, uterine cancer, endometrial hyperplasia, endometriosis, uterine fibroids, adenomyosis, polycystic ovary syndrome, dysmenorrhea, menorrhagia, uterine bleeding, infertility, prostadynia, benign prostatic hyperplasia, urinary dysfunction, lower urinary tract symptoms, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), Systemic Lupus Erythematosus (SLE), multiple sclerosis, obesity, rheumatoid arthritis, Chronic Obstructive Pulmonary Disease (COPD), lung cancer, colon cancer, tissue wounds, skin wrinkles and cataracts.

18. A compound according to any one of claims 1 to 13 for use in the treatment of a disease selected from: breast cancer, prostate cancer, ovarian cancer, uterine cancer, endometrial hyperplasia, endometriosis, uterine fibroids, adenomyosis, polycystic ovary syndrome, dysmenorrhea, menorrhagia, uterine bleeding, infertility, prostadynia, benign prostatic hyperplasia, urinary dysfunction, lower urinary tract symptoms, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), Systemic Lupus Erythematosus (SLE), multiple sclerosis, obesity, rheumatoid arthritis, Chronic Obstructive Pulmonary Disease (COPD), lung cancer, colon cancer, tissue wounds, skin wrinkles and cataracts.

19. A pharmaceutical composition comprising an effective amount of one or more compounds according to any one of claims 1 to 13 and one or more pharmaceutically acceptable excipients.

20. The pharmaceutical composition according to claim 19, in combination with one or more other active ingredients.

Technical Field

The present invention relates to novel steroidal C-15 derivatives, their pharmaceutically acceptable salts and their use in therapy. The invention further relates to pharmaceutical compositions comprising these compounds as active ingredients and to processes for their preparation.

Background

17 β -hydroxysteroid dehydrogenase (17 β -HSD), also known as 17-ketosteroid reductase (17-KSR), is an NAD (H) -and/or NAPD (H) -dependent ethanol oxidoreductase, which catalyzes the final key step in the formation of all estrogens and androgens. More specifically, 17 β -HSD catalyzes the dehydrogenation (oxidation) of 17-hydroxysteroids to the corresponding 17-ketosteroids or catalyzes the hydrogenation (reduction) of inactive 17-ketosteroids to the corresponding active 17-hydroxysteroids.

Since both estrogens and androgens have the highest affinity for the receptor in its 17 β -hydroxy form, 17 β -HSD/KSR will regulate the biological activity of sex hormones. Currently, 15 human members of 17 β -HSD (types 1-15) have been described. The substrate and cofactor specificities of the different types of 17 β -HSD/KSR differ. 17KSR activity converts less active precursors to more potent forms, whereas 17 β -HSD activity decreases the potency of estrogen and androgen, thus protecting tissues from excessive hormonal effects.

Each type of 17 β -HSD has selective substrate affinity and unique tissue distribution, although in some cases overlap.

17 β -hydroxysteroid dehydrogenase type 1(17 β -HSD1) is most abundantly expressed in ovarian granulosa cells that develop into follicles in the ovary and human placenta, both of which are estrogen biosynthetic tissues. In addition, 17 β -HSD1 was expressed in estrogen target tissues, including breast, endometrium and bone. Human 17 β -HSD1 is specific for an estrogen substrate and catalyzes the reduction of estrone to estradiol in vivo.

On the other hand, 17 β -hydroxysteroid dehydrogenase type 2 (17 β -HSD2) converts estradiol, testosterone and 5 α -dihydrotestosterone into their less active forms, respectively: estrone, androstenedione, and 5 α -androstanedione. Due to its widespread and abundant expression in a variety of different estrogen and androgen target tissues such as the uterus, placenta, liver, and gastrointestinal and urinary tracts, the type 2 enzyme has been shown to protect tissues from excessive steroid action.

Estradiol (E2) is about 10 times as potent as estrone (E1) and about 80 times as potent as estriol (E3) in estrogenic action. Estradiol binds well to both estrogen receptors era and ER β, and thus regulates the expression of a variety of genes, as compared to certain other estrogens.

Although both 17 β -HSD1 and 17 β -HSD2 are present in healthy pre-menopausal humans, several studies have shown an increased ratio of 17 β -HSD1 to 17-HSD2 in tumors from post-menopausal, hormone-dependent breast cancer patients. Amplification of the 17HSD1 gene and loss of heterozygosity for the 17HSD2 allele are potential mechanisms associated with an increase in the reductive estrogen synthesis pathway in breast tumors. Increased ratio of type 1 to type 2 enzymes results in increased estradiol levels, which in turn promotes proliferation of cancerous tissue via Estrogen Receptors (ER). Thus, high levels of estrogen support certain cancers such as breast cancer and cancers of the lining of the uterus (i.e., endometrial and uterine cancers).

Similarly, it has been proposed that 17 β -HSD2 is down-regulated in endometriosis, whereas both aromatase and 17 β -HSD1 are expressed or up-regulated, compared to normal endometrium. This again leads to high concentrations of estradiol (E2) leading to tissue proliferation. Similar mechanisms are also elucidated in uterine leiomyomas (uterine fibroids) and endometrial hyperplasia.

A decrease in the endogenous estradiol concentration in the affected tissue will result in a decrease or impairment of the proliferation of 17 β -estradiol cells in said tissue and may therefore be used for the prevention and treatment of both malignant and benign estradiol dependent pathologies. Since the proposed 17 β -estradiol is involved in many malignant and benign pathologies, there is a great need for 17 β -hydroxysteroid dehydrogenase inhibitors, which can be used to attenuate the endogenous production of estradiol from estrone, which can have therapeutic value in the prevention or treatment of such conditions or diseases.

Poirier D. (2003) Curr Med Chem 10:453-77 and Poirier D. (2010) Expert opin. 1123-1145 several small molecule inhibitors of 17 β -HSD1 enzyme have been examined and reviewed. Furthermore, small molecule inhibitors of 17 β -HSD have been disclosed in WO 2001/42181, WO 2003/022835, WO 2003/033487, WO 2004/046111, WO 2004/060488, WO 2004/110459, WO 2005/032527 and WO 2005/084295.

WO2004/085457 discloses steroid compounds capable of inhibiting 17 beta-hydroxysteroid dehydrogenase. WO2006/003012 discloses 2-substituted D-class-estratriene (D-homo-estriene) derivatives useful in the treatment of estrogen dependent diseases which can be affected by inhibition of 17 β -hydroxysteroid dehydrogenase type 1. Similarly, WO2006/003013 provides 2-substituted estratrienones (estratriinones) which are useful in the prevention and treatment of estrogen dependent diseases affected by inhibition of 17 β -hydroxysteroid dehydrogenase type 1.

15-substituted estradiol analogues that act as locally active estrogens are provided in WO 2004/085345. WO2006/027347 discloses 15 β -substituted estradiol derivatives with selective estrogenic activity for use in the treatment or prevention of estrogen receptor related diseases and physiological conditions. Furthermore, WO2005/047303 discloses 3,15 substituted estrone derivatives capable of inhibiting 17 β -hydroxysteroid dehydrogenase type 1.

International application WO2008/034796 relates to estratritriazoles (estratrienes) suitable for use in the treatment and prevention of steroid hormone dependent diseases or disorders requiring the inhibition of 17 β -hydroxysteroid dehydrogenase enzymes such as 17 β -HSD1, type 2 or type 3 enzymes. Inhibitors of 17 β -HSD type 3 enzymes have been disclosed in WO 99/46279.

International applications WO2014/207309, WO2014/207310 and WO2014/207311 relate to estrone C-15 thiazole derivatives, estrone C-17 ketoamine C-15 thiazole derivatives and estradiol C-15 thiazole derivatives, respectively, and their use in therapy.

Disclosure of Invention

It is an object of the present invention to provide compounds useful in the treatment of conditions and diseases associated with elevated estradiol levels and/or treatable by the inhibition of the 17 β -HSD1 enzyme. It is another object of the present invention to provide compounds that exhibit little or no inhibitory effect on 17 β -HSD2 enzyme.

One of the problems associated with known 17 β -HSD1 inhibitors is the handling (displacement), in particular metabolic stability, of the compound. It is therefore a further object of the present invention to provide compounds with improved metabolic stability.

Some other problems associated with known 17 β -HSD1 inhibitors are the formation of binding metabolites and the species selectivity of the compounds. It is therefore a further object of the present invention to provide compounds having improved properties with respect to these parameters.

Another problem associated with known 17 β -HSD1 inhibitors is that while some inhibitors may exhibit 17 β -HSD1 inhibition, the inhibitors may not exhibit low 17 β -HSD2 inhibition, metabolic stability, and/or inhibitory properties of other species. It is therefore a further object of the present invention to provide compounds having improved one or more of said properties, including inhibition of 17 β -HSD 1.

The present invention provides novel compounds of formula (I)

Wherein

R1 and R2 are each independently selected from H and halogen;

(i) r3 is selected from H and C1-4-alkyl, and

r4 is selected from

-C1-6-alkyl optionally substituted with OH;

--(CH₂)_n-R5, wherein n is 1 to 3 and R5 is a 3-to 7-membered alicyclic ring;

-a 4-to 7-membered unsubstituted saturated alicyclic ring or a 4-to 7-membered unsubstituted heterocyclic ring containing one heteroatom selected from nitrogen, sulfur and oxygen;

-a 5-membered partially unsaturated or aromatic heterocycle and a 6-membered saturated heterocycle, said 5-membered partially unsaturated or aromatic heterocycle comprising 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen and optionally substituted with one or two heteroatoms selected from halogen, CN, C1-4-alkyl, C1-3- (per) haloalkyl, OH, C1-3-alkoxy, C (o) N (C1-3-alkyl)₂Said 6-membered saturated heterocyclic ring comprising 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted with one or two substituents independently selected from halogen, CN, C1-4-alkyl, C1-3- (per) haloalkyl, OH, and C1-3-alkoxy;

-a 5-membered unsubstituted unsaturated or aromatic heterocyclic ring comprising 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen;

-a 5-membered unsaturated or aromatic heterocyclic ring and a 6-membered saturated heterocyclic ring, said 5-membered unsaturated or aromatic heterocyclic ring comprising 1 to 3 heteroatoms independently selected from nitrogen and oxygen, and optionally substituted with one or two heteroatoms independently selected from halogen, CN, C1-4-alkyl, C1-3- (per) haloalkyl, OH, C1-3-alkoxy, C (o) N (C1-3-alkyl)₂Said 6-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur and optionally substituted with one or two substituents independently selected from halogen, CN, C1-4 alkyl, C1-3- (per) haloalkyl, OH and C1-3-alkoxy;

-phenyl, a 6-membered unsaturated or aromatic heterocyclic ring and a 6-membered saturated heterocyclic ring, said 6-membered unsaturated or aromatic heterocyclic ring comprising 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen, and optionally substituted with 1 to 5 heteroatoms independently selected from halogen, CN, C1-4 alkaneAlkyl, C1-3- (per) haloalkyl, OH, oxo, C1-3-alkoxy, morpholino, C (O) N (C1-3-alkyl)₂Said 6-membered saturated heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, optionally substituted with C1-4 alkyl; and

-a 6-membered saturated heterocyclic ring comprising 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur and optionally substituted with 1 to 3 substituents independently selected from halogen, CN, C1-4-alkyl, C1-3- (per) haloalkyl, OH, oxo and C1-3-alkoxy, or two adjacent substituents may form a 5-or 6-membered saturated fused ring;

or

(ii) R3 and R4 form together with the nitrogen atom to which they are attached a group selected from: a 4-to 7-membered saturated heterocyclic ring comprising the nitrogen atom and optionally one additional heteroatom selected from nitrogen, oxygen and sulfur, including sulfonyl, and optionally substituted with a substituent selected from: halogen, CN, methyl, C1-3- (per) haloalkyl, OH, oxo, C1-3-alkoxy, and a 4-to 7-membered alicyclic ring or a 4-to 7-membered saturated heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, optionally substituted with C1-4-alkyl;

or

(iii) R3 and R4 form together with the nitrogen atom to which they are attached a group selected from a 4-to 7-membered saturated heterocyclic ring containing the nitrogen atom, and which forms a fused ring or spiro ring with a saturated or unsaturated 4-to 7-membered alicyclic ring or a 4-to 7-membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur;

if only hydrogen H is present at the same time¹And H²One of (1), hydrogen H¹And H²The position of the double bond in the pyrazole ring attached being based on hydrogen H¹And H²Which one exists to determine

Or a pharmaceutically acceptable salt thereof.

The invention also relates to pharmaceutical compositions comprising an effective amount of one or more compounds of formula (I).

The invention also relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use as a medicament.

The invention also relates to compounds of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of estradiol dependent malignant or benign diseases or disorders.

Finally, the present invention provides a process for the preparation of the compounds according to formula (I) and their intermediate compounds according to formula (II).

Detailed Description

The compounds of the present disclosure contain a steroidal core structure, which has a defined stereochemistry, in the natural configuration of estrogens.

The compounds of the present disclosure bear a side chain at C15, which, together with the particular substitution pattern of the a ring and the C16-C17 fused pyrazole ring, provide the inventive features of the compounds of the present disclosure. These three modifications to the natural steroids enhance the metabolic and/or inhibitory properties of the compounds of the present disclosure. In addition, the metabolic and/or inhibitory properties against other species (e.g. rabbits) are enhanced. Rabbits are by far the most common non-rodent species used to assess reproductive toxicity of small molecules. Thus, target inhibition in rabbits may be considered an important and/or desirable feature of the new compounds.

The compounds of the present disclosure show inhibitory selectivity between 17 β -HSD1 and 17 β -HSD 2. It is understood that the compounds of the present disclosure exhibit greater inhibition of 17 β -HSD1 than 17 β -HSD 2.

The compounds of the present disclosure exhibit at least 40%, preferably at least 60%, more preferably at least 70%, even more preferably at least 80%, most preferably at least 90% inhibition of 17 β -HSD 1. The term "17 β -HSD1 inhibition" as used herein and hereinafter refers to the inhibition of 17 β -HSD1 by a compound of the present disclosure (at a concentration of 100nM) as determined using the methods disclosed in the chapter "pharmacological test" of the present disclosure.

Additionally or alternatively, the compounds of the present disclosure exhibit equal to or less than 40%, preferably equal to or less than 20%, more preferably equal to or less than 10% inhibition of 17 β -HSD 2. The term "17 β -HSD2 inhibition" as used herein and hereinafter refers to the inhibition of 17 β -HSD2 by a compound of the present disclosure (at a concentration of 1 μ M) as determined using the methods disclosed in the chapter "pharmacological test" of the present disclosure.

Additionally or alternatively, the compounds of the present disclosure exhibit metabolic stability corresponding to T1/2 of at least 5 minutes, preferably at least 10 minutes, more preferably at least 20 minutes, even more preferably at least 40 minutes, even more preferably at least 80 minutes, even more preferably at least 100 minutes, and most preferably at least 140 minutes. The term "metabolic stability" as used herein and hereinafter refers to the sensitivity of a compound of the present disclosure to biotransformation. Examples of metabolic stability include, but are not limited to, in vitro metabolic stability as determined by incubation of human hepatocytes with a compound of the present disclosure (at a concentration of 1 μ M) and as represented by the half-life (T1/2, min) as determined by the method disclosed in the "pharmacological test" section of the present disclosure.

Additionally or alternatively, the compounds of the present disclosure exhibit inhibition in other species, wherein the inhibition is at least 10%, more preferably at least 20%, even more preferably at least 40%, most preferably at least 50%. The term "inhibition in other species" as used herein and hereinafter refers to 17 β -HSD1 inhibition of the compounds of the present disclosure in other species than human. Examples of other species include, but are not limited to, rabbits, rats, mice, pigs, and dogs. Examples of inhibition in other species include, but are not limited to, inhibition of the conversion of E1 to E2 in rabbit placental tissue by a compound of the present disclosure (at a concentration of 100nM) determined using the methods disclosed in the "pharmacological test" section of the present disclosure.

It is to be understood that a combination of characteristic 17 β -HSD1 inhibition, 17 β -HSD2 inhibition, metabolic stability, and/or inhibition in other species may be desirable. Thus, the novel and inventive compounds of the present disclosure may exhibit an excellent combination of the features described.

The term "halogen" as used herein and hereinafter alone or as part of another group refers to group VIIa elements and includes F, Cl, Br, and I groups.

The term "alkyl" as used herein and hereinafter is an aliphatic linear, branched or cyclic hydrocarbon radical, especially a linear or branched hydrocarbon radical having the indicated number of carbon atoms, e.g. C_1-6-alkyl has 1 to 6 carbon atoms in the alkyl moiety, and thusE.g. C_1-4Alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl and C_1-6Alkyl additionally includes branched and straight-chain pentyl and hexyl radicals.

The term "alicyclic" as used herein and hereinafter refers to a cyclic aliphatic hydrocarbon, which is a hydrocarbon group having a cyclic structure, with only carbon atoms forming the ring structure. Alicyclic rings can be saturated, partially unsaturated, or unsaturated.

The term "(per) haloalkyl" as used herein and hereinafter refers to alkyl groups wherein one or more hydrogen atoms are replaced by halogen: in particular I, Br, F or Cl. Examples of haloalkyl groups include, but are not limited to, chloromethyl, fluoromethyl, and-CH₂CF₃. The term "perhaloalkyl" is understood to mean an alkyl group in which all the hydrogen atoms are replaced by halogen atoms. Preferred examples include trifluoromethyl (-CF)₃) And trichloromethyl (-CCl)₃)。

The term "C" as used herein and hereinafter_1-3By-alkoxy "is meant-O- (C)_1-3-alkyl) group, wherein "C_1-3-alkyl "has the meaning defined above. Examples of preferred alkoxy groups include, but are not limited to, methoxy, ethoxy, and isopropoxy.

The term "sulfonyl" as used herein and hereinafter refers to a compound having the general structure-S (═ O)₂-or-SO₂-sulfonyl wherein sulfur (S) is attached to two separate carbon atoms and sulfur is substituted with two oxo groups. The sulfonyl group may also be part of a ring structure with the carbon atom to which it is attached. The ring structure may include only carbon atoms in addition to sulfonyl groups or other heteroatoms such as, but not limited to, nitrogen, oxygen, and sulfur.

The term "6-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur" refers to a monocyclic ring, which is saturated and has 4 to 6 ring atoms, and contains 1 heteroatom selected from N, S and O, while the remaining ring atoms are carbon atoms. It may be substituted at any suitable ring atom (including N) by one or two substituents as indicated, in particular one substituent. Preferred substituents include, but are not limited to, halogen, especially fluorine, CN, methoxy and methyl.

The term "4-to 6-membered unsubstituted saturated heterocyclic ring containing 1 heteroatom selected from nitrogen, sulfur and oxygen" refers to a monocyclic ring, which is saturated and has 4 to 6 ring atoms and contains 1 heteroatom selected from N, S and O, while the remaining ring atoms are carbon atoms. Representative groups include oxetanyl, pyrrolidinyl, piperidinyl and tetrahydropyranyl, particularly oxetanyl and tetrahydropyranyl.

The term "5-membered partially unsaturated heterocyclic ring containing 1 to 3 heteroatoms selected from nitrogen, sulfur and oxygen" refers to a partially unsaturated monocyclic ring having 5 ring atoms, which contains at least one double bond between the ring atoms and contains 1 to 3 heteroatoms selected from N, S and O, while the remaining ring atoms are carbon atoms. It may be substituted at any suitable ring atom (including N) by one or two substituents as indicated, in particular one substituent. Preferred substituents include, but are not limited to, halogen, especially fluorine, CN, methoxy and methyl.

The term "5-membered unsubstituted unsaturated or aromatic heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen" refers to a monocyclic ring having 5 ring atoms, and which may be aromatic or unsaturated and contains 1 to 3 heteroatoms independently selected from N, S and O, while the remaining ring atoms are carbon atoms.

The term "5-membered unsaturated or aromatic heterocyclic ring" refers to a monocyclic ring having 5 ring atoms, and which may be aromatic or unsaturated and contains 1 to 3 heteroatoms independently selected from N and O, while the remaining ring atoms are carbon atoms. It may be substituted at any suitable ring atom (including N) by one or two substituents as indicated, in particular one substituent. Preferred substituents include, but are not limited to, halogen, especially fluorine, CN, methoxy and methyl. Representative groups include oxazolyl and methyloxazolyl.

The term "6-membered unsaturated or aromatic heterocyclic ring comprising 1 to 3 additional heteroatoms independently selected from nitrogen and oxygen" refers to a monocyclic ring having 6 ring atoms, and which may be aromatic or unsaturated, containing 1 to 3 heteroatoms independently selected from N, S and O, while the remaining ring atoms are carbon atoms. It may be substituted at any suitable ring atom (including N) by one or two, preferably one, substituent as indicated, in particular one substituent. Preferred substituents include, but are not limited to, halogen, especially fluorine, CN, methoxy and methyl. Advantageously, the substituents are located in the para and meta positions of the ring. Representative groups include pyridyl, fluoropyridyl, cyanopyridyl, methylpyridyl, dimethylpyridyl, isopropylpyridyl, hydroxypyridyl, methoxypyridyl, morpholinopyridyl, methylpiperazinylpyridyl, pyrazinyl, methylpyridazinyl, and methoxypyridazinyl; in particular fluoropyridyl, methoxypyridyl, methylpyridazinyl and methoxypyridazinyl.

The term "a 5-to 6-membered saturated heterocyclic ring containing a nitrogen atom" refers to a saturated monocyclic ring having 6 ring atoms and containing 1 nitrogen atom with the remaining ring atoms being carbon atoms. It may be substituted at any suitable ring atom (including N) by one or two substituents as indicated, in particular one substituent. Preferred substituents include, but are not limited to, halogen, especially fluorine, CN, methoxy and methyl. Representative groups include pyrrolidinyl and methoxymethylpyrrolidinyl.

The term "unsubstituted bicyclic spiro or fused heterocyclic ring comprising said nitrogen atom and optionally 1 or 2 additional heteroatoms selected from nitrogen, oxygen and sulfur" refers to a bicyclic ring system wherein the rings may be linked together as a spiro ring system or as a fused system, preferably as a spiro ring system, and as indicated comprise a nitrogen atom and optionally 1 or 2 additional heteroatoms selected from N, O and S, while the remaining ring atoms are carbon atoms. Representative groups include oxaazaspiro [4.5] decyl (oxazaspiro [4.5] decanoyl).

The term "5-or 6-membered saturated fused ring" refers to a fused ring that is saturated or partially unsaturated, and thus adds 3 to 4 additional ring atoms to the original ring being fused, and optionally contains 1 to 3 heteroatoms each independently selected from N, S and O, with the remaining ring atoms being carbon atoms.

The term "optionally substituted" as used herein and hereinafter for phenyl "Represents phenyl unsubstituted or independently substituted by one or more, especially 1,2 or 3, substituents attached at any available atom to yield a stable compound, e.g. pyridinyl may be substituted once by the indicated substituent attached to any suitable position of the pyridinyl ring. In general, "substituted" refers to a substituent as defined herein, wherein one or more bonds to a hydrogen atom contained therein is replaced with a bond to a non-hydrogen atom, unless otherwise specified. In particular, the substituents are each independently selected from halogen, in particular F; c_1-4-alkyl, in particular methyl; OH; c_1-4-alkoxy, in particular methoxy; and CN.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. "comprising" or "comprises" means that the subsequently described set can, but need not, include other elements.

The expression "pharmaceutically acceptable" means useful for preparing pharmaceutical compositions that are generally safe, non-toxic and biologically or otherwise innocuous, and includes use for veterinary as well as human pharmaceutical uses.

The expression "acid addition salts" includes any non-toxic organic and inorganic acid addition salts which the compounds of formula (I) may form. Exemplary inorganic acids that form suitable salts include, but are not limited to, hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid. Exemplary organic acids that form suitable salts include, but are not limited to, acetic, lactic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic, methanesulfonic, salicylic, and the like. As used herein, the term "acid addition salt" also includes solvates, such as hydrates, alcoholates and the like, that the compounds and salts thereof are able to form. These salts also include salts useful for chiral resolution of racemates.

The expression "base addition salt" includes any non-toxic base addition salt which the compound of formula (I) may form. Suitable base salts include, but are not limited to, those derived from inorganic bases such as aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium, and zinc, particularly sodium and ammonium salts. Other examples of organic base addition salts include salts of trialkylamines, such as triethylamine and trimethylamine, and choline salts.

The invention relates to novel compounds of formula (I)

Wherein

R1 and R2 are each independently selected from H and halogen;

(i) r3 is selected from H and C1-4 alkyl, and

r4 is selected from

-C1-6-alkyl optionally substituted with OH;

--(CH2)_n-R5, wherein n is 1 to 3 and R5 is a 3-to 7-membered alicyclic ring;

-a 4 to 7 membered unsubstituted saturated alicyclic or unsubstituted heterocyclic ring containing one heteroatom selected from nitrogen, sulfur and oxygen;

-a 5-membered partially unsaturated or aromatic heterocycle comprising 1 to 3 heteroatoms selected from nitrogen, sulphur and oxygen, and optionally substituted with one or two heteroatoms selected from halogen, CN, C1-4-alkyl, C1-3- (per) haloalkyl, OH, C1-3-alkoxy, C (o) N (C1-3-alkyl) and a 6-membered saturated heterocycle₂Said 6-membered saturated heterocyclic ring comprising 1 to 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur and optionally substituted with one or two substituents independently selected from halogen, CN, C1-4-alkyl, C1-3- (per) haloalkyl, OH, and C1-3-alkoxy;

-a 5-membered unsubstituted unsaturated or aromatic heterocyclic ring comprising 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen;

-a 5-membered unsaturated or aromatic heterocyclic ring and a 6-membered saturated heterocyclic ring, said 5-membered unsaturated or aromatic heterocyclic ring comprising 1 to 3 heteroatoms independently selected from nitrogen and oxygen, and optionally substituted with one or two heteroatoms independently selected from halogen, CN, C1-4-alkyl, C1-3- (per) haloalkyl, OH, C1-3-Alkoxy, C (O) N (C1-3-alkyl)₂Said 6-membered saturated heterocyclic ring containing 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur and optionally substituted with one or two substituents independently selected from halogen, CN, C1-4 alkyl, C1-3- (per) haloalkyl, OH and C1-3-alkoxy;

-phenyl, a 6-membered unsaturated or aromatic heterocyclic ring and a 6-membered saturated heterocyclic ring, said 6-membered unsaturated or aromatic heterocyclic ring comprising 1 to 3 heteroatoms independently selected from nitrogen, sulfur and oxygen, and optionally substituted with 1 to 5 heteroatoms independently selected from halogen, CN, C1-4 alkyl, C1-3- (per) haloalkyl, OH, oxo, C1-3-alkoxy, morpholino, C (o) N (C1-3-alkyl)₂Said 6-membered saturated heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, optionally substituted with C1-4 alkyl; and

-a 6-membered saturated heterocyclic ring comprising 1 to 3 heteroatoms independently selected from nitrogen, oxygen and sulfur and optionally substituted with 1 to 3 substituents independently selected from halogen, CN, C1-4-alkyl, C1-3- (per) haloalkyl, OH, oxo and C1-3-alkoxy, or two adjacent substituents may form a 5-or 6-membered saturated fused ring;

or

(ii) R3 and R4 form together with the nitrogen atom to which they are attached a group selected from: a 4-to 7-membered saturated heterocyclic ring containing the nitrogen atom and optionally one selected from nitrogen, oxygen and sulfur including SO₂And optionally substituted with a substituent selected from: halogen, CN, methyl, C1-3- (per) haloalkyl, OH, oxo, C1-3-alkoxy, and a 4-to 7-membered alicyclic ring or a 4-to 7-membered saturated heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen, and sulfur, optionally substituted with C1-4-alkyl;

or

(iii) R3 and R4 form together with the nitrogen atom to which they are attached a group selected from a 4-to 7-membered saturated heterocyclic ring containing the nitrogen atom, and which forms a fused ring or spiro ring with a 4-to 7-membered saturated or unsaturated alicyclic ring or a 4-to 7-membered heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur;

if only hydrogen H is present at the same time¹And H²One of (1), hydrogen H¹And H²The position of the double bond in the pyrazole ring attached being based on hydrogen H¹And H²Which one exists to determine

Or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, the pyrazole ring of the compound is of the form shown in formula (Ia),

wherein R1, R2, R3, R4 and R5 of formula (Ia) are as defined above.

In one embodiment of the invention, the substituent R1 is selected from H, F and Cl, the substituent R2 is selected from H, F and Cl, and the substituents R3, R4 and R5 are as defined above.

In one embodiment of the invention, the substituent R1 is selected from H, F and Cl, the substituent R2 is H or F, and the substituents R3, R4 and R5 are as defined above.

In one embodiment of the invention, the substituent R1 is H, the substituent R2 is F and the substituents R3, R4 and R5 are as defined above.

In one embodiment of the invention, the substituent R3 is H and the substituent R4 is a 6-membered unsaturated or aromatic heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with one or two groups selected from CN, C1-4 alkyl, C1-3-alkoxy, halogen and C (O) N (C1-3-alkyl)₂Or alternatively R4 is a substituent having the formula:

in one embodiment of the invention, the substituent R3 is H and the substituent R4 is a 5-membered unsaturated or aromatic heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with one or two groups selected from CN, C1-4-alkyl, C1-3-alkoxy, halogen and C (O) N (C1-3-alkyl)₂Is substituted with the substituent(s).

In one embodiment of the invention, the substituent R4 is a 5-membered unsubstituted unsaturated or aromatic heterocyclic ring comprising 1 to 3 heteroatoms, wherein 1 to 3 heteroatoms of the 5-membered unsubstituted unsaturated or aromatic heterocyclic ring are independently selected from nitrogen and oxygen, 1 to 3 heteroatoms of the 5-membered unsubstituted unsaturated or aromatic heterocyclic ring are independently selected from 2 nitrogen and 1 sulfur, or 1 to 3 heteroatoms of the 5-membered unsubstituted unsaturated or aromatic heterocyclic ring are independently selected from 2 nitrogen and 1 oxygen, and the substituents R1, R2 and R3 are as defined above, or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, substituent R1 is selected from H, Cl or F, substituent R2 is selected from H, Cl or F, substituent R3 is H, and substituent R4 is a 6-membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with one or two heteroatoms selected from CN, C1-4 alkyl, C1-3-alkoxy, halogen and C (o) N (C1-3-alkyl)₂Or alternatively, the substituent R4 is a substituent having the formula:

or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, substituent R1 is H or F, substituent R2 is H or F, substituent R3 is H, and substituent R4 is a 6-membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with one or two heteroatoms selected from CN, C1-4 alkyl, C1-3-alkoxy, halogen and C (O) N (C1-3-alkyl)₂Or alternatively, the substituent R4 is a substituent having the formula:

or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, the substituent R1 is H, the substituent R2 is H or F, and the substituent R3 isH, the substituent R4 is a 6-membered aromatic heterocycle having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, which is optionally substituted by one or two heteroatoms selected from CN, C1-4-alkyl, C1-3-alkoxy, halogen and C (O) N (C1-3-alkyl)₂Or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, substituent R1 is H, substituent R2 is F, substituent R3 is H, substituent R4 is a 6-membered aromatic heterocyclic ring having 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur, optionally substituted with one or two heteroatoms selected from CN, methyl, methoxy, F and c (o) N (methyl)₂Or alternatively, the substituent R4 is a substituent having the formula:

or a pharmaceutically acceptable salt thereof.

In one embodiment of the invention, the compound of formula (I) is a compound selected from the following list:

-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (6-methoxypyridazin-3-yl) -propionamide,

-N- (5-cyanopyridin-2-yl) -3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide,

-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (4-fluoropyridin-2-yl) propanamide,

-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5-methoxypyridin-2-yl) propanamide,

-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (4-methylpyridin-2-yl) propanamide,

-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [ [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (2-oxo-1, 2,5,6,7, 8-hexahydroquinolin-3-yl) propionamide,

-6- (3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamido) -N, N-dimethylnicotinamide,

-N- (6-methoxypyridazin-3-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide,

-N, N-dimethyl-6- (3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamido) nicotinamide,

-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (1-methyl-1H-pyrazol-3-yl) -propionamide,

-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (1-methyl-1H-pyrazol-4-yl) -propionamide,

-N- (5- (tert-butyl) isoxazol-3-yl) -3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propionamide,

-N- (5-fluoropyridin-2-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide,

-N- (4-fluoropyridin-2-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide, and

-3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (1-methyl-1H-pyrazol-3-yl) propanamide,

or a pharmaceutically acceptable salt thereof.

The invention also relates to a process for the preparation of a compound according to formula (I), in which process a compound of formula (II) is reacted with hydrazine hydrate to form a compound according to formula (I).

The method for preparing the compound having formula (I) according to the present invention more specifically includes a method of dissolving the compound of formula (II) in methanol (1.5 mL). Hydrazine hydrate (200 mol%) was added and stirred under nitrogen at +50 ℃ for 30 minutes. The solvent was evaporated. The evaporation residue was dissolved in ethyl acetate and washed three times with 1N hydrochloric acid. The aqueous layers were combined, washed with ethyl acetate and finally neutralized (pH 8) and the product extracted with ethyl acetate. The product is purified by chromatography or crystallization. Further details of various methods of preparing the compounds according to the invention can be found in the examples.

The invention also relates to intermediates according to formula (II).

Furthermore, the invention relates to compounds of formula (I) for use as medicaments. In particular, the medicament may be for the treatment or prevention of a disease selected from: breast cancer, prostate cancer, ovarian cancer, uterine cancer, endometrial hyperplasia, endometriosis, uterine fibroids (uterine fibroses), adenomyosis, polycystic ovary syndrome, dysmenorrhea, menorrhagia, uterine bleeding, infertility (pregnancy), prostadynia (prostatonia), benign prostatic hyperplasia, urinary dysfunction, lower urinary tract symptoms, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), Systemic Lupus Erythematosus (SLE), multiple sclerosis, obesity, rheumatoid arthritis, Chronic Obstructive Pulmonary Disease (COPD), lung cancer, colon cancer, tissue wounds, skin wrinkles and cataracts.

The invention further relates to pharmaceutical compositions comprising an effective amount of one or more compounds of formula (I) and one or more pharmaceutically acceptable excipients. The pharmaceutical composition may also comprise one or more other active ingredients.

Representative examples of compounds of formula (I) are shown in table 1.

Examples of the invention

Preparation of synthetic starting materials and precursors

Preparation of starting Material acid IX

The compound SM-IX was synthesized from estrone (scheme 1.). The method of Horwitz et al (J.Med.chem.,1986,29(5), 692-698) produces amines SM-III which are fluorinated using the conditions of WO2008124922 of Labrie et al. Fluoride SM-IV is converted to enone SM-VI by Kobayashi et al (Tetrahedron,71(35), 5918-. Allylation, hydroboration and oxidation of SM-VI to SM-IX are carried out as described in patents WO2005/047303 and WO 2006/125800.

Compound SM-IV:

a solution of compound SM-III (11.00g,40.8mmol,100 mol-%) in methylene chloride (430mL) was added neat boron trifluoride etherate (7.9mL,64.20mmol,157 mol-%) while stirring at-15 deg.C under nitrogen (addition time of about 10-15 minutes). The reaction mixture was stirred at-15 ℃ for 15 minutes, then a solution of tert-butyl nitrite (5.9mL, 49.80mmol, 122 mol-%) in dichloromethane (50mL) was added dropwise thereto over a period of 10 minutes. The reaction mixture was stirred at-15 ℃ for a further 15 minutes and then held at 0-5 ℃ for 30 minutes.

The solution was added to n-pentane (2.25L) to give a beige precipitate. The liquid was decanted and the residue was washed with more n-pentane (400 mL). A beige solid (12.00g) was dried under vacuum at room temperature overnight.

The crude material was purified by flash column chromatography using n-hexane and ethyl acetate (10-30%) as solvent system. The yield of compound SM-IV as a cream solid was 70% (7.82 g).

¹H NMR(400MHz,CDCl₃)δppm 0.91(s,3H,-CH₃),1.34-1.70(m,6H),1.93-1.99(m,1H),2.04-2.21(m,3H),2.27-2.46(m,2H),2.48-2.56(m,1H),2.66-2.77(m,1H),2.95-3.03(m,1H),6.84-6.90(m,1H,-ArH),7.06-7.16(m,2H,2x-ArH)。

The compound SM-V:

tert-butyldimethylsilyl trifluoromethanesulfonate (7.1mL,31.10mmol,110 mol-%) was added dropwise over a period of 20 minutes to a stirred solution of compound SM-IV (7.70g,28.27mmol,100 mol-%) and triethylamine (6.0mL,42.72mmol,151 mol-%) in dichloromethane (75mL) at room temperature under nitrogen and stirred for 2 hours (h).

The reaction mixture was diluted with dichloromethane (95mL) and washed with saturated aqueous sodium bicarbonate (2 × 70mL) and brine (70 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The yield of compound SM-V as a cream solid was quantitative (11.42g) and used in the next reaction without further purification.

¹H NMR(400MHz,CDCl₃)δppm 0.14-0.19(m,6H,2x-CH₃),0.86(s,3H,-CH₃),0.94(s,9H,3x-CH₃),1.21-1.62(m,5H),1.78-2.06(m,3H),2.08-2.16(m,1H),2.25-2.38(m,2H),2.64-2.88(m,1H),2.90-2.99(m,1H),4.48(dd,1H,J＝3.1,1.5Hz),6.82-6.88(m,1H,-ArH),7.05-7.13(m,2H,2x-ArH)。

Compound SM-VI:

a mixture of compound SM-V (11.42g,28.27mmol,100 mol-%) and palladium acetate (0.63g,2.83mmol,10 mol-%) in dimethyl sulfoxide (75mL) and dichloromethane (50mL) was stirred at 35 ℃ under an oxygen atmosphere (balloon) for 16 hours, palladium acetate (126 mg, 0.56 mmol,2 mol%) was added to the mixture, and stirring was continued at 35 ℃ for 7 hours.

The reaction mixture was cooled to room temperature and poured into saturated aqueous sodium bicarbonate (300 mL). The mixture was extracted with ethyl acetate (400 mL). The organic layer was washed with water (300mL) and brine (200mL), dried over sodium sulfate, filtered and concentrated to give an orange/brown solid.

The crude material was purified by flash column chromatography using n-hexane and ethyl acetate (0-30%) as solvent system. The yield of compound SM-VI as a pink/white solid was 72% (5.50 g).

¹H NMR(400MHz,CDCl₃)δppm 1.11(s,3H,-CH₃),1.46-1.58(m,1H),1.66-1.88(m,3H),1.97-2.07(m,1H),2.23-2.31(m,1H),2.35-2.54(m,3H),2.72-2.84(m,1H),3.03(dd,1H,J＝17.9,6.4Hz),6.11(dd,1H,J＝6.0,3.2Hz),6.83-6.92(m,1H,-ArH),7.05-7.18(m,2H,2x-ArH),7.63-7.66(m,1H)。

MS m/z(ES⁺)：271(M+H)。

Compound SM-VII:

copper iodide (7.90g,41.48mmol,350 mol-%), lithium chloride (1.76g,41.48mmol,350 mol-%) and anhydrous tetrahydrofuran (60mL) were charged under a nitrogen atmosphere into a dry three-neck flask. The mixture was stirred at room temperature for 20 minutes and cooled to-70 ℃. Allyl magnesium bromide (41.5mL, 41.48mmol,350 mol%) was then added dropwise, maintaining the temperature below-70 ℃. Trimethylchlorosilane (5.3mL,41.48mmol,350 mol-%) was added dropwise to the reaction mixture, maintaining the temperature at-70 ℃ and then a solution of the compound SM-VI (3.20g,11.85mmol,350 mol-%) in anhydrous tetrahydrofuran (60mL) was added dropwise, maintaining the temperature below-65 ℃. The reaction mixture was allowed to slowly warm to room temperature and stirred overnight.

The mixture was poured into saturated aqueous ammonium chloride (75mL) and extracted with ethyl acetate (3X 70 mL). The combined extracts were washed with 1M HCl (2X 50mL), water (2X 50mL) and dilute aqueous ammonia (5X 25mL) (until the solution was colorless). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography using n-hexane and ethyl acetate (10%) as solvent systems. The yield of compound SM-VII was 77% (2.85 g).

¹H NMR(400MHz,CDCl₃)δppm 1.05(s,3H,-CH₃),1.40-1.57(m,3H),1.71-1.82(m,2H),1.89-1.96(m,1H),2.04-2.20(m,2H),2.31-2.50(m,6H),2.72-2.84(m,1H),2.94-3.03(m,1H),5.02-5.08(m,2H,CH＝CH₂),5.69-5.81(m,1H,CH＝CH₂),6.88(t,1H,ArH,J＝8.7Hz),7.05-7.16(m,2H,2xArH)。

Compound SM-VIII:

compound SM-VII (2.85g,9.13mmol,100 mol-%) and anhydrous tetrahydrofuran (70mL) were charged to a dry, nitrogen purged flask. A solution of 1M borane THF complex (18.3mL,18.30mmol,200 mol-%) was added dropwise to the previous solution. The resulting reaction mixture was refluxed for 1 hour, cooled to-5 ℃ in an ice bath, and 3M aqueous sodium hydroxide (28mL) was added very carefully. After addition was complete and effervescence ceased, 30% hydrogen peroxide (28mL) was added and the mixture was gently refluxed for 2 hours.

The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3 × 70 mL). The combined extracts were washed with water (2 × 50mL) and brine (50mL), dried over sodium sulfate, filtered and concentrated. The yield of compound SM-VIII was quantitative (3.09 g).

¹H NMR(400MHz,CDCl₃)δppm 0.82(s,3H,-CH₃),1.13-1.64(m,9H),1.81-1.88(m,1H),1.91-2.06(m,2H),2.16-2.27(m,2H),2.30-2.39(m,1H),2.63-2.74(m,1H),2.81-2.89(m,1H),3.54-3.69(m,3H),6.76-6.82(m,1H,-ArH),6.98-7.08(m,2H,2x-ArH)。

Acid SM-IX [3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanoic acid ]

Periodic acid (5.15g, 22.60mmol, 500 mol%) and chromium trioxide (23mg, 0.23mmol, 5.0 mol%) were dissolved in a mixture of acetonitrile (36 ml) and water (12 ml). The solution was cooled to 0 ℃ in an ice/salt bath. A slurry of compound SM-VIII (1.5g,4.52mmol,100 mol-%) in acetonitrile (30mL) was added to the previous solution over a period of 40 minutes. The temperature is maintained at 0 ℃ or below. The reaction mixture was stirred at 0 ℃ for 1 hour, then the mixture was slowly warmed to room temperature and stirred for 3.5 hours.

The reaction mixture was poured into aqueous disodium hydrogen phosphate (about 5g in 100mL) and extracted with ethyl acetate (3X 60 mL). The organic extracts were combined and washed with 5% aqueous sodium bisulfite (2X 40mL), water (50mL) and brine (50mL), dried over sodium sulfate, filtered and concentrated. The crude material was purified by flash column chromatography using n-hexane, ethyl acetate (10-30%) and acetic acid (1%) as solvent systems. The product was dissolved in toluene (50mL) and stirred for 15 minutes. The solvent was removed in vacuo and the solid was dried in vacuo at 50 ℃. The crude yield of acid SM-IX as a white solid was 71% (1.11 g).

¹H NMR(400MHz,CDCl₃)δppm 0.99(s,3H,-CH₃),1.31-1.53(m,3H),1.55-1.78(m,3H),1.83-2.00(m,2H),2.09-2.17(m,1H),2.23-2.47(m,7H),2.68-2.80(m,1H),2.88-2.97(m,1H),6.81(t,1H,-ArH,J＝8.6Hz),6.98-7.10(m,2H,2x-ArH)。

MS m/z(ES-):343(M-H)。

Preparation of starting Material acid SM-XV

C-3 fluoro SM-XV is synthesized from estrone via the compound SM-X (scheme 2.), which can be synthesized as disclosed by Messinger et al in Mol Cell Endocrinol 2009(301) 216-224. Detailed procedures for the synthesis of compound X from estrone are described in WO2008065100, WO2005/047303 and WO 2006/125800. The acid SM-X was methylated by heating in methanol in the presence of sulfuric acid followed by triflation (triflation). Bis-tributyltin derivatives SM-XIII were prepared from the corresponding triflates SM-XII and then fluorinated to XIV in 75% yield (cf. WO 2010059943 and Furuya et al, JACS 2009,13(15), 1662). Several methods of deoxofluorination of estrone are available (PCT Int.appl. for Labrie, Fernand et al, 16/9/9946279,1999; PCT Int.appl. for Labrie, Fernand et al, 21/10/2004089971,2004).

Compound XIII:

compound SM-XII (10.0g,20.47mmol,100 mol-%) and 1, 4-dioxane (120mL) were added to the screw cap sealed tube. Bistributyltin (230.7mL, 40.99mmol, 200 mol-%) and LiCl (4.2g, 102.3mmol, 500 mol-%) were added to the reaction mixture. The reaction mixture was degassed with argon for 10 minutes, and then Pd (PPh) was added thereto₃)4(1.41g, 1.22mmol, 6 mol-%). The tube was sealed under nitrogen and the mixture was placed in a preheated oil bath at 10Heat and stir at 0 ℃ for 4 hours. The mixture was cooled to room temperature and quenched with water (100mL), extracted with ethyl acetate (2 × 200mL), then filtered through celite, washing well with ethyl acetate. The solvent was concentrated to a brown viscous oil. The crude product was purified by flash chromatography eluting with a gradient of 0 to 10% ethyl acetate in hexanes to give compounds SM-XIII.

¹H NMR(400MHz,CDCl₃) Delta ppm of 7.29-7.19(m,3H),3.69(s,3H),2.95(bs,2H),2.42-0.87(m, 46H). MS m/z (ES +): the ionization is not good.

Compound SM-XIV:

to a stirred solution of compound SM-XIII (14.0g, 22.2mmol, 1.0eq (eq)) in acetone (140mL) was added AgOTf (11.41g, 44.4mmol, 2.0eq) at room temperature. The reaction mixture was cooled to 0 ℃ and 1-chloromethyl-4-fluoro-1, 4-diazobicyclo [2.2.2] octane bis (hexafluorophosphate) (12.53g, 26.6mmol, 1.2eq) was added and the reaction mixture was stirred for 40 min. The reaction was quenched with water (100mL) and extracted with ethyl acetate (2X 150 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude compound was purified by flash chromatography using 0-20% ethyl acetate in hexane. Compound SM-XIV (6.0g, 75.9%) was obtained as a white solid.

¹H NMR (400MHz, DMSO-d6) delta ppm 7.30-7.27(m,1H),7.10-7.08(d,1H, J ═ 8Hz),6.94-6.89(m,1H),3.59(s,3H),2.87(bs,2H),2.45-2.07(m,8H),1.86-1.32(m,8H),0.95(s, 3H). MS m/z (ES +): the ionization is not good.

Acid SM-XV:

to a stirred solution of compound SM-XIV (6.0g,16.7mmol,1.0eq) in THF (60mL), water (10.5mL) was added LiOH₂O (1.41g,33.5,2.0eq) and stirred at RT (RT) for 4 hours. Cooling the reaction mixtureTo 10 ℃ and neutralized with 1N HCl (pH 6) and extracted with ethyl acetate (2 × 50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude compound was triturated with n-pentane (2X 10mL) and then purified by preparative HPLC to give the acid SM-XV as a white solid (2.2g, 38.19%).

¹H NMR(400MHz,DMSO-d6)δppm:12.06(s,1H),7.29-7.27(d,1H,J＝8Hz),7.16-7.14(d,2H,J＝8Hz),2.87(bs,2H),2.37-2.12(m,8H),1.82-1.67(m,4H),1.55-1.38(m,4H),0.84(s,3H)。MS m/z(ES+)：343.23(M-H)。

Acid SM-XVII

The triflate salt SM-XII in scheme 3 was prepared according to the method of WO2008065100 to Messinger et al. SM-XII is converted to the chloro derivative SM-XVI by using t-BuBrettPhos (di-tert-butyl (2 ', 4', 6 '-triisopropyl-3, 6-dimethoxy- [1,1' -biphenyl ] -2-yl) phosphine) in the presence of tris (dibenzylideneacetone) dipalladium (0) (Pan et al, Organic Letters,13(18), 4974-4976; 2011) and then treated with LiOH in THF: water to give the desired acid SM-XVII.

Compound SM-XVI:

to a screw cap sealed tube, tris (dibenzylideneacetone) dipalladium (0) (0.084g,0.092mmol,3 mol-%) and t-BuBrettPhos (0.133g,0.27mmol,9 mol-%) and 1, 4-dioxane (10mL) were added and the tube was sealed under nitrogen. The mixture was stirred and heated in a preheated oil bath at 130 ℃ for 3 minutes. The catalyst mixture was cooled to room temperature and the mixture was added to a solution of compound SM-XII (1.5g,3.04mmol,100 mol-%) in 1, 4-dioxane (11mL), potassium chloride (0.908g,12.28mmol,400 mol-%) and potassium fluoride (0.178g,3.0mmol,100 mol-%). The mixture was stirred and heated in a preheated oil bath at 130 ℃ for 3 hours. The mixture was cooled to room temperature, then filtered through celite, washing with ethyl acetate. The solvent was concentrated to leave a brown viscous oil. The crude product was purified by flash chromatography eluting with a gradient from 0 to 20% SM-compound XVI.

¹H NMR (400MHz, DMSO-d6) δ ppm 7.29-7.27(d,1H, J ═ 8Hz),7.16-7.14(d,2H, J ═ 8Hz),3.59(s,3H),2.87(bs,2H),2.41-2.07(m,8H),1.85-1.38(m,8H),0.95(s, 3H). MS m/z (ES +): the ionization is not good.

Acid SM-XVII:

to a stirred solution of compound SM-XVI (1.7g,4.54mmol,1.0eq) in THF: MeOH: water (12.5mL,2:2:1) at room temperature was added LiOH₂O (0.572g,13.6,3.0 eq). The reaction mixture was heated at 80 ℃ for 1.5 hours. The progress of the reaction was monitored by TLC and LC-MS. The reaction mixture was cooled to room temperature, diluted with 10mL of water and washed with 3X 3mL of ethyl acetate. The aqueous layer was neutralized with 1N HCl (pH 6) and extracted with ethyl acetate (2 × 50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was triturated with n-pentane (2X 10mL) to give the acid SM-XVII (1.3g, 79%) as a white solid.

¹H NMR(400MHz,DMSO-d6)δppm:12.06(s,1H),7.29-7.27(d,1H,J＝8Hz),7.16-7.14(d,2H,J＝8Hz),2.87(bs,2H),2.37-2.12(m,8H),1.82-1.67(m,4H),1.55-1.38(m,4H),0.84(s,3H)。MS m/z(ES+)：358.9(M-H)。

Preparation of starting Material acid SM-XXVI:

the compound SM-XXVI is synthesized from estrone via the triflate SM-XVIII, which is prepared by the method of WO2008065100 to Messinger et al. C15-C16 SM-XXIII was prepared according to the method described in WO 2008065100. Allylation, hydroboration and oxidation of SM-XXIII to SM-XXVI are carried out as described in patents WO2005/047303 and WO 2006/125800.

Acid SM-XXVI:

a stirred solution of (8R,9S,13S,14S,15R) -15- (3-hydroxypropyl) -13-methyl-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-17-ol (44.0g 0.140mol) in acetone (875mL) was cooled to 0 ℃. In another RBF, jones reagent was prepared by dissolving chromic acid (35g, 0.350mol) in water (350ml) and concentrated sulfuric acid (41.14g, 0.420 mol). The prepared Jones reagent was added to the solution of the starting material over 45 minutes, maintaining the temperature at 0-2 deg.C for 2-3 hours. The reaction mass was quenched with ice-cold water (875mL), and the viscous mass was filtered and dissolved in 3N NaOH solution (200 mL). The mixture was extracted with ethyl acetate (3X 200 mL). The aqueous layer was taken up in 2N aqueous HCl (pH 6) and extracted with ethyl acetate (3 × 200 ml). The combined organic layers were washed with brine (200mL), dried over anhydrous sodium sulfate, and the solvent was evaporated to give the solid acid SM-XXVI3- ((8R,9S,13S,14S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propionic acid (24g, 52%) as a white solid.

¹H NMR(400MHz,DMSO-d6)δppm:12.0(s,1H),7.27-7.25(d,1H,J＝8Hz),7.13-7.05(m,3H,),2.87(bs,2H),2.41-2.10(m,8H),1.87-1.36(m,8H),0.95(s,3H)。

MS m/z(ES+)：325.23(M-H)。

General information

Commercial grade reagents and solvents were used without further purification. Thin Layer Chromatography (TLC) on Merck plates; precoated aluminum plate. Visualization of the plate was performed by the following technique: 1) ultraviolet irradiation (254nm), 2) immersing the plate in an anisaldehyde or vanillin solution, followed by heating. The 1H-NMR spectra were measured with the indicated solvents using a Bruker DPX (200MHz) or Avance III 400(400MHz) spectrometer.

The synthesis method of the step A comprises the following steps:

method A1: general scheme for preparation of amides by the T3P Process

The acid (100mg, 100 mol%) was dissolved in dry THF (3 mL). The corresponding amide (200 mol%) and pyridine (300 mol%) were added. T3P (200 mol%) was added dropwise to the reaction mixture. Stirring at room temperature or +50 ℃ until the reaction is complete. The evaporation residue was dissolved in EtOAc and 10% NaHCO was carefully added₃. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with dilute hydrochloric acid, water and brine, and dried over sodium sulfate. The crude product is usually purified by chromatography.

Method A2: general procedure for the preparation of amides by the EDCI method

The acid (150mg, 100 mol%) was dissolved in dry DMF or DCM (4 mL). HOBt (220 mol%) and EDCI (220 mol%) and amine (200 mol%) were added to the reaction mixture and stirring was continued at +50 ℃ until the reaction was complete. When the product was precipitated by adding water, water (4ml) was added to the reaction mixture, which was then washed several times with water.

Method A3: improved process for preparing amides by EDCI process

The acid (200mg, 100 mol%) was dissolved in dry dichloromethane (4 mL). Amine (150 mol%), N-methylmorpholine (300 mol%) and 1-hydroxy-1H-benzotriazole (220 mol%) were added to the reaction mixture. After stirring for 5 minutes, the reaction mixture was cooled to 0-5 ℃. EDCl (220 mol%) was added to the reaction mixture. Stirring was carried out at room temperature until the reaction was complete. The reaction mixture was diluted with DCM (ca. 5ml) and washed with 0.5N HCl solution (2X 10ml), water (3X 10ml) and brine (2X 10 ml). The organic layer was dried over sodium sulfate. The crude product will be purified if desired.

The synthesis method of the step B comprises the following steps:

the method B comprises the following steps: general procedure for the preparation of hydroxymethylene by the Ethyl formate/NaH-method

The steroidal C-17 carbonyl intermediate containing the appropriate amide unit at the C-15 position (95mg,100 mol%) was co-evaporated with toluene (3X 10mL) and then dissolved in dry THF (400. mu.l). To the reaction mixture was added dry toluene (1000 μ l), ethyl formate (600 mol%) and NaH (450 mol%) under nitrogen, followed by stirring at room temperature until the reaction was complete. The solvent was evaporated, the residue was dissolved in EtOAc and washed with dilute hydrochloric acid, water and brine, dried over sodium sulfate.

The synthesis method of the step C comprises the following steps:

the method C comprises the following steps: general procedure for preparation of pyrazoles by hydrazine hydrate method

The hydroxymethylene derivative (90-100mg, 100 mol%) was dissolved in methanol (1.5 mL). Hydrazine hydrate (200 mol%) was added and stirred for 30 minutes at +50 ℃ under nitrogen. The solvent was evaporated. The evaporation residue was dissolved in ethyl acetate and washed three times with 1N hydrochloric acid. The aqueous layers were combined, washed with ethyl acetate and finally neutralized (pH 8) and the product extracted with ethyl acetate. The product is purified by chromatography or crystallization or trituration.

Compound 1

N- (5-cyanopyridin-2-yl) -3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 1 was prepared according to method a1 from the acid SM-IX and 5-cyano-2-aminopyridine by stirring overnight at room temperature. The yield thereof was found to be 83%.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.33-2.48(m,15H),2.57(m,1H),2.68-2.90(m,2H),6.97(dd,1H),7.14(m,2H),8.25(s,2H),8.78(s,1H),11.04(s,1H)。

Compound 2

N- (5-cyanopyridin-2-yl) -3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 2 was prepared from compound 1 by method B by stirring overnight at room temperature in 51% yield.

¹H NMR(400MHz,DMSO-d₆):1.00(s,3H),1.38-2.37(m,12H),2.64(m,2H),2.74-2.96(m,3H),6.96(dd,1H),7.14(m,2H),7.57(s,1H),8.23(m,2H),8.76(s,1H),11.03(s,1H)。

Compound 3

N- (5-cyanopyridin-2-yl) -3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 3 was prepared from compound 2 by method C and purified by chromatography in 80% yield.

¹H NMR(400MHz,DMSO-d₆):1.11(s,3H),1.43-2.45(m,11H),2.56(m,2H),2.76-2.93(m,3H),6.97(dd,1H),7.16(m,2H),7.39(s,1H),8.25(m,2H),8.79(d,1H),11.08(s,1H),12.13(br s,1H)。

Compound 4

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-methoxypyridazin-3-yl) -propionamide

Compound 4 was prepared by method a2 from the acid SM-IX and 3-amino-6-methoxypyridazine by stirring at room temperature for 4 hours. The yield thereof was found to be 95%.

¹H-NMR(200MHz,DMSO-d₆):0.98(s,3H),1.20-2.47(m,16H),2.60-2.97(m,2H),3.98(s,3H),6.89-7.06(m,1H),7.08-7.21(m,2H),7.25(d,1H),8.26(d,1H),10.94(br s,1H)。

Compound 5

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopentan [ a ] phenanthren-15-yl) -N- (6-methoxypyridazin-3-yl) propanamide

Compound 5 was prepared from compound 4 by method B in 89% yield.

¹H NMR(400MHz,DMSO-d₆):1.00(s,3H),1.38-2.37(m,11H),2.68-2.98(m,5H),3.98(s,3H),6.97(dd,1H),7.14(m,2H),7.23(d,1H),7.55(s,1H),8.24(d,2H),10.87(s,1H)。

Compound 6

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (6-methoxypyridazin-3-yl) propanamide

Compound 6 was prepared from compound 5 by method C, purifying the crude product by trituration with a heptane-ethanol 1:1 mixture in 55% yield.

¹H NMR(400MHz,DMSO-d₆):1.11(s,3H),1.41-2.44(m,11H),2.53-2.92(m,5H),3.99(s,3H),6.97(dd,1H),7.15(m,2H),7.24(d,1H),7.42(s,1H),8.26(d,1H),10.97(s,1H),12.13(br s,1H)。

Compound 7

N- (3, 5-difluoropyridin-2-yl) -3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 7 was prepared from the acid SM-IX by stirring at room temperature for 2 hours by method a1 using 2-amino-3, 5-difluoropyridine as the amine. The yield thereof was found to be 91%.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.34-2.55(m,16H),2.69-2.90(m,2H),6.97(dd,1H),7.14(m,2H),8.01(dd,1H),8.34(d,1H),10.31(s,1H)。

Compound 8

N- (3, 5-difluoropyridin-2-yl) -3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 8 was prepared by method B from compound 7 by stirring at room temperature for three hours in 96% yield.

¹H NMR(400MHz,DMSO-d₆):0.99(s,3H),1.39-2.45(m,12H),2.67-2.96(m,5H),6.97(dd,1H),7.14(m,2H),7.57(s,1H),8.00(m,1H),8.33(d,1H),10.31(s,1H)。

Compound 9

N- (3, 5-Difluoropyridin-2-yl) -3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 9 was prepared from compound 8 by method C in 84% yield.

¹H NMR(400MHz,DMSO-d₆):1.11(s,3H),1.37-2.48(m,13H),2.71-2.92(m,3H),6.97(dd,1H),7.16(m,2H),7.44(s,1H),8.00(m,1H),8.34(d,1H),10.36(s,1H),12.14(br s,1H)。

Compound 10

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-fluoropyridin-2-yl) propanamide

Compound 10 was prepared from the acid SM-IX by method a1 with stirring at room temperature for 3 hours using 2-amino-5-fluoropyridine as the amine in 99% yield.

¹H NMR(200MHz,DMSO-d₆):0.98(s,3H),1.24-2.46(m,16H),2.59-3.03(m,2H),6.90-7.05(m,1H),7.06-7.22(m,2H),7.73(td,1H),8.15(dd,1H),8.32(d,1H),10.63(s,1H)。MS m/z(TOF ES⁺)：439(M+1)

Compound 11

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-fluoropyridin-2-yl) propanamide

Compound 11 was prepared from compound 10 by method B in 99% yield.

¹H NMR(400MHz,DMSO-d₆):0.99(s,3H),1.39-2.37(m,11H),2.58(m,2H),2.70-2.97(m,3H),6.96(dd,1H),7.14(m,2H),7.54(s,1H),7.71(m,1H),8.14(dd,1H),8.30(d,1H),10.55(s,1H),10.99(br s,1H)。

Compound 12

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5-fluoropyridin-2-yl) propanamide

Compound 12 was prepared from compound 11 by method C in 90% yield.

¹H NMR(400MHz,DMSO-d₆):1.11(s,3H),1.48-2.42(m,13H),2.72-2.93(m,3H),6.97(dd,1H),7.16(m,2H),7.40(s,1H),7.72(m,1H),8.15(m,1H),8.31(d,1H),10.66(s,1H),12.15(br s,1H)。

Compound 13

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-fluoropyridin-2-yl) propanamide

Compound 13 was synthesized by method a1 in 83% yield in THF over an overnight reaction time using the acid SM-IX and 2-amino-4-fluoropyridine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.36-1.46(m,3H),1.58-1.74(m,4H),1.89-1.94(m,1H),2.16-2.43(m,7H),2.68-2.91(m,3H),6.95-7.04(m,2H),7.05-7.20(m,2H),7.93(dd,1H),8.34(dd,1H),10.83(s,1H)。

Compound 14

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-fluoropyridin-2-yl) propanamide

Compound 14 was prepared from compound 13 by method B in 44% yield.

¹H NMR(400MHz,DMSO-d₆):1.00(s,3H),1.32-2.30(m,12H),2.55-2.96(m,5H),6.96(dd,1H),7.02(m,1H),7.14(m,2H),7.56(s,1H),7.92(dd,1H),8.34(m,1H),10.80(s,1H)。

Compound 15

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (4-fluoropyridin-2-yl) propanamide

Compound 15 was prepared from compound 14 by method C in 57% yield.

¹H NMR(400MHz,DMSO-d₆):1.11(s,3H),1.40-2.42(m,13H),2.76-2.93(m,3H),6.97(dd,1H),7.03(m,1H),7.16(m,2H),7.40(s,1H),7.93(dd,1H),8.36(dd,1H),10.87(s,1H),12.16(br s,1H)。

Compound 16

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyridin-2-yl) propanamide

Compound 16 was synthesized by method a2 in DMF with the acid SM-IX and 2-aminopyridine as starting materials in 51% yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.34-1.47(m,3H),1.59-1.68(m,4H),1.78-1.90(m,1H),2.17-2.46(m,8H),2.68-2.82(m,2H),6.95-6.99(m,1H),7.07-7.13(m,1H),7.14-7.20(m,2H),7.76(dd,1H),8.10(d,1H),8.30(dd,1H),10.50(s,1H)。

Compound 17

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyridin-2-yl) propanamide

Compound 17 was prepared from compound 16 by method B in 97% yield.

¹H NMR(400MHz,DMSO-d₆):0.99(s,3H),1.35-2.23(m,12H),2.68-2.98(m,5H),6.96(dd,1H),7.05(m,1H),7.14(m,2H),7.70(s,1H),7.75(dd,1H),8.09(d,1H),8.30(m,1H),10.70(s,1H)。

Compound 18

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (pyridin-2-yl) propionamide

Compound 18 was prepared from compound 17 by method C in 91% yield.

¹H NMR(400MHz,DMSO-d₆):1.11(s,3H),1.40-2.45(m,13H),2.67-2.99(m,3H),6.97(dd,1H),7.07(m,1H),7.16(m,2H),7.41(s,1H),7.76(dd,1H),8.10(d,1H),8.30(d,1H),10.54(s,1H),12.13(br s,1H)。

Compound 19

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopropa [ a ] phenanthren-15-yl) -N- (5-methoxypyridin-2-yl) propanamide

Compound 19 was synthesized by method a2 in 80% yield in DMF using the acid SM-IX and 5-methoxy-2-aminopyridine as starting materials, stirred at +50 ℃ for 2 hours over an overnight reaction time.

¹H-NMR(200MHz,CDCl₃):1.07(s,3H),1.35-2.53(m,16H),2.72-3.03(m,2H),3.85(s,3H),6.83-6.92(m,1H),7.05-7.18(m,2H),7.24-7.30(m,1H),7.92-8.01(m,2H),8.15(d,1H)。

Compound 20

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-methoxypyridin-2-yl) propanamide

Compound 20 was prepared from compound 19 by method B in quantitative yield.

¹H NMR(400MHz,DMSO-d₆):0.99(s,3H),1.41-2.35(m,12H),2.68-2.96(m,4H),3.80(s,3H),6.96(m,1H),7.14(m,2H),7.40(d,1H),7.55(s,1H),8.01(s,2H),10.32(s,1H),11.04(br s,1H)。

Compound 21

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5-methoxypyridin-2-yl) propanamide

Compound 21 was prepared from compound 20 by method C in 57% yield.

¹H NMR(400MHz,DMSO-d₆):1.10(s,3H),1.40-2.47(m,13H),2.70-2.99(m,3H),3.80(s,3H),6.97(m,1H),7.16(m,2H),7.41(s,2H),8.03(m,2H),10.41(s,1H),12.12(br s,1H)。

Compound 22

4- (3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanoyl) piperazin-2-one

Compound 22 was synthesized by method a1 in THF in 81% yield over a three hour reaction time using the acid SM-IX and piperazin-2-one as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.37-2.45(m,17H),2.68-2.90(m,2H),3.57-3.64(m,4H),3.93(dd,1H),6.97(m,1H),7.13-7.20(m,2H),8.09(d,1H)。

Compound 23

4- (3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanoyl) piperazin-2-one

Compound 23 was prepared from compound 22 by method B in 71% yield.

¹H NMR(400MHz,DMSO-d₆):0.97(s,3H),1.35-2.37(m,14H),2.67-2.92(m,3H),3.16-3.25(m,3H),3.58-3.67(m,2H),3.93(d,1H),6.97(dd,1H),7.14(m,2H),7.53(s,1H),8.11(d,1H)。

Compound 24

4- (3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanoyl) piperazin-2-one

Compound 24 was prepared from compound 23 by method C in 36% yield.

¹H NMR(400MHz,DMSO-d₆):1.09(s,3H),1.30-2.47(m,13H),2.67-2.92(m,3H),3.15-3.25(m,2H),3.51-3.68(m,2H),3.92(d,1H),4.02-4.08(dd,1H),6.98(m,1H),7.16(m,2H),7.45(d,1H),8.10(d,1H),12.12(br s,1H)。

Compound 25

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-methylpyridin-2-yl) propanamide

Compound 25 was synthesized by method a2 starting from the acid SM-IX and 2-amino-4-methylpyridine in THF using 200 mol-% EDCI and HOBT for 4.5 hours with a yield of 37% after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.48(m,16H),2.30(s,3H),2.65-2.78(m,1H),2.80-2.92(m,1H),6.90-6.93(m,1H),6.94-7.00(m,1H),7.10-7.21(m,2H),7.95(s,1H),8.13-8.17(m,1H),10.42(s,1H)。

Compound 26

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-methylpyridin-2-yl) propanamide

Compound 26 was synthesized by method B from compound 25 in quantitative yield over a 5 hour reaction time using 500 mol-% ethyl formate and 300 mol-% NaH.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.33-2.60(m,13H),2.30(s,3H),2.65-3.00(m,3H),6.92(d,1H),6.94-7.00(m,1H),7.10-7.21(m,2H),7.55(s,1H),7.94(s,1H),8.14(d,1H),10.35(s,1H),11.00(br s,1H)。

Compound 27

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (4-methylpyridin-2-yl) propanamide

Compound 27 was synthesized from compound 26 by method C in a reaction time of 0.5 hours in 51% yield.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.33-2.60(m,13H),2.30(s,3H),2.69-2.95(m,3H),6.92(d,1H),6.94-7.00(m,1H),7.10-7.21(m,2H),7.42(s,1H),7.96(s,1H),8.16(d,1H),10.47(s,1H),12.16(br s,1H)。

Compound 28

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (2-oxo-1, 2,5,6,7, 8-hexahydroquinolin-3-yl) propionamide

Compound 28 was synthesized in 86% yield in THF by method a1 over an overnight reaction time using the acid SM-IX and 3-amino-1, 2,5,6,7, 8-hexahydroquinolin-2-one as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.30-2.47(m,24H),2.65-2.93(m,2H),6.94-7.00(m,1H),7.12-7.21(m,2H),8.01(s,1H),9.15(s,1H),11.68(br s,1H)。

Compound 29

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (2-oxo-1, 2,5,6,7, 8-hexahydroquinolin-3-yl) propanamide

Compound 29 was synthesized by method B from compound 28 in an overnight reaction time in 73% yield.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.65(m,21H),2.65-2.97(m,3H),6.94-7.00(m,1H),7.11-7.21(m,2H),7.55(s,1H),8.00(s,1H),9.00(s,1H),11.20(br s,1H),11.68(s,1H)。

Compound 30

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (2-oxo-1, 2,5,6,7, 8-hexahydroquinolin-3-yl) propionamide

Compound 30 was synthesized by method C from compound 29 in a reaction time of 2 hours in a yield of 72%.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.30-2.65(m,21H),2.69-2.97(m,3H),6.94-7.00(m,1H),7.11-7.21(m,2H),7.42(s,1H),8.00(s,1H),9.15(s,1H),11.68(s,1H),12.12(br s,1H)。

Compound 31

6- (3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamido) -N, N-dimethylnicotinamide

Compound 31 was synthesized by method a1 in quantitative yield in THF over an overnight reaction time by using the acid SM-IX and 6-amino-N, N-lutidine-3-carboxamide as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.47(m,16H),2.66-2.94(m,2H),2.98(s,6H),6.94-7.00(m,1H),7.12-7.21(m,2H),7.85(dd,1H),8.14(d,1H),8.38(d,1H),10.72(s,1H)。

Compound 32

6- (3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamido) -N, N-dimethylnicotinamide

Compound 32 was synthesized by method B from compound 31 in 33% yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.65(m,13H),2.66-2.94(m,3H),2.97(s,6H),6.93-7.00(m,1H),7.11-7.21(m,2H),7.55(s,1H),7.84(dd,1H),8.14(d,1H),8.37(d,1H),10.66(s,1H),10.98(br s,1H)。

Compound 33

6- (3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamido) -N, N-dimethylnicotinamide

Compound 33 was synthesized by method C from compound 32 in a reaction time of 1 hour in 59% yield.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.35-2.60(m,13H),2.69-2.94(m,3H),2.98(s,6H),6.93-7.02(m,1H),7.11-7.21(m,2H),7.41(s,1H),7.85(dd,1H),8.15(d,1H),8.39(d,1H),10.76(s,1H),12.14(br s,1H)。

Compound 34

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-isopropylpyridin-2-yl) propanamide

Compound 34 was synthesized by method a1 in THF using the acid SM-IX and 2-amino-5-isopropylpyridine as starting materials, reaction time 4 hours, and 20% yield after chromatographic purification.

¹H-NMR(200MHz,CDCl₃):1.07(s,3H),1.25(s,3H),1.28(s,3H),1.34-2.60(m,17H),2.72-3.05(m,2H),6.83-6.92(m,1H),7.05-7.18(m,2H),7.57-7.63(m,1H),8.09-8.17(m,2H),8.49(br s,1H)。

Compound 35

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-isopropylpyridin-2-yl) propanamide

Compound 35 was synthesized from compound 34 by method B using 1000 mol-% ethyl formate and 600 mol-% NaH over an overnight reaction time in 51% yield after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.21(s,6H),1.30-2.63(m,14H),2.64-3.05(m,3H),6.93-7.00(m,1H),7.11-7.21(m,2H),7.56(s,1H),7.63-7.67(m,1H),7.99-8.02(m,1H),8.18(s,1H),10.41(s,1H),11.03(br s,1H)。

Compound 36

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5-isopropylpyridin-2-yl) propionamide

Compound 36 was synthesized by method C from compound 35 at 60 ℃ and 1 hour reaction time in 88% yield.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.20(s,3H),1.21(s,3H),1.35-2.49(m,14H),2.64-2.95(m,3H),6.93-7.00(m,1H),7.11-7.21(m,2H),7.41(s,1H),7.66(dd,1H),8.03(d,1H),8.19(d,1H),10.48(s,1H),12.13(br s,1H)。

Compound 37

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-morpholinopyridin-2-yl) propanamide

Compound 37 was synthesized in DCM by method a1 using the acid SM-IX and 5-morpholinopyridin-2-amine as starting materials and triethylamine as base for 2 hours in 82% yield after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.46(m,16H),2.63-2.80(m,1H),2.81-2.96(m,1H),3.03-3.15(m,4H),3.68-3.80(m,4H),6.90-7.03(m,1H),7.10-7.22(m,2H),7.40(dd,1H),7.95-8.01(m,2H),10.29(s,1H)。

Compound 38

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-morpholinopyridin-2-yl) propanamide

Compound 38 was synthesized from compound 37 by method B using 1500 mol-% ethyl formate and 1050 mol-% NaH over a2 day reaction time with a 57% yield after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.60(m,13H),2.63-2.99(m,3H),3.03-3.15(m,4H),3.68-3.80(m,4H),6.90-7.03(m,1H),7.10-7.22(m,2H),7.39(dd,1H),7.56(s,1H),7.95(d,1H),7.99(d,1H),10.28(s,1H),11.04(br s,1H)。

Compound 39

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5-morpholinopyridin-2-yl) propanamide

Compound 39 was synthesized from compound 38 by method C in a reaction time of 1 hour with a yield of 71% after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.35-2.49(m,13H),2.67-2.95(m,3H),3.05-3.14(m,4H),3.69-3.78(m,4H),6.92-7.03(m,1H),7.12-7.22(m,2H),7.39(dd,1H),7.41(s,1H),7.97(d,1H),8.00(d,1H),10.32(s,1H),12.11(br s,1H)。

Compound 40

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5- (4-methylpiperazin-1-yl) pyridin-2-yl) propionamide

Compound 40 was synthesized by method a1 using the acid SM-IX and 1-methyl-4- (6-aminopyridin-3-yl) piperazine as starting materials and triethylamine as base for 2 hours in DCM with 83% yield after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.42(m,16H),2.21(s,3H),2.43-2.48(m,4H),2.63-2.80(m,1H),2.81-2.96(m,1H),3.05-3.15(m,4H),6.93-7.03(m,1H),7.10-7.22(m,2H),7.39(dd,1H),7.92-8(m,2H),10.27(s,1H)。

Compound 41

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5- (4-methylpiperazin-1-yl) pyridin-2-yl) propionamide

Compound 41 was synthesized by method B from compound 40 in 57% yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.49(m,13H),2.28(s,3H),2.51-2.60(m,4H),2.63-2.96(m,3H),3.10-3.20(m,4H),6.93-7.03(m,1H),7.09-7.22(m,2H),7.39(dd,1H),7.57(s,1H),7.93(d,1H),7.99(d,1H),10.28(s,1H)。

Compound 42

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5- (4-methylpiperazin-1-yl) -pyridin-2-yl) propionamide

Compound 42 was synthesized by method C from compound 41 in a reaction time of 2.5 hours with a yield of 53%.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.30-2.49(m,13H),2.21(s,3H),2.42-2.59(m,4H),2.65-2.96(m,3H),3.05-3.20(m,4H),6.93-7.03(m,1H),7.09-7.22(m,2H),7.36-7.39(m,1H),7.40(s,1H),7.95(d,1H),7.99(d,1H),10.31(s,1H),12.12(br s,1H)。

Compound 43

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (tetrahydro-2H-pyran-4-yl) propanamide

Compound 43 was synthesized by method a3 in DCM over a reaction time of 5 hours using the acid SM-IX and 4-aminotetrahydropyran as starting materials in 56% yield after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):0.96(s,3H),1.30-2.41(m,20H),2.67-2.76(m,1H),2.85-2.90(m,1H),3.29-3.30(m,2H),3.70-3.77(m,1H),3.80-3.83(m,2H),6.94-7.00(m,1H),7.10-7.22(m,2H),7.84(d,1H)。

Compound 44

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (tetrahydro-2H-pyran-4-yl) propanamide

Compound 44 was synthesized by method B from compound 43 in quantitative yield over a 6 hour reaction time by using 1000 mol-% ethyl formate and 600 mol-% NaH.

¹H-MR(400MHz,DMSO-d₆):0.97(s,3H),1.30-2.45(m,17H),2.65-2.95(m,3H),3.25-3.45(m,2H),3.70-3.95(m,3H),6.94-7.00(m,1H),7.10-7.22(m,2H),7.49(s,1H),8.14(d,1H),11.59(br s,1H)。

Compound 45

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (tetrahydro-2H-pyran-4-yl) propanamide

Compound 45 was synthesized by method C from compound 44 in a reaction time of 1.5 hours in 76% yield.

¹H-NMR(400MHz,DMSO-d₆):1.09(s,3H),1.30-2.49(m,17H),2.65-2.95(m,3H),3.25-3.45(m,2H),3.70-3.90(m,3H),6.94-7.01(m,1H),7.10-7.22(m,2H),7.40(s,1H),7.86(d,1H),12.12(br s,1H)。

Compound 46

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-methoxypyridin-2-yl) propanamide

Compound 46 was synthesized by method a2 in THF using the acid SM-IX and 2-amino-4-methoxypyridine as starting materials at room temperature for 10 hours and overnight with a 47% yield after chromatographic purification. The reaction requires 250 mol-% amine, EDCI and HOBT.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.48(m,16H),2.65-2.78(m,1H),2.80-2.92(m,1H),3.81(s,3H),6.68-6.72(m,1H),6.94-7.00(m,1H),7.10-7.21(m,2H),7.73(s,1H),8.10-8.13(m,1H),10.47(s,1H)。

Compound 47

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-methoxypyridin-2-yl) propanamide

Compound 47 was synthesized by method B from compound 46 in a reaction time of 2.5 hours with a yield of 86%.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.65(m,13H),2.62-2.97(m,3H),3.80(s,3H),6.65-6.70(dd,1H),6.93-7.00(m,1H),7.10-7.21(m,2H),7.58(s,1H),7.73(d,1H),8.10-8.13(d,1H),10.46(s,1H),11.04(br s)。

Compound 48

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (4-methoxypyridin-2-yl) propanamide

Compound 48 was synthesized by method C from compound 47 in a reaction time of 3 hours with a yield of 47%.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.30-2.49(m,13H),2.70-2.97(m,3H),3.80(s,3H),6.68-6.72(dd,1H),6.93-7.01(m,1H),7.10-7.21(m,2H),7.39(s,1H),7.73(d,1H),8.10-8.14(d,1H),10.50(s,1H),12.12(br s)。

Compound 49

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyrazin-2-yl) propanamide

Compound 49 was synthesized by method a1 in DCM over a reaction time of 5 hours using the acid SM-IX and aminopyrazine as starting materials in 53% yield after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.60(m,16H),2.69-2.78(m,1H),2.84-2.92(m,1H),6.94-7.00(m,1H),7.12-7.20(m,2H),8.33-8.40(m,2H),9.35(s,1H),10.81(s,1H)。

Compound 50

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyrazin-2-yl) propanamide

Compound 50 was synthesized by method B from compound 49 in quantitative yield over an overnight reaction time by using 750 mol-% ethyl formate and 450 mol-% NaH.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.49(m,13H),2.55-2.99(m,3H),6.94-7.00(m,1H),7.11-7.20(m,2H),7.54(s,1H),8.33-8.40(m,2H),9.34(s,1H),10.75(s,1H),10.98(br s,1H)。

Compound 51

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (pyrazin-2-yl) propionamide

Compound 51 was synthesized from compound 50 by method C in a1 hour reaction time with a 30% yield after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.35-2.60(m,13H),2.65-2.99(m,3H),6.94-7.01(m,1H),7.11-7.20(m,2H),7.40(s,1H),8.33-8.41(m,2H),9.35(s,1H),10.85(s,1H),12.16(br s,1H)。

Compound 52

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (1-methyl-1H-pyrazol-3-yl) propanamide

Compound 52 was synthesized by method a1 in 80% yield in THF in an overnight reaction time by using the acid SM-IX and 1-methyl-1H-pyrazol-3-amine as starting materials and 300 mol-% of T3P.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.30-2.49(m,16H),2.65-2.92(m,2H),3.72(s,3H),6.43(d,1H),6.94-7.00(m,1H),7.12-7.20(m,2H),7.52(d,1H),10.36(s,1H)。

Compound 53

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (1-methyl-1H-pyrazol-3-yl) propanamide

Compound 53 was synthesized by method B from compound 52 in quantitative yield over a 4 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.49(m,13H),2.65-2.96(m,3H),3.72(s,3H),6.42(d,1H),6.93-7.02(m,1H),7.11-7.23(m,2H),7.51(d,1H),7.54(s,1H),10.35(s,1H),11.02(br s,1H)。

Compound 54

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (1-methyl-1H-pyrazol-3-yl) propanamide

Compound 54 was synthesized by method C from compound 53 in a reaction time of 1 hour with a yield of 69%.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.30-2.49(m,13H),2.65-2.96(m,3H),3.73(s,3H),6.44(d,1H),6.93-7.02(m,1H),7.11-7.23(m,2H),7.40(s,1H),7.52(d,1H),10.41(s,1H),12.12(br s,1H)。

Compound 55

(13S,15R) -4-fluoro-15- (3- (isoindolin-2-yl) -3-oxopropyl) -13-methyl-6, 7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 55 was synthesized by method a1 in quantitative yield in THF over an overnight reaction time by using the acid SM-IX and isoindoline as starting materials.

¹H-NMR(400MHz,CDCl₃):1.09(s,3H),1.34-2.60(m,16H),2.72-3.05(m,2H),4.82(s,4H),6.83-6.92(m,1H),7.05-7.18(m,2H),7.25-7.34(m,4H)。

Compound 56

(13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -15- (3- (isoindolin-2-yl) -3-oxopropyl) -13-methyl-6, 7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 56 was synthesized by method B from compound 55 in 34% yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.62(m,13H),2.63-3.05(m,3H),4.65(s,2H),4.75-4.88(m,2H),6.93-7.02(m,1H),7.11-7.23(m,2H),7.25-7.40(m,4H),7.55(s,1H),11.09(br s,1H)。

Compound 57

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -1- (isoindolin-2-yl) propan-1-one

Compound 57 was synthesized by method C from compound 56 in a reaction time of 1 hour in 93% yield.

¹H-NMR(400MHz,DMSO-d₆):1.12(s,3H),1.30-2.49(m,13H),2.63-3.00(m,3H),4.64(s,2H),4.80-4.99(m,2H),6.91-7.05(m,1H),7.11-7.23(m,2H),7.25-7.40(m,4H),7.48(s,1H),12.13(br s,1H)。

Compound 58

N- (cyclopropylmethyl) -3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N-methylpropanamide

Compound 58 was synthesized by method a1 in THF in 34% yield in an overnight reaction time by using the acid SM-IX and 400 mol-% (cyclopropylmethyl) (methyl) amine, 600 mol-% pyridine and 400 mol-% T3P.

¹H-NMR(400MHz,CDCl₃) 0.21-0.27(m,2H),0.45-0.55(m,1H),0.55-0.65(m,1H),0.87-1.02(m,1H),1.08(s,3H),1.30-2.65(m,16H),2.75-3.00(m,2H),3.01/3.07(2x s,3H, isomer), 3.13-3.36(m,2H),6.83-6.12) (m,2H),7.04-7.18(m, 2H).

Compound 59

N- (cyclopropylmethyl) -3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N-methylpropanamide

Compound 59 was synthesized by method B from compound 58 in quantitative yield over an overnight reaction time by using 1200 mol-% ethyl formate and 800 mol-% NaH.

¹H-NMR(400MHz,DMSO-d₆) 0.15-0.27(m,2H),0.35-0.55(m,2H),0.90-1.02(m,1H),1.17(s,3H),1.30-2.49(m,13H),2.59-3.00(m,3H),2.88/3.04(2x s,3H, isomer), 3.05-3.30(m,2H),6.93-7.02(m,1H),7.11-7.23(m,2H),7.48-7.51(br s,1H),11.33/11.50(2x br s,1H, isomer).

Compound 60

N- (cyclopropylmethyl) -3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N-methylpropanamide

Compound 60 was synthesized from compound 59 by method C in a1 hour reaction time with a 30% yield after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):0.15-0.27(m,2H),0.35-0.55(m,2H),0.90-1.02(m,1H),1.10(s,3H),1.30-2.49(m,13H),2.68-3.00(m,3H),286/3.04(2x s,3H, isomer), 3.05-3.30(m,2H),6.93-7.02(m,1H),7.11-7.23(m,2H),7.38-7.45(2x br s,1H, isomer), 12.12(br s, 1H).

Compound 61

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (1-methyl-1H-pyrazol-4-yl) -propionamide

Compound 61 was synthesized by method a2 in 70% yield from acid SM-IX and 1-methyl-1H-pyrazol-4-amine as starting materials in DMF.

¹H-NMR(400MHz,CDCl₃):1.07(s,3H),1.39-2.48(m,16H),2.76-3.02(m,2H),3.49(s,3H),6.88(dd,1H),7.06-7.15(m,2H),7.36(m,2H),7.91(s,1H)。

Compound 62

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (1-methyl-1H-pyrazol-4-yl) propanamide

Compound 62 was synthesized by method B from compound 61 in an overnight reaction time in 76% yield.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.36-2.45(m,13H),2.69-2.93(m,3H),3.77(s,3H),6.97(m,1H),7.09-7.22(m,2H),7.36(s,1H),7.55(s,1H),7.84(s,1H),9.98(s,1H),11.10(br s,1H)。

Compound 63

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (1-methyl-1H-pyrazol-4-yl) propanamide

Compound 63 was synthesized by method C from compound 62 in a reaction time of 1 hour with a yield of 84%.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.47-2.29(m,13H),2.67-2.92(m,3H),3.77(s,3H),6.98(m,1H),7.16(m,2H),7.37(d,2H),7.87(s,1H),9.95(s,1H),12.15(br s,1H)。

Compound 64

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-methyl-1, 3, 4-oxadiazol-2-yl) propanamide

Compound 64 was synthesized by method a2 in DMF with acid SM-IX and 5-methyl-1, 3, 4-oxadiazol-2-ylamine as starting materials in a reaction time of 5 hours with a yield of 45%.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.30-2.43(m,16H),2.44(s,3H),2.66-2.98(m,2H),6.92-7.03(m,1H),7.10-7.22(m,2H),11.50(br s,1H)。

Compound 65

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-methyl-1, 3, 4-oxadiazol-2-yl) propanamide

Compound 65 was synthesized by method B from compound 64 in an overnight reaction time with 97% yield by using 900 mol-% ethyl formate and 600 mol-% NaH.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.65(m,13H),2.43(s,3H),2.66-2.99(m,3H),6.92-7.03(m,1H),7.10-7.22(m,2H),7.56(s,1H),10.96(br s,1H),11.52(br s,1H)。

Compound 66

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5-methyl-1, 3, 4-oxadiazol-2-yl) propanamide

Compound 66 was synthesized by method C from compound 65 in a reaction time of 2.5 hours in 3% yield.

¹H-NMR(400MHz,CDCl₃):1.18(s,3H),1.40-2.50(m,13H),2.57(s,3H),2.65-3.05(m,3H),6.84-6.95(m,1H),7.03-7.17(m,2H)。

Compound 67

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (piperidin-1-yl) propanamide

Compound 67 was synthesized by method a3 in DCM over a reaction time of 4 hours using the acid SM-IX and piperidin-1-amine as starting materials in 45% yield after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆) 0.95/0.96(2x s,3H, isomer), 1.30-2.45(m,23H),2.60-2.98(m,5H),6.92-7.03(m,1H),7.10-7.22(m,2H),8.33/8.75(2x s,1H, isomer).

Compound 68

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (piperidin-1-yl) propanamide

Compound 68 was synthesized by method B from compound 67 in 77% yield over an overnight reaction time by using 1200 mol-% ethyl formate and 800 mol-% NaH.

¹H-NMR(400MHz,DMSO-d₆) 0.97(s,3H),1.30-2.45(m,20H),2.56-2.95(m,6H),6.92-7.03(m,1H),7.10-7.22m,2H),7.50/7.53(2x s,1H, isomer), 8.49/9.05(2x s,1H, isomer), 11.37(br s, 1H).

Compound 69

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (piperidin-1-yl) propanamide

Compound 69 was synthesized by method C from compound 68 in a reaction time of 1 hour in a yield of 72%.

¹H-NMR(400MHz,DMSO-d₆) 1.08/1.09(2x s,3H, isomer), 1.29-2.49(m,20H),2.59-2.95(m,6H),6.92-7.03(m,1H),7.10-7.22(m,2H),7.32/7.41(2x s,1H, isomer), 8.31/8.79(2x s,1H, isomer), 12.11(br s, 1H).

Compound 70

N- (tert-butyl) -3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 70 was synthesized in DCM by method a1 using the acid SM-IX, 300 mol-% tert-butylamine, 450 mol-% pyridine and 300 mol-% T3P for a reaction time overnight, followed by heating at 40 ℃ for 5 hours with a yield of 81%.

¹H-NMR(400MHz,DMSO-d₆):0.95(s,3H),1.25(s,9H),1.30-2.43(m,16H),2.66-2.95(m,2H),6.92-7.02(m,1H),7.10-7.22(m,2H),7.46(s,1H)。

Compound 71

N- (tert-butyl) -3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 71 was synthesized by method B from compound 70 in a reaction time of 2.5 hours in 77% yield.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.28(s,9H),1.30-2.43(m,13H),2.66-2.95(m,3H),6.92-7.02(m,1H),7.10-7.22(m,2H),7.50(s,1H),7.93(s,1H),11.91(br s,1H)。

Compound 72

N- (tert-butyl) -3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 72 was synthesized by method C from compound 71 in a reaction time of 30 minutes in 89% yield.

¹H-NMR(400MHz,DMSO-d₆):1.09(s,3H),1.25(s,9H),1.30-2.45(m,13H),2.66-2.95(m,3H),6.92-7.02(m,1H),7.10-7.22(m,2H),7.38(s,1H),7.45(s,1H),12.12(br s,1H)。

Compound 73

(13S,15R) -4-fluoro-13-methyl-15- (3- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -3-oxopropyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 73 was synthesized by method a3 using the acid SM-IX and 1- (1-methyl-4-piperidinyl) piperazine as starting materials in DCM over a reaction time of 5 hours in 70% yield after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):0.96(s,3H),1.30-2.49(m,28H),2.12(s,3H),2.65-2.95(m,3H),3.35-3.50(m,4H),6.92-7.02(m,1H),7.10-7.22(m,2H)。

Compound 74

(13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-15- (3- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) -3-oxopropyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 74 was synthesized by method B from compound 73 in a reaction time of 6 hours in 89% yield.

¹H-NMR(400MHz,CDCl₃):1.08(s,3H),1.35-3.10(m,29H),2.29(s,3H),3.40-3.70(m,4H),6.83-6.92(m,1H),7.02-7.22(m,2H),7.66(s,1H)。

Compound 75

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -1- (4- (1-methylpiperidin-4-yl) piperazin-1-yl) propan-1-one

Compound 75 was synthesized by method C from compound 74 in a1 hour reaction time in 85% yield.

¹H-NMR(400MHz,DMSO-d₆):1.09(s,3H),1.30-2.49(m,24H),2.12(s,3H),2.65-2.95(m,5H),3.35-3.50(m,4H),6.92-7.02(m,1H),7.10-7.22(m,2H),7.41(s,1H),12.11(br s,1H)。

Compound 76

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-methylisoxazol-3-yl) propanamide

Compound 76 was synthesized by method a1 in 95% yield in DCM over a reaction time of 4 hours using the acid SM-IX and 3-amino-5-methylisoxazole as starting materials.

¹H-NMR(200MHz,DMSO-d₆):0.97(s,3H),1.24-2.46(m,16H),2.37(s,3H),2.58-3.01(m,2H),6.64(s,1H),6.88-7.06(m,1H),7.07-7.25(m,2H),10.88(s,1H)。

Compound 77

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-methylisoxazol-3-yl) propanamide

Compound 77 was synthesized by method B from compound 76 in quantitative yield over a1 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.60(m,13H),2.36(s,3H),2.65-3.10(m,3H),6.63(s,1H),6.91-7.06(m,1H),7.07-7.25(m,2H),7.53(s,1H),10.82(s,1H),11.00(br s,1H)。

Compound 78

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5-methylisoxazol-3-yl) propanamide

Compound 78 was synthesized by method C from compound 77 in a reaction time of 0.5 hours in 59% yield.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.32-2.49(m,13H),2.36(s,3H),2.65-3.10(m,3H),6.65(s,1H),6.93-7.04(m,1H),7.09-7.25(m,2H),7.38(s,1H),10.92(s,1H),12.14(br s,1H)。

Compound 79

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (1,3, 4-thiadiazol-2-yl) propanamide

Compound 79 was synthesized by method a3 in DCM over a reaction time of 5.5 hours using the acid SM-IX and 2-amino-1, 3, 4-thiadiazole as starting materials in 61% yield after chromatographic purification.

¹H-NMR(200MHz,CDCl₃):1.03(s,3H),1.20-3.05(m,18H),6.80-6.95(m,1H),7.03-7.18(m,2H),8.82(s,1H),13.67(br s,1H)。

Compound 80

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (1,3, 4-thiadiazol-2-yl) propanamide

Compound 80 was synthesized by method B from compound 81 in an overnight reaction time with a yield of 98%.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.49(m,13H),2.65-3.05(m,3H),6.91-7.04(m,1H),7.10-7.25(m,2H)、7.57(s,1H)、9.13(s,1H)、10.98(br s,1H)、12.63(br s,1H)。

Compound 81

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (1,3, 4-thiadiazol-2-yl) propanamide

Compound 81 was synthesized by method C from compound 80 in a reaction time of 30 minutes with a yield of 98%.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.35-2.49(m,11H),2.51-3.01(m,5H),6.91-7.04(m,1H),7.10-7.25(m,2H)、7.37(s,1H)、9.15(s,1H)、12.15(br s,1H)、12.61(br s,1H)。

Compound 82

3- ((13S,15R) -3-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-methoxypyridin-2-yl) propanamide

Compound 82 was synthesized by method a2 in 62% yield in DMF over a reaction time of 2 hours using the acid SM-IX and 5-methoxypyridin-2-amine as starting materials.

¹H-NMR(200MHz,CDCl₃):1.07(s,3H),1.39-2.50(m,16H),2.94(m,2H),3.85(s,3H),6.79-6.88(m,2H),7.19-7.30(m,2H),7.90(br s,1H),7.95(d,1H),8.14(d,1H)。

Compound 83

3- ((13S,15S, Z) -3-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-methoxypyridin-2-yl) propanamide

Compound 83 was prepared from compound 82 by method B in quantitative yield.

¹H NMR(400MHz,DMSO-d₆):0.99(s,3H),1.48-2.46(m,12H),2.83-2.97(m,3H),3.79(s,3H),6.89-6.95(m,2H)),7.27(m,1H),7.40(dd,1H),7.54(s,1H),8.01(dd,2H),10.31(s,1H),11.05(br s,1H)。

Compound 84

3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5-methoxypyridin-2-yl) propanamide

Compound 84 was prepared from compound 83 by method C in 71% yield.

¹H NMR(400MHz,DMSO-d₆):1.10(s,3H),1.40-1.74(m,5H),2.02-2.48(m,8H),2.78-2.98(m,3H),3.80(s,3H)),6.90-7.09(m,2H),7.30(m,1H),7.41(dd,2H),8.02(d,1H),8.05(d,1H),10.41(s,1H),12.13(br s,1H)。

Compound 85

3- ((13S,15R) -3-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-isopropylpyridin-2-yl) propanamide

Compound 85 was synthesized by method a1 in 60% yield over an overnight reaction time using the acid SM-XV and 2-amino-5-isopropylpyridine as starting materials.

¹H NMR(200MHz,DMSO-d₆):0.98(s,3H),1.20(d,6H),1.28-2.49(m,16H),2.74–3.02(m,3H),6.79-7.03(m,2H),7.19-7.39(m,1H),7.66(d,1H),8.02(d,1H),8.19(s,1H),10.43(s,1H)。

Compound 86

3- ((13S,15S, Z) -3-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-isopropylpyridin-2-yl) -propionamide

Compound 86 was prepared from compound 85 by method B in 98% yield.

¹H NMR(400MHz,DMSO-d₆):0.99(s,3H),1.19&1.21(2x s,6H),1.38-2.35(m,12H),2.55(m,2H),2.84-2.97(m,4H),6.89-6.95(m,2H),7.28(m,1H),7.55(s,1H),7.65(dd,1H),8.00(d,1H),8.17(d,1H),10.37(s,1H)。

Compound 87

3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5-isopropylpyridin-2-yl) propanamide

Compound 87 was prepared from compound 86 by method C in 71% yield.

¹H NMR(400MHz,DMSO-d₆):1.18(s,3H),1.21&1.23(2x s,6H),1.46-2.31(m,11H),2.58-2.63(m,3H),2.91-3.02(m,4H),6.91-6.96(m,2H),7.31(m,1H),7.91(dd,2H),8.05(d,1H),8.22(s,1H),11.67(s,1H)。

Compound 88

3- ((13S,15R) -3-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-methoxypyridin-2-yl) propanamide

Compound 88 was prepared by method a2 from the acid SM-XV and 4-methoxy-2-aminopyridine by first stirring at +50 ℃ for 5 hours then overnight at room temperature in 84% yield.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.37-2.45(m,16H),2.94(m,2H),3.80(s,3H),6.69(dd,1H),6.92(m,2H),7.29(dd,1H),7.73(d,1H),8.11(d,1H),10.46(s,1H)。

Compound 89

3- ((13S,15S, Z) -3-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-methoxypyridin-2-yl) -propionamide

Compound 89 was prepared from compound 88 by method B in quantitative yield.

¹H NMR(400MHz,DMSO-d₆):0.99(s,3H),1.45-2.32(m,12H),2.55(m,1H),2.83-2.97(m,3H),3.80(s,3H),6.68(dd,1H),6.92(m,2H),7.28(dd,1H),7.53(s,1H),7.72(s,1H),8.10(d,1H),10.38(s,1H),10.98(br s，1H)。

Compound 90

3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (4-methoxypyridin-2-yl) propanamide

Compound 90 was prepared from compound 89 by method C in 71% yield.

¹H NMR(400MHz,DMSO-d₆) 1.10(s,3H),1.39-2.46(m,13H),2.81(m,1H),2.92(m,2H),3.80(s,3H),6.70(dd,1H),6.93(m,2H),7.30(dd,1H),7.39(s,1H),7.74(d,1H),8.12(d,1H),10.50(s,1H),12.13(br s, 1H). Mass spectrum M/z 475(M +1)

Compound 91

3- ((13S,15R) -3-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-methylpyridin-2-yl) propanamide

Compound 91 was prepared by method a2 from the acid SM-XV and 4-methyl-2-aminopyridine by stirring at +50 ℃ for 7 hours then overnight at room temperature in 41% yield.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.33-2.48(m,18H),2.89(m,2H),6.92(m,3H),7.29(dd,2H),7.95(s,1H),8.15(d,1H),10.41(s,1H)。

Compound 92

3- ((13S,15S, Z) -3-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-methylpyridin-2-yl) -propionamide

Compound 92 was prepared from compound 91 by method B in quantitative yield.

¹H NMR(400MHz,DMSO-d₆):0.99(s,3H),1.35-2.45(m,12H),2.55(m,1H),2.88(m,3H),3.80(s,3H),6.92(m,3H),7.28(m,1H),7.54(s,1H),7.94(s,1H),8.14(s,1H),10.33(s,1H),11.00(br s,1H)。

Compound 93

3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (4-methylpyridin-2-yl) -propionamide

Compound 93 was prepared from compound 92 by method C in 55% yield.

¹H NMR(400MHz,DMSO-d₆) 1.10(s,3H),1.41-2.38(m,16H),2.81(m,1H),2.92(m,2H),6.93(m,3H),7.30(m,1H),7.40(s,1H),7.96(s,1H),8.16(d,1H),10.45(s,1H),12.12(br s, 1H). Mass spectrum M/z 459(M +1)

Compound 94

3- ((13S,15R) -3-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-morpholinopyridin-2-yl) propanamide

Compound 94 was synthesized by method a1 using the acid SM-XV and 5-morpholinopyridin-2-amine as starting materials and triethylamine as base for 2 hours in DCM and purified by chromatography in 63% yield.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.47(m,16H),2.81-2.96(m,2H),3.06-3.12(m,4H),3.70-3.78(m,4H),6.90-6.95(m,2H),7.25-7.32(t,1H),7.40(dd,1H),7.95-8.01(m,2H),10.28(s,1H)。

Compound 95

3- ((13S,15S, Z) -3-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-morpholinopyridin-2-yl) propanamide

Compound 95 was synthesized by method B from compound 94 in 94% yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.60(m,13H),2.81-3.00(m,3H),3.06-3.12(m,4H),3.70-3.78(m,4H),6.88-6.95(m,2H),7.25-7.32(t,1H),7.40(dd,1H),7.54(s,1H),7.92-8.01(m,2H),10.24(s,1H)1H),11.02(br s,1H)。

Compound 96

3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5-morpholinopyridin-2-yl) propanamide

Compound 96 was synthesized by method C from compound 95 in 73% yield over a1 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.30-2.50(m,13H),2.75-2.95(m,3H),3.06-3.12(m,4H),3.70-3.78m,4H),6.88-6.96(m,2H),7.26-7.33(t,1H),7.38-7.43(m,2H),7.94-8.01(m,2H),10.32(s,1H),12.11(br s,1H)。

Compound 97

3- ((13S,15R) -3-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-fluoropyridin-2-yl) propanamide

Compound 97 was synthesized by method a1 in 93% yield in DCM using the acid SM-XV and 2-amino-5-fluoropyridine as starting materials in a reaction time of 2 hours.

¹H-NMR(200MHz,DMSO-d₆):0.98(s,3H),1.22-2.45(m,16H),2.80-2.95(m,2H),6.83-7.03(m,2H),7.20-7.39(m,1H),7.73(td,1H),8.14(dd,1H),8.31(d,1H),10.62(s,1H)。

Compound 98

3- ((13S,15S, Z) -3-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-fluoropyridin-2-yl) propanamide

Compound 98 was synthesized by method B from compound 97 in 81% yield over an overnight reaction time by using 500 mol-% ethyl formate and 300 mol-% NaH.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.60(m,13H),2.80-2.99(m,3H),6.85-7.03(m,2H),7.20-7.39(m,1H),7.58(s,1H),7.71(td,1H),8.13(dd,1H),8.30(d,1H),10.62(s,1H)。

Compound 99

3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5-fluoropyridin-2-yl) propanamide

Compound 99 was synthesized by method C from compound 98 in a reaction time of 1 hour with a yield of 45%.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.35-2.49(m,13H),2.79-2.99(m,3H),6.85-7.00(m,2H),7.25-7.35(m,1H),7.40(s,1H),7.73(td,1H),8.14(dd,1H),8.31(d,1H),10.66(s,1H),12.12(s,1H)。

Compound 100

N- (5- (tert-butyl) isoxazol-3-yl) -3- ((13S,15R) -3-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 100 was prepared from the acid SM-XV and 3-amino-5-tert-butylisoxazole by method a1, stirring at room temperature for 5 hours, yield 39%. The product was used directly in the next step.

Compound 101

N- (5- (tert-butyl) isoxazol-3-yl) -3- ((13S,15S, Z) -3-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 101 was prepared from compound 100 by method B in quantitative yield.

¹H NMR(400MHz,CDCl₃):1.16(s,3H),1.26(s,9H),1.32-2.84(m,17H),6.68-6.85(m,3H),7.19-7.23(m,1H),7.31(s,1H),9.47(s,1H)

Compound 102

N- (5- (tert-butyl) isoxazol-3-yl) -3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 102 was prepared from compound 101 by method C in 46% yield.

¹H NMR(400MHz,DMSO-d₆):1.10(s,3H),1.29(s,9H),1.41-2.43(m,13H),2.80-2.92(m,3H),6.61(m,1H),6.93(m,2H),7.30(m,1H),7.39(s,1H),10.97(s,1H),12.13(s,1H)。

Compound 103

3- ((13S,15R) -3-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-fluoropyridin-2-yl) propanamide

Compound 103 was synthesized by method a1 in DCM over a reaction time of 3 hours using the acid SM-XV and 2-amino-6-fluoropyridine as starting materials in 82% yield.

¹H-NMR(200MHz,DMSO-d₆):0.98(s,3H),1.33-2.47(m,16H),2.89(m,2H),6.84(dd,1H),6.92(m,2H),7.29(m,1H),7.94(dd,1H),8.01(m,1H),10.67(s,1H)。

Compound 104

3- ((13S,15S, Z) -3-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-fluoropyridin-2-yl) propanamide

Compound 104 was synthesized by method B from compound 103 in a reaction time of two hours in 92% yield.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.36-2.33(m,12H),2.57(m,2H),2.89(m,3H),6.81(dd,1H),6.92(m,2H),7.28(m,1H),7.57(s,1H),7.93(dd,1H),8.00(m,1H),10.66(s,1H)。

Compound 105

3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (6-fluoropyridin-2-yl) propanamide

Compound 105 was synthesized by method C from compound 104 in a reaction time of 30 minutes with a yield of 50%.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.42-2.38(m,14H),2.78-2.95(m,3H),6.83(m,1H),6.93(m,2H),7.30(m,1H),7.39(s,1H),7.94(m,1H),8.00(m,1H),10.72(s,1H)。

Compound 106

3- ((13S,15R) -3-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-methoxypyridazin-3-yl) propanamide

Compound 106 was synthesized by method a2 in 79% yield in THF using the acid SM-XV and 3-amino-6-methoxypyridazine as starting materials in a reaction time of 3 hours.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.47(m,16H),2.79-3.02(m,2H),3.98(s,3H),6.85-7.03(m,2H),7.24(d,1H),7.26-7.35(m,1H),8.25(d,1H),10.93(br s,1H)。

Compound 107

3- ((13S,15S, Z) -3-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-methoxypyridazin-3-yl) propanamide

Compound 107 was synthesized by method B from compound 106 in quantitative yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.47(m,13H),2.55-3.00(m,3H),3.98(s,3H),6.85-7.03(m,2H),7.23(d,1H),7.25-7.33(m,1H),7.55(s,1H),8.23(d,1H),10.88(s,1H),10.96(br s,1H)。

Compound 108

3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (6-methoxypyridazin-3-yl) propanamide

Compound 108 was synthesized by method C from compound 107 in a reaction time of 1 hour in 92% yield.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.30-2.47(m,13H),2.75-3.00(m,3H),3.98(s,3H),6.85-7.03(m,2H),7.23(d,1H),7.25-7.33(m,1H),7.41(s,1H),8.25(d,1H),10.96(s,1H),12.12(br s,1H)。

Compound 109

3- ((13S,15R) -3-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-methylpyridazin-3-yl) propanamide

Compound 109 was synthesized by method a2 in THF in 79% yield over a reaction time of 3 hours using the acid SM-XV and 3-amino-6-methylpyridazine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.46(m,16H),2.55(s,3H),2.80-3.00(m,2H),6.85-7.02(m,2H),7.23-7.35(m,1H),7.54(d,1H),8.22(d,1H),11.03(br s,1H)。

Compound 110

3- ((13S,15S, Z) -3-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-methylpyridazin-3-yl) propanamide

Compound 110 was synthesized from compound 109 by method B in quantitative yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.70(m,13H),2.55(s,3H),2.80-3.00(m,3H),6.85-7.02(m,2H),7.21-7.33(m,1H),7.52(d,1H),7.53(s,1H),8.21(d,1H),10.96(br s,2x 1H)。

Compound 111

3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (6-methylpyridazin-3-yl) propanamide

Compound 111 was synthesized from compound 110 by method C with a reaction time of 1 hour, and the yield was 24% after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.30-2.59(m,13H),2.55(s,3H),2.77-3.00(m,3H),6.85-7.02(m,2H),7.23-7.33(m,1H),7.41(s,1H),7.53(d,1H),8.22(d,1H),11.07(s,1H),12.13(br s,1H)。

Compound 112

3- ((13S,15R) -3-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyridazin-3-yl) propanamide

Compound 112 was synthesized by method a2 in THF with SM-XV acid and 3-aminopyridazine as starting materials in a reaction time of 3.5 hours with a yield of 79%.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.62(m,16H),2.80-2.95(m,2H),6.85-7.03(m,2H),7.20-7.31(m,1H),7.67(dd,1H),8.32(d,1H),8.95(d,1H),11.13(s,1H)。

Compound 113

3- ((13S,15S, Z) -3-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyridazin-3-yl) propanamide

Compound 113 was synthesized by method B from compound 112 in quantitative yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.70(m,13H),2.80-2.99(m,3H),6.85-7.03(m,2H),7.20-7.33(m,1H),7.55(s,1H),7.65(dd,1H),8.31(d,1H),8.93(d,1H),11.06(s,1H),11.07(br s,1H)。

Compound 114

3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (pyridazin-3-yl) propanamide

Compound 114 was synthesized from compound 113 by method C, reaction time 1h, and yield 45% after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.30-2.65(m,13H),2.80-2.99(m,3H),6.85-7.02(m,2H),7.25-7.35(m,1H),7.42(s,1H),7.66(dd,1H),8.33(d,1H),8.95(d,1H),11.17(s,1H),12.14(br s,1H)。

Compound 115

(13S,15R) -3-fluoro-13-methyl-15- (3-oxo-3- (pyrrolidin-1-yl) propyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 115 was synthesized by method a1 using the acid SM-XV and pyrrolidine as starting materials in DCM for 4 hours in 46% yield after chromatographic purification.

¹H-NMR(200MHz,CDCl₃):1.07(s,3H),1.33-2.50(m,20H),2.79-3.09(m,2H),3.35-3.55(m,4H),6.70-6.90(m,2H),7.17-7.26(m,1H)。

Compound 116

(13S,15S, Z) -3-fluoro-16- (hydroxymethylene) -13-methyl-15- (3-oxo-3- (pyrrolidin-1-yl) propyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 116 was synthesized by method B from compound 115 in a reaction time of 2 hours with a yield of 98%.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.30-2.46(m,17H),2.80-3.00(m,3H),3.25-3.45(m,4H),6.86-6.98(m,2H),7.25-7.35(m,1H),7.52(s,1H)。

Compound 117

3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -1- (pyrrolidin-1-yl) propan-1-one

Compound 117 was synthesized by method C from compound 116 in a reaction time of 0.5 hours in 88% yield.

¹H-NMR(400MHz,DMSO-d₆):1.09(s,3H),1.30-2.44(m,17H),2.80-3.00(m,3H),3.21-3.49(m,4H),6.87-6.98(m,2H),7.27-7.35(m,1H),7.40(s,1H),12.10(br s,1H)。

Compound 118

3- ((13S,15R) -3-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyrazin-2-yl) propanamide

Compound 118 was synthesized by method a1 in 44% yield in DCM over a reaction time of 3 hours using the acids SM-XV and aminopyrazine as starting materials.

¹H-NMR(400MHz,CDCl₃):1.08(s,3H),1.30-2.65(m,16H),2.85-3.08(m,2H),6.74-6.95(m,2H),7.20-7.26(m,1H),7.80(s,1H),8.25(d,1H),8.37(d,1H),9.53(s,1H)。

Compound 119

3- ((13S,15S, Z) -3-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyrazin-2-yl) propanamide

Compound 119 was synthesized by method B from compound 118 in 99% yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.68(m,13H),2.80-3.08(m,3H),6.80-6.96(m,2H),7.25-7.35(m,1H),7.60(s,1H),8.32(d,1H),8.37(d,1H),9.33(s,1H),10.86(br s,1H),10.96(br s,1H)。

Compound 120

3- ((8aS,12S) -4-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (pyrazin-2-yl) propanamide

Compound 120 was synthesized by method C from compound 119 in quantitative yield over a1 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.30-2.60(m,13H),2.79-3.01(m,3H),6.85-6.99(m,2H),7.25-7.35m,1H),7.39(s,1H),8.34(d,1H),8.39(d,1H),9.35(s,1H),10.84(s,1H),12.13(br s,1H)。

Compound 121

3- ((13S,15R) -3-chloro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (2-oxo-1, 2,5,6,7, 8-hexahydroquinolin-3-yl) propionamide

Compound 121 was synthesized by method a1 in 79% yield in THF using the acid SM-XVII and 3-amino-1, 2,5,6,7, 8-hexahydroquinolin-2-one as starting materials, and reacted overnight.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.30-2.47(m,24H),2.80-2.95(m,2H),7.14-7.17(m,2H),7.28-7.31m,1H),8.01(s,1H),9.14(s,1H),11.68(s,1H)。

Compound 122

3- ((13S,15S, Z) -3-chloro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (2-oxo-1, 2,5,6,7, 8-hexahydroquinolin-3-yl) propionamide

Compound 122 was synthesized by method B from compound 121 in an overnight reaction time in 76% yield.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.60(m,22H),2.80-2.95(m,2H),7.14-7.17(m,2H),7.28-7.31m,1H),7.54(s,1H),7.99(s,1H),8.99(s,1H),11.09(br s,1H),11.66(s,1H)。

Compound 123

3- ((8aS,12S) -4-chloro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (2-oxo-1, 2,5,6,7, 8-hexahydroquinolin-3-yl) propionamide

Compound 123 was synthesized by method C from compound 122 in a reaction time of 1 hour with a yield of 46%.

¹H-NMR(400MHz,DMSO-d₆):1.09(s,3H),1.30-2.59(m,21H),2.75-2.96(m,3H),7.14-7.19(m,2H),7.28-7.33(m,1H),7.41(s,1H),8.00(s,1H),9.14(s,1H),11.68(s,1H),12.11(br s,1H)。

Compound 124

6- (3- ((13S,15R) -3-chloro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propionylamino) -N, N-dimethylnicotinamide

Compound 124 was synthesized by method a1 in 85% yield in THF using the acid SM-XVII and 6-amino-N, N-lutidine-3-carboxamide as starting materials in an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.47(m,16H),2.80-2.95(m,2H),2.97(s,6H),7.14-7.17(m,2H),7.28-7.31(m,1H),7.85(dd,1H),8.14(d,1H),8.38(d,1H),10.71(s,1H)。

Compound 125

6- (3- ((13S,15S, Z) -3-chloro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamido) -N, N-dimethylnicotinamide

Compound 125 was synthesized by method B from compound 124 in quantitative yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.40(m,12H),2.50-2.65(m,2H),2.80-2.95(m,2H),2.97(s,6H),7.13-7.17(m,2H),7.26-7.30(m,1H),7.54(s,1H),7.84(dd,1H),8.13(d,1H),8.37(d,1H),10.64(s,1H),10.98(br s,1H)。

Compound 126

6- (3- ((8aS,12S) -4-chloro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamido) -N, N-dimethylnicotinamide

Compound 126 was synthesized by method C from compound 125 in a reaction time of 1 hour with a yield of 63%.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.30-2.60(m,13H),2.70-2.97(m,3H),2.98(s,6H),7.14-7.19(m,2H),7.28-7.32(m,1H),7.41(s,1H),7.85(dd,1H),8.15(d,1H),8.39(d,1H),10.76(s,1H),12.12(br s,1H)。

Compound 127

3- ((13S,15R) -3-chloro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-fluoropyridin-2-yl) propanamide

Compound 127 was synthesized by method a1 in 90% yield in THF within a reaction time of 4 hours using the acid SM-XVII and 2-amino-4-fluoropyridine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.47(m,16H),2.81-2.96(m,2H),7.00-7.06(m,1H),7.14-7.17m,2H)、7.27-7.31(m,1H)、7.92(dd,1H)、8.30-8.37(m,1H)、10.82(s,1H)。

Compound 128

3- ((13S,15S, Z) -3-chloro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-fluoropyridin-2-yl) propanamide

Compound 128 was synthesized by method B from compound 127 in quantitative yield over a 4 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.65(m,13H),2.81-2.99(m,3H),6.98-7.06(m,1H),7.09-7.20m,2H),7.26-7.31(m,1H),7.55(s,1H),7.92(dd,1H),8.30-8.37(m,1H),10.76(s,1H),10.96(br s,1H)。

Compound 129

3- ((8aS,12S) -4-chloro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (4-fluoropyridin-2-yl) propanamide

Compound 129 was synthesized by method C from compound 128 in a reaction time of 1 hour with a yield of 72%.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.30-2.53(m,13H),2.76-2.99(m,3H),6.99-7.06(m,1H),7.10-7.20(m,2H),7.27-7.32(m,1H),7.40(s,1H),7.93(dd,1H),8.30-8.38(m,1H),10.86(s,1H),12.12(br s,1H)。

Compound 130

3- ((13S,15R) -3-chloro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (3, 5-difluoropyridin-2-yl) propanamide

Compound 130 was synthesized by method a1 in 90% yield in THF using the acid SM-XVII and 2-amino-3, 5-difluoropyridine as starting materials in a reaction time of 5 hours.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.47(m,16H),2.80-2.94(m,2H),7.15-7.16(m,2H),7.28-7.30(m,1H)，7.98-8.03(m,1H)，8.34-8.35(m,1H),10.31(m,1H)。

Compound 131

3- ((13S,15S, Z) -3-chloro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (3, 5-difluoropyridin-2-yl) propionamide

Compound 131 was synthesized from compound 130 by method B in quantitative yield over a3 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.62(m,13H),2.80-3.00(m,3H),7.13-7.19(m,2H),7.25-7.31(m,1H),7.59(s,1H),7.93-8.03(m,1H),8.31-8.34(m,1H),10.37(s,1H),10.99(br s,1H)。

Compound 132

3- ((8aS,12S) -4-chloro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (3, 5-difluoropyridin-2-yl) propionamide

Compound 132 was synthesized by method C from compound 131 in a reaction time of 1.5 hours in 67% yield.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.30-2.49(m,13H),2.80-3.00(m,3H),7.13-7.19(m,2H),7.27-7.31(m,1H),7.43(s,1H),7.96-8.04(m,1H),8.34(s,1H),10.34(s,1H),12.13(br s,1H)。

Compound 133

3- ((13S,15R) -3-chloro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-fluoropyridin-2-yl) propanamide

Compound 133 was synthesized by method a1 in 71% yield in THF using the acid SM-XVII and 2-amino-6-fluoropyridine as starting materials in an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.30-2.47(m,16H),2.80-2.95(m,2H),6.83(dd,1H),7.14-7.17(m,2H),7.28-7.31(m,1H),7.91-7.97(m,1H),8.00-8.03(m,1H),10.68(s,1H)。

Compound 134

3- ((13S,15S, Z) -3-chloro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-fluoropyridin-2-yl) propanamide

Compound 134 was synthesized by method B from compound 133 in a reaction time of 6 hours with a yield of 69%.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.60(m,13H),2.80-2.99(m,3H),6.81(dd,1H),7.12-7.20(m,2H),7.25-7.31(m,1H),7.55(s,1H),7.88-7.97(m,1H),7.98-8.02(m,1H),10.66(br s,1H),10.95(br s,1H)。

Compound 135

3- ((8aS,12S) -4-chloro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (6-fluoropyridin-2-yl) propanamide

Compound 135 was synthesized from compound 134 by method C in 49% yield over a1 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.30-2.55(m,13H),2.75-2.99(m,3H),6.83(dd,1H),7.11-7.20(m,2H),7.27-7.33(m,1H),7.39(s,1H),7.89-7.98(m,1H),7.99-8.04(m,1H),10.72(s,1H),12.12(br s,1H)。

Compound 136

N- (5-isopropylpyridin-2-yl) -3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 136 was prepared by method a1 from the acid SM-XXVI and 5- (1-methyl-ethyl) -2-pyridylamine by stirring at room temperature overnight. The yield after chromatographic purification was 75%.

¹H-NMR(200MHz,CDCl₃):1.07(s,3H),1.24&1.28(2xs,6H),1.45-2.58(m,16H),2.95(m,3H),7.13-7.18(m,3H),7.29-7.31(m,1H),7.58(dd,1H),8.07(d,1H),8.14(br s,2H)。

Compound 137

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-isopropylpyridin-2-yl) -propionamide

Compound 137 was prepared from compound 136 by method B in 97% yield.

¹H NMR(400MHz,DMSO-d₆):1.00(s,3H),1.19&1.21(2xs,6H),1.38-1.78(m,8H),1.90-1-97(m,1H),2.15(m,1H),2.33(m,2H),2.55(m,1H),2.80-3.00(m,4H),7.05-7.12(m,3H),7.26(m,1H),7.56(s,1H),7.65(dd,1H),8.00(d,1H),8.17(d,1H),10.39(s,1H),11.0(br s,1H)。

Compound 138

N- (5-Isopropylpyridin-2-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 138 was prepared from compound 137 by method C in 93% yield.

¹H NMR(400MHz,DMSO-d₆):1.11(s,3H),1.20&1.21(2xs,6H),1.37-2.45(m,13H),2.79-2.94(m,4H),7.06-7.14(m,3H),7.28(m,1H),7.40(s,1H),7.66(dd,1H),8.02(d,1H),8.19(d,1H),10.46(s,1H),12.11(br s，1H)。

Compound 139

N- (5-methoxypyridin-2-yl) -3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 139 was synthesized by method a1 from the acid SM-XXVI and 5-methoxy-2-aminopyridine at reflux for 2 hours in 99% yield.

¹H-NMR(200MHz,CDCl₃):1.07(s,3H),1.40-2.57(m,17H),2.96(m,2H),3.85(s,3H),7.13-7.18(m,3H),7.2-7.30(m,2H),7.96(d,1H),8.15(d,1H)。

Compound 140

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-methoxypyridin-2-yl) -propionamide

Compound 140 was prepared from compound 139 in quantitative yield by method B.

¹H NMR(400MHz,DMSO-d₆):1.00(s,3H),1.36-2.55(m,13H),2.81-2.95(m,3H),3.82(s,3H),7.05-7.13(m,3H)),7.27(m,1H),7.40(dd,1H),7.55(s,1H),8.01(dd,2H),10.33(s,1H),11.01(br s,1H)。

Compound 141

N- (5-methoxypyridin-2-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 141 was prepared from compound 140 by method C in 86% yield.

¹H NMR(400MHz,DMSO-d₆):1.11(s,3H),1.41-1.81(m,5H),2.02-2.67(m,8H),2.79-2.98(m,3H),3.80(s,3H),7.07-7.14(m,3H),7.28(m,1H),7.40(dd,2H),8.02(d,1H),8.05(d,1H),10.39(s,1H),12.09(br s,1H)。

Compound 142

4- (3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanoyl) piperazin-2-one

Compound 142 was synthesized by method a1 from the acid SM-XXVI and piperazin-2-one by stirring at room temperature for 2 hours in 86% yield.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.37-2.45(m,14H),2.87(m,2H),3.16-3.24(m,3H),3.63(m,3H),3.93(s,1H),4.04(s,1H),7.10(m,3H),7.27(d,1H),8.08(d,1H)。

Compound 143

4- (3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanoyl) piperazin-2-one

Compound 143 was prepared from compound 142 by method B with stirring overnight at room temperature in 80% yield.

¹H NMR(400MHz,DMSO-d₆):0.98(s,3H),1.38-2.35(m,12H),2.56(m,1H),2.88(m,3H),3.16(m,3H),3.54-3.66(m,2H),3.93(d,1H),3.99(s,1H),7.09(m,3H),7.26(m,1H),7.53(s,1H),8.08(d,1H)。

Compound 144

4- (3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanoyl) piperazin-2-one

Compound 144 was prepared from compound 143 by method C in 36% yield.

¹H NMR(400MHz,DMSO-d₆):1.10(s,3H),1.35-2.46(m,15H),2.90(m,2H),3.15-3.25(m,2H),3.51-3.65(m,2H)),3.92(d,1H),7.11(m,3H),7.28(m,1H),7.44(d,1H),8.10(d,1H),12.11(br s,1H)。

Compound 145

(13S,15R) -13-methyl-15- (3-oxo-3- (pyrrolidin-1-yl) propyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 145 was synthesized by method a1 from the acid SM-XXVI and pyrrolidine in a reaction time of two hours in 93% yield.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.37-2.43(m,20H),2.87(m,2H),3.27(t,2H),3.40(t,2H),7.09(m,3H),7.27(m,1H)。

Compound 146

(13S,15S, Z) -16- (hydroxymethylene) -13-methyl-15- (3-oxo-3- (pyrrolidin-1-yl) propyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 146 was prepared from compound 145 by method B in 58% yield.

¹H NMR(400MHz,DMSO-d₆):0.97(s,3H),1.35-2.40(m,16H),2.88(m,3H),3.26-3.45(m,4H),7.09(m,3H),7.27(m,1H),7.50(s,1H),11.42(br s,1H)。

Compound 147

3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -1- (pyrrolidin-1-yl) propan-1-one

Compound 147 was prepared from compound 146 by method C in 86% yield.

¹H NMR(400MHz,DMSO-d₆):1.10(s,3H),1.39-2.43(m,17H),2.81-2.97(m,3H),3.25-3.30(m,2H),3.38-3.48(m,2H),7.10(m,3H),7.29(m,1H),7.41(s,1H),12.11(br s,1H)。

Compound 148

3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (2-oxo-1, 2,5,6,7, 8-hexahydroquinolin-3-yl) propionamide

Compound 148 was synthesized by method A1 in 59% yield in THF using the acid SM-XXVI and 3-amino-1, 2,5,6,7, 8-hexahydroquinolin-2-one as starting materials in an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.30-2.60(m,24H),2.79-2.99(m,2H),7.00-7.15(m,3H),7.23-7.30(m,1H),8.01(s,1H),9.13(s,1H),11.67(s,1H)。

Compound 149

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (2-oxo-1, 2,5,6,7, 8-hexahydroquinolin-3-yl) propionamide

Compound 149 was synthesized by method B from compound 148 in quantitative yield over a reaction time of 2 days by using 900 mol-% ethyl formate and 800 mol-% NaH.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.60(m,21H),2.70-2.99(m,3H),7.00-7.15(m,3H),7.23-7.30(m,1H),7.52(s,1H),8.00(s,1H),8.97(s,1H),11.08(br s,1H),11.66(s,1H)。

Compound 150

3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (2-oxo-1, 2,5,6,7, 8-hexahydroquinolin-3-yl) propionamide

Compound 150 was synthesized from compound 149 by method C in a1 hour reaction time with 47% yield after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.30-2.60(m,21H),2.75-2.99(m,3H),7.00-7.15(m,3H),7.23-7.30(m,1H),7.41(s,1H),8.00(s,1H),9.15(s,1H),11.68(br s,1H),12.10(br s,1H)。

Compound 151

3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (tetrahydro-2H-pyran-4-yl) propanamide

Compound 151 was synthesized by method A1 from the acid SM-XXVI and 4-aminotetrahydropyran by stirring at room temperature for 2 hours in THF in 99% yield.

¹H-NMR(400MHz,DMSO-d₆):0.96(s,3H),1.33-2.40(m,20H),2.87(m,2H),3.31(m,1H),3.36(m,1H),3.70-3.83(m,3H),7.08(m,3H),7.27(d,1H),7.82(d,1H)。

Compound 152

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (tetrahydro-2H-pyran-4-yl) propanamide

Compound 152 was prepared from compound 151 by method B in 89% yield.

¹H NMR(400MHz,DMSO-d₆):0.98(s,3H),1.13-2.40(m,20H),2.88(m,3H),3.74-3.84(m,2H),7.09(m,3H),7.27(m,1H),7.48(br s,1H),8.14(d,1H),11.57(br s,1H)。

Compound 153

3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (tetrahydro-2H-pyran-4-yl) propanamide

Compound 153 was prepared from compound 152 by method C in 59% yield.

¹H NMR(400MHz,DMSO-d₆):1.09(s,3H),1.30-2.39(m,17H),2.77(m,1H),2.89(m,2H),3.36(m,2H),3.80(m,3H),7.09(m,3H),7.28(m,1H),7.38(br s,1H),7.85(d,1H),12.10(br s,1H)。

Compound 154

N- (6-methoxypyridazin-3-yl) -3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 154 was synthesized by method a1 in 91% yield in THF using the acids SM-XXVI and 3-amino-6-methoxypyridazine as starting materials in an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.55(m,16H),2.81-2.96(m,2H),3.98(s,3H),7.00-7.15(m,3H),7.22-7.30(m,2H),8.25(d,1H),10.93(s,1H)。

Compound 155

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-methoxypyridazin-3-yl) propanamide

Compound 155 was synthesized by method B from compound 154 in a reaction time of 3 hours with a yield of 96%.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.65(m,13H),2.81-3.05(m,3H),3.98(s,3H),7.00-7.15(m,3H),7.20-7.30(m,2H),7.60(s,1H),8.24(d,1H),10.98(s,1H)。

Compound 156

N- (6-methoxypyridazin-3-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 156 was synthesized by method C from compound 155 in 74% yield over a1 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.40-2.60(m,13H),2.80-3.02(m,3H),3.98(s,3H),7.00-7.15(m,3H),7.23(d,1H),7.25-7.32(m,1H),7.41(s,1H),8.25(d,1H),10.96(s,1H),12.11(br s,1H)。

Compound 157

N- (5-fluoropyridin-2-yl) -3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 157 was synthesized by method a1 in quantitative yield in THF over a reaction time of 6 hours using the acid SM-XXVI and 2-amino-5-fluoropyridine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.55(m,16H),2.81-2.96(m,2H),7.00-7.15(m,3H),7.25-7.29(m,1H),7.69-7.76(m,1H),8.11-8.17(m,1H),8.31(d,1H),10.62(s,1H)。

Compound 158

N- (5-Fluoropyridin-2-yl) -3- ((13S,15S, Z) -16- (Hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 158 was synthesized by method B from compound 157 in quantitative yield over a3 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.65(m,13H),2.80-2.98(m,3H),7.00-7.15(m,3H),7.23-7.29(m,1H),7.53(s,1H),7.65-7.69(m,1H),8.10-8.17(m,1H),8.30(d,1H),10.54(s,1H),10.96(s,1H)。

Compound 159

N- (5-Fluoropyridin-2-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 159 was synthesized by method C from compound 158 in a1 hour reaction time in 84% yield.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.35-2.55(m,13H),2.78-2.99(m,3H),7.00-7.15(m,3H),7.25-7.30m,1H),7.40(s,1H),7.68-7.76(m,1H),8.12-8.18(m,1H),8.30(d,1H),10.66(s,1H),12.15(br s,1H)。

Compound 160

N- (4-fluoropyridin-2-yl) -3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 160 was synthesized by method a 1% yield in THF in an overnight reaction time by using the acid SM-XXVI and 290 mol-% 2-amino-4-fluoropyridine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.47(m,16H),2.81-2.96(m,2H),7.00-7.06(m,1H),7.07-7.16(m,3H),7.25-7.30(m,1H),7.92(dd,1H),8.30-8.37(m,1H),10.82(s,1H)。

Compound 161

N- (4-fluoropyridin-2-yl) -3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 161 was synthesized by method B from compound 160 in quantitative yield over an overnight reaction time and using 1200 mol-% ethyl formate and 800 mol-% NaH.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.70(m,13H),2.80-2.99(m,3H),6.98-7.04(m,1H),7.05-7.16(m,3H),7.25-7.30(m,1H),7.53(s,1H),7.91(dd,1H),8.30-8.37(m,1H),10.74(s,1H),10.95(br s,1H)。

Compound 162

N- (4-Fluoropyridin-2-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 162 was synthesized by method C from compound 161 in a reaction time of 1 hour with a yield of 47%.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.40-2.50(m,13H),2.78-2.99(m,3H),6.98-7.06(m,1H),7.07-7.16(m,3H),7.25-7.30(m,1H),7.39(s,1H),7.93(dd,1H),8.32-8.38(m,1H),10.86(s,1H),12.12(br s,1H)。

Compound 163

N- (4-methoxypyridin-2-yl) -3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 163 was synthesized by method a1 in 53% yield in THF using the acid SM-XXVI and 2-amino-4-methoxypyridine as starting materials in a reaction time of 6 hours.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.47(m,16H),2.81-2.96(m,2H),3.80(s,3H),6.69(dd,1H),7.05-7.16(m,3H),7.25-7.30(m,1H),7.72(d,1H),8.11(d,1H),10.46(s,1H)。

Compound 164

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-methoxypyridin-2-yl) propanamide

Compound 164 was synthesized by method B from compound 163 over a reaction time of 4 hours in 94% yield.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.60(m,13H),2.81-3.00(m,3H),3.80(s,3H),6.68(dd,1H),7.05-7.14(m,3H),7.25-7.30(m,1H),7.54(s,1H),7.72(d,1H),8.10(d,1H),10.39(s,1H),10.97(br s,1H)。

Compound 165

N- (4-methoxypyridin-2-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 165 was synthesized by method C from compound 164 in a reaction time of 1 hour with a yield of 76%.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.35-2.49(m,13H),2.79-3.00(m,3H),3.80(s,3H),6.68(dd,1H),7.05-7.14(m,3H),7.25-7.30(m,1H),7.39(s,1H),7.73(d,1H),8.12(d,1H),10.49(s,1H),12.12(br s,1H)。

Compound 166

3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-methylpyridin-2-yl) propanamide

Compound 166 was synthesized by method a1 in 82% yield in THF using the acid SM-XXVI and 2-amino-4-methylpyridine as starting materials in a reaction time of 6 hours.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.48(m,19H),2.80-2.95(m,2H),6.92(d,1H),7.02-7.19(m,3H),7.25-7.29(m,1H),7.95(s,1H),8.15(d,1H),10.41(s,1H)。

Compound 167

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-methylpyridin-2-yl) propanamide

Compound 167 was synthesized from compound 166 by method B in quantitative yield over a3 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.65(m,16H),2.80-3.05(m,3H),6.91(d,1H),7.02-7.15(m,3H),7.25-7.29(m,1H),7.54(s,1H),7.94(s,1H),8.14(d,1H),10.33(s,1H),10.97(br s,1H)。

Compound 168

3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (4-methylpyridin-2-yl) propionamide

Compound 168 was synthesized by method C from compound 167 in a reaction time of 1 hour in 63% yield.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.30-2.49(m,16H),2.79-3.03(m,3H),6.92(d,1H),7.05-7.15(m,3H),7.27-7.31(m,1H),7.41(s,1H),7.96(s,1H),8.15(d,1H),10.45(s,1H),12.11(br s,1H)。

Compound 169

3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyridin-2-yl) propanamide

Compound 169 was synthesized by method a1 in 75% yield in THF over night reaction time using the acids SM-XXVI and 2-aminopyridine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.45(m,16H),2.80-2.96(m,2H),7.00-7.15(m,4H),7.21-7.30(m,1H),7.70-7.82(m,1H),8.09(d,1H),8.28-8.33(m,1H),10.50(s,1H)。

Compound 170

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyridin-2-yl) propanamide

Compound 170 was synthesized by method B from compound 169 in quantitative yield over a 4 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.65(m,13H),2.80-3.05(m,3H),7.00-7.15(m,4H),7.24-7.30(m,1H),7.56(s,1H),7.70-7.80(m,1H),8.08(d,1H),8.28-8.32(m,1H),10.46(s,1H),10.98(br s,1H)。

Compound 171

3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (pyridin-2-yl) propionamide

Compound 171 was synthesized by method C from compound 170 in a reaction time of 1 hour with a yield of 87%.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.35-2.60(m,13H),2.78-3.02(m,3H),7.03-7.15(m,4H),7.26-7.30(m,1H),7.41(s,1H),7.70-7.80(m,1H),8.10(d,1H),8.28-8.32(m,1H),10.53(s,1H),12.12(br s,1H)。

Compound 172

N- (cyclopropylmethyl) -N-methyl-3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 172 was synthesized by method a1 in 80% yield in THF by using the acid SM-XXVI and 400 mol-% (cyclopropylmethyl) (methyl) amine, 600 mol-% pyridine and 400 mol-% T3P, reacting overnight at room temperature and at 40 ℃ for 4 hours.

¹H-NMR(400MHz,CDCl₃) 0.21-0.27(m,2H),0.45-0.55(m,1H),0.55-0.65(m,1H),0.87-1.02(m,1H),1.07(s,3H),1.35-2.65(m,16H),2.85-3.05(m,2H),3.01/3.07(2x s,3H, isomer), 3.13-3.36(m,2H),7.00-7.30(m,2H),7.25-7.33(m,1H)。

Compound 173

N- (cyclopropylmethyl) -3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N-methylpropanamide

Compound 173 was synthesized by method B from compound 172 in a reaction time of 5 hours in 96% yield.

¹H-NMR(400MHz,DMSO-d₆) 0.17-0.27(m,2H),0.39-0.55(m,2H),0.72-0.90(m,1H),0.97/0.98(2x s,3H, isomer), 1.30-2.70(m,13H),2.80-3.03(m,3H),2.88/3.04(2x s,3H, isomer), 3.05-3.25(m,2H),7.00-7.15(m,3H)7.21-7.30(m,1H),7.49/7.50(2x s,1H, isomer), 11.44(br s, 1H).

Compound 174

N- (cyclopropylmethyl) -N-methyl-3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 174 was synthesized by method C from compound 173 in a reaction time of 1.5 hours in 46% yield.

¹H-NMR(400MHz,DMSO-d₆) 0.17-0.27(m,2H),0.35-0.55(m,2H),0.85-1.00(m,1H),1.10(s,3H),1.25-2.49(m,13H),2.80-3.00(m,3H),2.85/3.04(2x s,3H, isomer), 3.05-3.25(m,2H),7.00-7.15(m,3H),7.21-7.30(m,1H),7.38/7.42(2x br s,1H, isomer), 12.11(br s, 1H).

Compound 175

(13S,15R) -13-methyl-15- (3-oxo-3- (8-oxa-2-azaspiro [4.5] decan-2-yl) propyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 175 was synthesized by method A1 in 98% yield in THF using the acids SM-XXVI and 8-oxa-2-aza-spiro (4,5) decane hydrochloride, 800 mol-% pyridine and 400 mol-% T3P in an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.30-2.46(m,22H),2.84-2.95(m,2H),3.17-3.25(m,1H),3.29-3.40(m,2H),3.46-3.65(m,5H),7.00-7.15(m,3H),7.24-7.29(m,1H)。

Compound 176

(13S,15S, Z) -16- (hydroxymethylene) -13-methyl-15- (3-oxo-3- (8-oxa-2-azaspiro [4.5] decan-2-yl) propyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 176 was synthesized by method B from compound 175 in an overnight reaction time with 97% yield.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.46(m,19H),2.80-2.99(m,3H),3.17-3.29(m,1H),3.30-3.40(m,2H),3.41-3.69(m,5H),7.00-7.15(m,3H),7.24-7.29(m,1H),7.49(s,1H),11.46(br s,1H)。

Compound 177

3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -1- (8-oxa-2-azaspiro [4.5] decan-2-yl) propan-1-one

Compound 177 was synthesized by method C from compound 176 in a reaction time of 0.5 hours in a yield of 68%.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.30-2.46(m,19H),2.80-2.99(m,3H),3.20(s,1H),3.27-3.40(m,2H),3.41-3.69(m,5H),7.00-7.16(m,3H),7.24-7.29(m,1H),7.41/7.45(2x br s,1H),12.11/12.48(2x br s),1H)。

Compound 178

(13S,15R) -15- (3- (isoindolin-2-yl) -3-oxopropyl) -13-methyl-6, 7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 178 was synthesized by method a1 in 56% yield in THF over night reaction time using acid SM-XXVI and isoindoline as starting materials.

¹H-NMR(400MHz,CDCl₃):1.09(s,3H),1.39-2.60(m,16H),2.85-3.08(m,2H),4.82(s,4H),7.05-7.20(m,3H),7.25-7.34(m,5H)。

Compound 179

(13S,15S, Z) -16- (hydroxymethylene) -15- (3- (isoindolin-2-yl) -3-oxopropyl) -13-methyl-6, 7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

By method B, compound 179 was synthesized from compound 178 in an overnight reaction time using 1200 mol-% ethyl formate and 800 mol-% NaH, with a yield of 81% after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.66(m,13H),2.79-3.05(m,3H),4.65(s,2H),4.75-4.88(m,2H),7.05-7.15(m,3H),7.25-7.40(m,5H),7.54(s,1H),11.09(br s,1H)。

Compound 180

1- (isoindolin-2-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propan-1-one

Compound 180 was synthesized by method C from compound 179 in a reaction time of 1 hour with a yield of 92%.

¹H-NMR(400MHz,DMSO-d₆):1.12(s,3H),1.35-2.49(m,13H),2.85-3.01(m,3H),4.64(s,2H),4.80-4.95(m,2H),7.05-7.15(m,3H),7.25-7.40(m,5H),7.47(s,1H),12.12(br s,1H)。

Compound 181

N, N-dimethyl-6- (3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propionamido) nicotinamide

Compound 181 was synthesized by method a1 in 76% yield in THF over night reaction time by using the acids SM-XXVI and 6-amino-N, N-lutidine-3-carboxamide as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.56(m,16H),2.79-2.96(m,2H),2.97(s,6H),7.00-7.15(m,3H),7.21-7.30(m,1H),7.85(dd,1H),8.14(d,1H),8.38(d,1H),10.71(s,1H)。

Compound 182

6- (3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamido) -N, N-dimethylnicotinamide

Compound 182 was synthesized by method B from compound 181 in quantitative yield over an overnight reaction time by using 1200 mol-% ethyl formate and 1000 mol-% NaH.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.66(m,13H),2.79-3.03(m,3H),2.97(s,6H),7.00-7.15(m,3H),7.21-7.30(m,1H),7.54(s,1H),7.84(dd,1H),8.13(d,1H),8.37(d,1H),10.64(s,1H),10.97(br s,1H)。

Compound 183

N, N-dimethyl-6- (3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamido) nicotinamide

Compound 183 was synthesized by method C from compound 182 in a reaction time of 1 hour with a yield of 80%.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.30-2.60(m,13H),2.79-3.03(m,3H),2.98(s,6H),7.00-7.15(m,3H),7.21-7.30(m,1H),7.41(s,1H),7.85(dd,1H),8.15(d,1H),8.39(d,1H),10.76(s,1H),12.14(br s，1H)。

Compound 184

3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (1-methyl-1H-pyrazol-3-yl) propanamide

Compound 184 was synthesized by method a1 in THF with 85% yield by using the acid SM-XXVI and 1-methyl-1H-pyrazol-3-amine as starting materials and 400 mol% T3P for 2 days of reaction time and incubation at 40 ℃ for 4 hours.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.30-2.47(m,16H),2.79-2.96(m,2H),3.72(s,3H),6.42(d,1H),7.00-7.15(m,3H),7.23-7.30(m,1H),7.51(d,1H),10.36(s,1H)。

Compound 185

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (1-methyl-1H-pyrazol-3-yl) propanamide

Compound 185 was synthesized by method B from compound 184 in quantitative yield over a 5 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.47(m,13H),2.79-2.96(m,3H),3.72(s,3H),6.42(d,1H),7.00-7.15(m,3H),7.23-7.30(m,1H),7.51(d,1H),7.54(s,1H),10.38(s,1H),11.06(br s,1H)。

Compound 186

3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (1-methyl-1H-pyrazol-3-yl) propanamide

Compound 186 was synthesized by method C from compound 185 over a reaction time of 1 hour in 62% yield.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.30-2.47(m,13H),2.75-2.96(m,3H),3.72(s,3H),6.43(d,1H),7.00-7.15(m,3H),7.23-7.30(m,1H),7.40(s,1H),7.52(d,1H),10.40(s,1H),12.11(br s,1H)。

Compound 187

3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyrazin-2-yl) propanamide

Compound 187 was synthesized by method a1 in 66% yield in THF over overnight reaction time using the acids SM-XXVI and aminopyrazine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.60(m,16H),2.79-2.97(m,2H),7.00-7.15(m,3H),7.23-7.30m,1H),8.34(d,1H),8.39(d,1H),9.35(s,1H),10.81(s,1H)。

Compound 188

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyrazin-2-yl) propanamide

Compound 188 was synthesized by method B from compound 187 in quantitative yield over a 4 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.70(m,13H),2.79-3.05(m,3H),7.00-7.15(m,3H),7.23-7.30(m,1H),7.54(s,1H),8.33(d,1H),8.37(d,1H),9.33(s,1H),10.73(s,1H),10.95(br s,1H)。

Compound 189

3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (pyrazin-2-yl) propionamide

Compound 189 was synthesized from compound 188 by method C in a1 hour reaction time and purified by chromatography in 43% yield.

¹H-NMR(400MHz,DMSO-d₆):1.12(s,3H),1.39-2.60(m,13H),2.79-3.05(m,3H),7.00-7.15(m,3H),7.23-7.30(m,1H),7.40(s,1H),8.34(d,1H),8.40(d,1H),9.35(s,1H),10.84(s,1H),12.15(br s,1H)。

Compound 190

N-cyclobutyl-3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 190 was synthesized by method a1 in 91% yield in THF over a reaction time of 5 hours using the acid SM-XXVI and cyclobutylamine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.95(s,3H),1.30-2.43(m,22H),2.79-2.97(m,2H),4.10-4.25(m,1H),7.00-7.15(m,3H),7.23-7.30(m,1H),8.07(d,1H)。

Compound 191

N-cyclobutyl-3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 191 was synthesized by method B from compound 190 in quantitative yield over a 4 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.30-2.43(m,19H),2.79-2.97(m,3H),4.10-4.25(m,1H),7.00-7.15(m,3H),7.23-7.30(m,1H),7.53(s,1H),8.39(d,1H)。

Compound 192

N-cyclobutyl-3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 192 was synthesized by method C from compound 191 in a reaction time of 1 hour with a yield of 80%.

¹H-NMR(400MHz,DMSO-d₆):1.09(s,3H),1.30-2.43(m,19H),2.70-2.98(m,3H),4.10-4.25(m,1H),7.00-7.15(m,3H),7.25-7.30(m,1H),7.37(s,1H),8.10(d,1H),12.12(br s,1H)。

Compound 193

3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-methylpyridazin-3-yl) propanamide

Compound 193 was synthesized by method a1 in 62% yield in THF within a reaction time of 2 days using the acids SM-XXVI and 3-amino-6-methylpyridazine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.49(m,16H),2.55(s,3H),2.79-2.97(m,2H),7.00-7.15(m,3H),7.23-7.30(m,1H),7.54(d,1H),8.22(d,1H),11.04(s,1H)。

Compound 194

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-methylpyridazin-3-yl) propanamide

Compound 194 was synthesized in quantitative yield from compound 193 by method B by using 1200 mol-% ethyl formate and 800 mol-% NaH over an overnight reaction time and then incubation at 30 ℃ for 5 hours.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.70(m,13H),2.55(s,3H),2.80-3.05(m,3H),7.00-7.15(m,3H),7.23-7.30(m,1H),7.52(d,1H),7.54(s,1H),8.21(d,1H),10.93(br s,1H)。

Compound 195

3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (6-methylpyridazin-3-yl) propionamide

Compound 195 was synthesized by method C from compound 194 in a reaction time of 1 hour in 53% yield.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.30-2.61(m,13H),2.55(s,3H),2.78-3.05(m,3H),7.00-7.15(m,3H),7.23-7.30(m,1H),7.41(s,1H),7.53(d,1H),8.22(d,1H),11.06(s,1H),12.12(br s,1H)。

Compound 196

3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5- (4-methylpiperazin-1-yl) pyridin-2-yl) propionamide

Compound 196 was synthesized by method a1 in 39% yield in THF using the acid SM-XXVI and 1-methyl-4- (6-aminopyridin-3-yl) piperazine as starting materials in a reaction time of 5 hours.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.49(m,16H),2.21(s,3H),2.40-2.49(m,4H),2.79-2.98(m,2H),3.05-3.15(m,4H),7.00-7.15(m,3H),7.23-7.30(m,1H),7.35-7.41(m,1H),7.90-8.00(m,2H),10.26(s,1H)。

Compound 197

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5- (4-methylpiperazin-1-yl) pyridin-2-yl) propionamide

Compound 197 was synthesized by method B from compound 196 in a 5 hour reaction time with 84% yield.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.49(m,13H),2.24(s,3H),2.43-2.55(m,4H),2.79-3.05(m,3H),3.05-3.15(m,4H),7.00-7.15(m,3H),7.23-7.30(m,1H),7.38(dd,1H),7.59(s,1H),7.93(d,1H),7.98(d,1H),10.31(s,1H)。

Compound 198

3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5- (4-methylpiperazin-1-yl) pyridin-2-yl) propionamide

Compound 198 was synthesized by method C from compound 197 in a reaction time of 1 hour with a yield of 81%.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.30-2.49(m,13H),2.22(s,3H),2.43-2.49(m,4H),2.77-3.05(m,3H),3.05-3.15(m,4H),7.00-7.15(m,3H),7.23-7.30(m,1H),7.38(dd,1H),7.40(s,1H),7.95(d,1H),7.98(d,1H),10.29(s,1H),12.10(br s,1H)。

Compound 199

N- (tert-butyl) -3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 199 was synthesized by method a1 in 68% yield in THF over a2 day reaction time using the acid SM-XXVI and tert-butylamine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.96(s,3H),1.24(s,9H),1.30-2.46(m,16H),2.82-2.97(m,2H),7.00-7.15(m,3H),7.24-7.29(m,1H),7.44(s,1H)。

Compound 200

N- (tert-butyl) -3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -propionamide

Compound 200 was synthesized by method B from compound 199 in quantitative yield over an overnight reaction time by using 1200 mol-% ethyl formate and 800 mol-% NaH.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.28(s,9H),1.30-2.47(m,13H),2.82-2.97(m,3H),7.01-7.15(m,3H),7.24-7.29(m,1H),7.46(s,1H),7.87(br s,1H),11.88(br s,1H)。

Compound 201

N- (tert-butyl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 201 was synthesized from compound 200 by method C in a1 hour reaction time with a 30% yield after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):1.09(s,3H),1.25(s,9H),1.13-2.47(m,13H),2.70-2.97(m,3H),7.01-7.16(m,3H),7.24-7.33(m,1H),7.37(s,1H),7.45(s,1H),12.10(br s,1H)。

Compound 202

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-fluoropyridin-2-yl) propanamide

Compound 202 was synthesized by method a1 in 88% yield in THF over a reaction time of 2 hours using the acid SM-IX and 2-amino-6-fluoropyridine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.35-1.46(m,3H),1.57-1.77(m,4H),1.93(m,1H),2.16-2.47(m,8H),2.68-2.90(m,2H),6.83(dd,1H),6.97(dd,1H),7.12-7.20(m,2H),7.95(dd,1H),8.01(d,1H),10.69(s,1H)。

Compound 203

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-fluoropyridin-2-yl) propanamide

Compound 203 was prepared by method B from compound 202 by stirring overnight at room temperature in 90% yield.

¹H NMR(400MHz,DMSO-d₆):0.99(s,3H),1.18-2.37(m,13H),2.45-2.96(m,4H),6.81(dd,1H),6.96(t,1H),7.12-7.19(m,2H),7.55(s,1H),7.92-8.02(m,2H),10.64(s,1H)。

Compound 204

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (6-fluoropyridin-2-yl) propanamide

Compound 204 was prepared from compound 203 by method C and purified by crystallization from acetonitrile in 16% yield.

¹H NMR(400MHz,DMSO-d₆):1.11(s,3H),1.41-2.42(m,13H),2.72-2.93(m,3H),6.83(dd,1H),6.98(t,1H),7.16(m,2H),7.40(s,1H),7.94(m,1H),8.02(d,1H),10.72(s,1H),12.13(br s,1H)。

Compound 205

N-cyclohexyl-3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 205 was synthesized by method a1 in 64% yield over a reaction time of 2 hours using acid SM-IX and cyclohexylamine as starting materials. The crude product was purified by chromatography.

¹H-NMR(400MHz,DMSO-d₆):0.95(s,3H),1.10-2.41(m,26H),2.67-2.76(m,1H),2.84-2.91(m,1H),3.50-3.53(m,1H),6.94-7.00(m,1H),7.10-7.22(m,2H),7.71(br d,1H)。

Compound 206

N-cyclohexyl-3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 206 was synthesized by method B from compound 205 in a reaction time of 2 hours in 67% yield.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.09-1.90(m,18H),2.03-2.16(m,2H),2.30-2.45(m,3H),2.65-2.76(m,1H),2.80-2.95(m,2H),3.50-3.65(m,1H),6.90-7.02(m,1H),7.08-7.25(m,2H),7.50(s,1H),8.14br s,1H)11.84(br s,1H)。

Compound 207

N-cyclohexyl-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 207 was synthesized by method C from compound 206 in a reaction time of 1 hour with a yield of 49%.

¹H-NMR(400MHz,DMSO-d₆):1.08(s,3H),1.09-1.80(m,16H),1.90-2.00(m,1H),2.00-2.25(m,4H),2.30-2.45(m,2H),2.65-2.80(m,2H),2.82-2.95(m,1H),3.45-3.60(m,1H),6.90-7.02(m,1H),7.08-7.25(m,2H),7.39(s,1H),7.73(d,1H)12.12(br s,1H)。

Compound 208

(13S,15R) -4-fluoro-13-methyl-15- (3-oxo-3- (pyrrolidin-1-yl) propyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 208 was synthesized by method a1 using the acid SM-IX and pyrrolidine as starting materials in a reaction time of 4 hours with a yield of 90%.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.43-2.45(m,20H),2.71–2.91(m,2H),3.39–3.47(m,4H),6.97(dd,1H),7.10-7.20(m,2H)。

Compound 209

(13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-15- (3-oxo-3- (pyrrolidin-1-yl) propyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 209 was prepared by method B from compound 208 by stirring at room temperature for 2 hours in 96% yield.

¹H NMR(400MHz,CDCl₃):1.08(s,3H),1.48-2.99(m,19H),3.16(m,1H),3.43-3.66(m,4H),6.88(dd,1H),7.09(m,2H),7.66(d,1H),12.41(d,1H)。

Compound 210

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -1- (pyrrolidin-1-yl) propan-1-one

Compound 210 was prepared from compound 209 by method C in 90% yield.

¹H NMR(400MHz,DMSO-d₆):1.10(s,3H),1.36-2.42(m,17H),2.67-2.91(m,3H),3.27-3.47(m,4H),6.98(dd,1H)),7.16(m,2H),7.41(s,1H),12.14(br s,1H)。MS m/z(TOF ES⁺)：422(M+1)

Compound 211

N- (5- (tert-butyl) isoxazol-3-yl) -3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 211 was synthesized by method a1 in 83% yield using acid SM-IX and 3-amino-5-tert-butylisoxazole as starting materials.

¹H NMR(400MHz,CDCl₃):1.06(s,3H),1.35(s,9H),1.44-1.95(m,8H),2.09-2.61(m,8H),2.75-3.00(m,2H),6.73(s,1H),6.88(t,1H),7.08(m,2H),9.54(s,1H)。

Compound 212

N- (5- (tert-butyl) isoxazol-3-yl) -3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 212 was prepared from compound 211 by method B with stirring at 0 ℃ for 2 hours in 91% yield.

¹H NMR(400MHz,DMSO-d₆):0.99(s,3H),1.28(s,9H),1.38-2.30(m,14H),2.68-2.95(m,3H),6.59(dd,1H),6.97(t,1H),7.14(m,2H),7.56(s,1H),10.92(s,1H)。

Compound 213

N- (5- (tert-butyl) isoxazol-3-yl) -3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 213 was prepared from compound 212 by method C in 90% yield.

1H NMR(400MHz,DMSO-d₆):1.10(s,3H),1.29(s,9H),1.40-2.44(m,13H),2.67-2.93(m,3H),6.61(s,1H),6.98(t,1H),7.16(m,2H),7.39(s,1H),10.97(s,1H),12.13(br s,1H)。MS m/z(TOF ES⁺)：491(M+1)

Compound 214

N, N-diethyl-3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 214 was synthesized by method a2 in THF in 97% yield in 2 hours reaction time using the acid SM-IX and diethylamine as starting materials and 200 mol% EDCI and HOBT.

¹H-NMR(200MHz,DMSO-d₆):0.97(s,3H),1.01(t,3H),1.11(t,3H),1.20-2.47(m,16H),2.60-2.99(m,2H),3.15-3.40(m,4H),6.90-7.06(m,1H),7.08-7.25(m,2H)。

Compound 215

N, N-diethyl-3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 215 was synthesized by method B from compound 214 in quantitative yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.03(t,3H),1.12(t,3H),1.30-2.45(m,13H),2.55-2.99(m,3H),3.15-4.00(m,4H),6.90-7.02(m,1H),7.08-7.25(m,2H),7.49(s,1H),11.46(br s,1H)。

Compound 216

N, N-diethyl-3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 216 was synthesized by method C from compound 215 in a reaction time of 0.5 hours with a yield of 86%.

¹H-NMR(400MHz,DMSO-d₆):1.00(t,3H),1.10(s,3H),1.12(t,3H),1.30-2.45(m,13H),2.69-2.95(m,3H),3.15-3.40(m,4H),6.90-7.02(m,1H),7.08-7.25(m,2H),7.39(s,1H),12.18(br s,1H)。

Compound 217

(13S,15R) -4-fluoro-13-methyl-15- (3-oxo-3- (8-oxa-2-azaspiro [4.5] decan-2-yl) propyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 217 was synthesized by method a3 in 93% yield over a reaction time of 4 hours using the acid SM-IX and 8-oxa-2-aza-spiro (4,5) decane hydrochloride as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.30-2.45(m,22H),2.65-2.76(m,1H),2.84-2.91(m,1H),3.19-3.22(m,1H),3.29-3.42(m,2H),3.46-3.65(m,5H),6.94-7.00(m,1H),7.10-7.22(m,2H)。

Compound 218

(13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-15- (3-oxo-3- (8-oxa-2-azaspiro [4.5] decan-2-yl) propyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 218 was synthesized by method B from compound 217 in 98% yield over an overnight reaction time by using 1000 mol-% ethyl formate and 600 mol-% NaH.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.30-2.46(m,19H),2.65-2.99(m,3H),3.18-3.66(m,8H),6.94-7.00(m,1H)、7.10-7.22(m,2H)、7.52(s,1H)。

Compound 219

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -1- (8-oxa-2-azaspiro [4.5] decan-2-yl) propan-1-one

Compound 219 was synthesized from compound 218 by method C in a one hour reaction time with a yield of 29% after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆) 1.09(s,3H),1.30-2.45(m,19H),2.65-2.99(m,3H),3.19-3.65(m,8H),6.94-7.00(m,1H),7.13-7.20(m,2H),7.40-7.44(m,1H, isomers), 12.12(br s, 1H).

Compound 220

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N, N-dimethylpropionamide

Compound 220 was synthesized by method a3 in DCM over a reaction time of 2 hours using acid SM-IX and dimethylamine hydrochloride as starting materials in 85% yield.

¹H-NMR(200MHz,DMSO-d₆):0.97(s,3H),1.28-2.40(m,16H),2.62-2.94(m,2H),2.82(s,3H),2.97(s,3H),6.90-7.03(m,1H),7.10-7.25(m,2H)。

Compound 221

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N, N-dimethylpropionamide

Compound 221 was synthesized by method B from compound 220 in quantitative yield over a reaction time of 4 hours by using 500 mol-% ethyl formate and 200 mol-% NaH.

¹H-NMR(200MHz,DMSO-d₆):0.97(s,3H),1.28-2.48(m,13H),2.62-2.94(m,3H),2.83(s,3H),2.97(s,3H),6.90-7.03(m,1H),7.10-7.25(m,2H),7.57(br s,1H)。

Compound 222

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N, N-dimethylpropionamide

Compound 222 was synthesized from compound 221 by method C by refluxing for 1 hour with 30% yield after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.28-2.48(m,13H),2.62-2.94(m,3H),2.81(s,3H),2.99(s,3H),6.92-7.03(m,1H),7.10-7.25(m,2H),7.42(s,1H),12.13(br s,1H)。

Compound 223

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (tetrahydrofuran-3-yl) propanamide

Compound 223 was synthesized by method a2 in 73% yield over a reaction time of 2 hours using the acid SM-IX and 3-aminotetrahydrofuran as starting materials.

¹H NMR(400MHz,DMSO-d₆):0.95(s,3H),1.34-2.41(m,18H),2.70–2.90(m,2H),344(m,1H),3.64-3.79(m,3H),4.22(m,1H),6.97(m,1H),7.14(m,2H),8.09(d,1H)。

Compound 224

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (tetrahydrofuran-3-yl) propanamide

Compound 224 was prepared from compound 223 by method B by stirring at room temperature for 1.5 hours in 98% yield.

¹H NMR(400MHz,DMSO-d₆):0.97(s,3H),1.45-2.36(m,15H),2.69-2.90(m,3H),3.48(m,3H),3.51-3.81(m,3H),6.97(t,1H),7.14(m,2H),7.52(s,1H),8.35(br s,1H)。

Compound 225

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (tetrahydrofuran-3-yl) propanamide

Compound 225 was prepared from compound 224 by method C and purified by chromatography in 96% yield.

¹H NMR(400MHz,DMSO-d₆):1.09(s,3H),1.36-2.41(m,15H),2.75-2.92(m,3H),3.45(m,1H),3.66-3.81(m,3H),4.23(m,1H),6.98(t,1H),7.15(m,2H),7.39(s,1H),8.12(d,1H),12.12(br s,1H)。

Compound 226

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-methylpyridazin-3-yl) propanamide

Compound 226 was synthesized by method a2 in 83% yield in THF within a reaction time of 4 hours by using 200 mol-% EDCI and HOBT and the acids SM-IX and 3-amino-6-methylpyridazine as starting materials.

¹H-NMR(200MHz,DMSO-d₆):0.98(s,3H),1.20-2.47(m,16H),2.55(s,3H),2.70-2.95(m,2H),6.89-7.06(m,1H),7.08-7.25(m,2H),7.54(d,1H),8.23(d,1H),11.05(s,1H)。

Compound 227

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (6-methylpyridazin-3-yl) propanamide

Compound 227 was synthesized by method B from compound 226 in quantitative yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.30-2.47(m,13H),2.55(s,3H),2.60-3.05(m,3H),6.90-7.05(m,1H),7.08-7.25(m,2H),7.53(d,1H),7.57(s,1H),8.22(d,1H),11.00(s,1H),11.01(br s,1H)。

Compound 228

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (6-methylpyridazin-3-yl) propanamide

Compound 228 was synthesized from compound 227 by method C in a reaction time of 0.5 hours in 47% yield.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.30-2.47(m,13H),2.55(s,3H),2.69-2.95(m,3H),6.90-7.05(m,1H),7.08-7.25(m,2H),7.41(s,1H),7.54(d,1H),8.23(d,1H),11.07(s,1H),12.16(br s,1H)。

Compound 229:

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (3-fluoropyridin-2-yl) propanamide

Compound 229 was synthesized by method a1 in 96% yield over an overnight reaction time using the acid SM-IX and 2-amino-3-fluoropyridine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.34-1.98(m,8H),2.18-2.47(m,8H),2.68-2.77(m,1H),2.84-2.90(m,1H),6.97(m,1H),7.10-7.20(m,2H),7.34(m,1H),7.77(dd,1H),8.24(d,1H),10.28(s,1H)。

Compound 230

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (3-fluoropyridin-2-yl) propanamide

Compound 230 was prepared from compound 229 by method B in 88% yield.

¹H NMR(400MHz,DMSO-d₆):0.99(s,3H),1.36-1.83(m,7H),1.94(m,1H),2.20-2.45(m,3H),2.55-2.97(m,5H)),6.97(dd,1H),7.14(m,2H),7.35(m,1H),7.55(s,1H),7.75(m,1H),8.23(d,1H),10.24(s,1H),11.01(br s,1H)。

Compound 231

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (3-fluoropyridin-2-yl) propanamide

Compound 231 was prepared from compound 230 by method C in 43% yield.

¹H NMR(400MHz,DMSO-d₆):1.11(s,3H),1.41-2.39(m,13H),2.67-2.92(m,3H),6.97(dd,1H),7.16(m,2H),7.34(m,1H),7.44(s,1H),7.76(m,1H),8.25(d,1H),10.32(s,1H),12.15(br s,1H)。

Compound 232

(13S,15R) -4-fluoro-13-methyl-15- (3-morpholino-3-oxopropyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 232 was synthesized by method a2 in 83% yield in DMF over a reaction time of two hours using the acid SM-IX and morpholine as starting materials.

¹H-NMR(200MHz,DMSO-d₆):0.97(s,3H),1.35-2.37(m,15H),2.76-2.92(m,3H),3.45(br s,4H),3.55(br s 4H),6.93-7.02(m,1H),7.16-7.23(m,2H)。

Compound 233

(13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-15- (3-morpholino-3-oxopropyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 233 was prepared in quantitative yield from compound 232 by method B by stirring at room temperature for 2.5 hours.

¹H NMR(400MHz,DMSO-d₆):0.97(s,3H),1.38-2.40(m,14H),2.73-3.00(m,5H),3.55(m,6H),6.97(m,1H),7.14(m,2H),7.55(br s,1H)。

Compound 234

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -1-morpholinopropan-1-one

Compound 234 was prepared from compound 233 by method C in 62% yield.

¹H NMR(400MHz,DMSO-d₆):1.09(s,3H),1.34-2.43(m,14H),2.74-2.94(m,3H),3.45-3.56(m,7H),6.98(m,1H),7.17(m,2H),7.42(s,1H),12.15(br s,1H)。MS m/z(TOF ES⁺)：438(M+1)

Compound 235

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyridazin-3-yl) propanamide

Compound 235 was synthesized by method a2 in 42% yield from ethanol using the acid SM-IX and 3-aminopyridazine as starting materials for 2 hours in DMF.

¹H-NMR(200MHz,DMSO-d₆):0.99(s,3H),1.36-2.45(m,16H),2.78-2.91(m,2H),6.92-6.97(m,1H),7.15-7.23(m,2H),7.67(dd,1H),8.33(d,1H),8.95(d,1H),11.14(s,1H)。

Compound 236

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyridazin-3-yl) propanamide

Compound 236 was synthesized by method B from compound 235 in quantitative yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.47(m,13H),2.57-2.95(m,3H),6.90-7.00(m,1H),7.10-7.20m,2H),7.64(dd,1H),7.73(br s,1H),8.32(d,1H),8.92(d,1H),11.04(br s,1H)。

Compound 237

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (pyridazin-3-yl) propanamide

Compound 237 was synthesized by method C from compound 236 in quantitative yield over a 0.5 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.30-2.47(m,13H),2.60-2.95(m,3H),6.90-7.05(m,1H),7.10-7.20(m,2H),7.42(s,1H),7.66(dd,1H),8.33(d,1H),8.95(d,1H),11.17(s,1H),12.15(br s,1H)。MS m/z(TOF ES⁺)：446(M+1)。

Compound 238

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-morpholinopyridin-2-yl) propanamide

Compound 238 was synthesized by method a3 in 40% yield in DMF over an overnight reaction time using the acid SM-IX and 4-morpholinopyridin-2-amine as starting materials. The crude product was purified by chromatography.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.34-2.48(m,16H),2.68-2.90(m,2H),3.22(m,4H),3.71(m,4H),6.60(dd,1H),6.97(m,1H),7.14(m,2H),7.67(s,1H),7.94(d,1H),10.22(s,1H)。

Compound 239

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (4-morpholinopyridin-2-yl) propanamide

Compound 239 was prepared by method B from compound 238 by stirring at room temperature for three hours in 68% yield. The product is obtained by neutralizing the acid phase during the work-up process.

¹H NMR(400MHz,DMSO-d₆):0.99(s,3H),1.18-2.37(m,13H),2.68-2.94(m,4H),3.23(m,4H),3.71(m,4H),6.60(d,1H),6.96(m,1H),7.14(m,2H),7.55(s,1H),7.63(s,1H),7.93(d,1H),10.18(br s,1H)。

Compound 240

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (4-morpholinopyridin-2-yl) propanamide

Compound 240 was prepared from compound 239 by method C and purified by heptane trituration in 27% yield.

¹H NMR(400MHz,DMSO-d₆):1.10(s,3H),1.42-2.42(m,12H),2.67(m,1H),2.76-2.92(m,3H),3.22(m,4H),3.71(m,4H),6.60(dd,1H),6.98(m,1H),7.16(m,2H),7.39(s,1H),7.67(s,1H),7.95(d,1H),10.25(s,1H),12.12(br s,1H)。

Compound 241

3- ((13S,15R) -4-fluoro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylpropanamide

Compound 241 was synthesized by method a2 as a 60:40 isomer mixture yield of 83% in DMF over a reaction time of 2 hours by using the acid SM-IX and 2-methyl-1- (methylamino) -2-propanol as starting materials.

¹H-NMR(400MHz,DMSO-d₆) 0.97(s,3H),1.04(s,3H),1.12(s,3H),1.35-1.90(m,8H),2.26-2.41(m,8H),2.68-2.87(m,3H),3.98(s,2H),3.28(m,2H),4.50(s,0.6H, isomer), 4.57(s,0.4, isomer), 6.97(m,1H),7.15(m, 2H).

Compound 242

3- ((13S,15S, Z) -4-fluoro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylpropanamide

Compound 242 was prepared from compound 241 by method B stirring at room temperature for 2 hours in 88% yield.

¹H NMR(400MHz,DMSO-d₆):0.9(s,3H),1.05(s,3H),1.11(s,3H),1.23-2.34(m,15H),2.56-2.91(m,5H),3.08(s,2H),4.51(br s,1H),6.97(m,1H),7.14(m,2H),7.55(s,1H)。

Compound 243

3- ((8aS,12S) -3-fluoro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (2-hydroxy-2-methylpropyl) -N-methylpropanamide

Compound 243 was prepared from compound 242 by method C in 89% yield as a 60:40 mixture of isomers.

¹H NMR(400MHz,DMSO-d₆) 1.03(d,4H),1.10(s,4H),1.13(s,1H),1.38-2.38(m,13H),2.70-2.99(m,4H),3.10(s,2H),3.28(m,2H),4.50(s,0.6H, isomer), 4.59(s,0.4H, isomer), 6.98(dd,1H),7.16(m,2H),7.40(m,1H),12.12(br s, 1H).

Compound 244

3- ((13S,15R, E) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-methylisoxazol-3-yl) propanamide

Compound 244 was synthesized by method a1 in 90% yield in THF over a reaction time of 5 hours using the acids SM-XXVI and 3-amino-5-methylisoxazole as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.29-2.49(m,16H),2.36(s,3H),2.80-2.95(m,2H),6.64(s,1H),7.05-7.15(m,3H),7.24-7.28(m,1H),10.88(s,1H)。MS m/z(TOF ES+)：407(M+1),429(M+Na)。

Compound 245

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-methylisoxazol-3-yl) propanamide

Compound 245 was synthesized by method B from compound 244 in an overnight reaction time in 59% yield.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.34-2.60(m,13H),2.36(s,3H),2.80-2.99(m,3H),6.62(s,1H),7.03-7.15(m,3H),7.23-7.30(m,1H),7.56(s,1H),10.88(s,1H),10.95(br s,1H)。

Compound 246

3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5-methylisoxazol-3-yl) propanamide

Compound 246 was synthesized by method C from compound 245 over a reaction time of 1.5 hours in 42% yield after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.34-2.50(m,13H),2.36(s,3H),2.80-2.99(m,3H),6.64(s,1H),7.05-7.15(m,3H),7.25-7.31(m,1H),7.37(s,1H),10.90(s,1H),12.11(br s,1H)。

Compound 247

(13S,15R) -13-methyl-15- (3-morpholino-3-oxopropyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 247 was synthesized by method a1 in 89% yield in THF over a reaction time of 1.5 hours using the acid SM-XXVI and pre-dried morpholine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.33-2.44(m,16H),2.87(m,2H),3.44(m,4H),3.56(m,4H),7.06-7.14(m,3H),7.27(m,1H)。

Compound 248

(13S,15S, Z) -16- (hydroxymethylene) -13-methyl-15- (3-morpholino-3-oxopropyl) -6,7,8,9,11,12,13,14,15, 16-decahydro-17H-cyclopenta [ a ] phenanthren-17-one

Compound 248 was synthesized by method B from compound 247 in quantitative yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.97(s,3H),1.35-2.47(m,13H),2.91(m,3H),3.44(m,4H),3.54(m,4H),7.10(m,3H)、7.26(d,1H)、7.50(s,1H)、11.18(br s,1H)。

Compound 249

3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -1-morpholinopropan-1-one

Compound 249 was synthesized by method C from compound 248 in a reaction time of 30 minutes in 66% yield.

¹H-NMR(400MHz,DMSO-d₆):1.10(s,3H),1.41-2.43(m,13H),2.89(s,3H),3.43-3.58(m,8H),7.10(m,3H),7.29(m,1H),7.41(s,1H),12.11(br s,1H)。

Compound 250

3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-morpholinopyridin-2-yl) propanamide

Compound 250 was synthesized by method a1 in 89% yield in THF using the acids SM-XXVI and 5-morpholinopyridin-2-amine as starting materials in an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.48(m,16H),2.80-2.95(m,2H),3.06-3.11(m,4H),3.70-3.78(m,4H),7.03-7.15(m,3H),7.25-7.29(m,1H),7.40(dd,1H),7.96(d,1H),8.00(d,1H),10.28(s,1H).

Compound 251

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (5-morpholinopyridin-2-yl) propanamide

Compound 251 was synthesized by method B from compound 250 in 83% yield over an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.34-2.60(m,13H),2.80-2.95(m,3H),3.06-3.11(m,4H),3.70-3.78(m,4H),7.03-7.15(m,3H),7.25-7.29(m,1H),7.40(dd,1H),7.54(s,1H),7.95(d,1H),8.00(d,1H),10.24(s,1H),11.02(br s,1H)。

Compound 252

3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (5-morpholinopyridin-2-yl) propionamide

Compound 252 was synthesized from compound 251 by method C in a reaction time of 1 hour with a yield of 73%.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.34-2.50(m,13H),2.78-2.95(m,3H),3.06-3.11(m,4H),3.70-3.78(m,4H),7.03-7.15(m,3H),7.25-7.29(m,1H),7.39(dd,1H),7.40(s,1H),7.95(d,1H),8.00(d,1H),10.30(s,1H),12.09(br s,1H)。

Compound 253

3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyridazin-3-yl) propanamide

Compound 253 was synthesized by method a1 in 43% yield in THF using the acids SM-XXVI and 3-aminopyridazine as starting materials in an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.62(m,16H),2.80-2.96(m,2H),7.05-7.15(m,3H),7.25-7.29(m,1H),7.66(dd,1H),8.32(d,1H),8.95(d,1H),11.13(s,1H)。

Compound 254

3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (pyridazin-3-yl) propanamide

Compound 254 was synthesized from compound 253 by method B in quantitative yield over a 6 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.34-2.70(m,13H),2.80-2.99(m,3H),7.03-7.15(m,3H),7.23-7.30(m,1H),7.56(s,1H),7.65(dd,1H),8.31(d,1H),8.93(d,1H),10.95(br s,1H),11.07(s,1H)。

Compound 255

3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (pyridazin-3-yl) propionamide

Compound 255 was synthesized by method C from compound 254 in a reaction time of 1 hour in 57% yield.

¹H-NMR(400MHz,DMSO-d₆):1.12(s,3H),1.38-2.63(m,13H),2.80-2.99(m,3H),7.03-7.15(m,3H),7.23-7.30(m,1H),7.41(s,1H),7.66(dd,1H),8.33(d,1H),8.95(d,1H),11.16(s,1H),12.13(br s,1H)。

Compound 256

N- (6-fluoropyridin-2-yl) -3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 256 was synthesized by method a1 in 92% yield in THF using the acid SM-XXVI and 2-amino-6-fluoropyridine as starting materials in a reaction time of 4 hours.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.47(m,16H),2.80-2.95(m,2H),6.83(dd,1H),7.05-7.15(m,3H),7.26-7.28(m,1H),7.91-7.97(m,1H),8.00-8.03(m,1H),10.69(s,1H)。

Compound 257 (Novak)

N- (6-Fluoropyridin-2-yl) -3- ((13S,15S, Z) -16- (Hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 257 was synthesized from compound 256 by method B in a2 hour reaction time with a yield of 46% after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.34-2.60(m,13H),2.80-2.99(m,3H),6.81(dd,1H),7.03-7.15(m,3H),7.23-7.30(m,1H),7.58(s,1H),7.88-7.97(m,1H),7.98-8.03(m,1H),10.69(s,1H),10.96(br s,1H)。

Compound 258

N- (6-Fluoropyridin-2-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 258 was synthesized by method C from compound 257 in a reaction time of 1.5 hours, with a yield of 29% after chromatographic purification.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.36-2.49(m,13H),2.75-2.99(m,3H),6.83(dd,1H),7.03-7.19(m,3H),7.25-7.33(m,1H),7.39(s,1H),7.90-7.99(m,1H),8.00-8.04(m,1H),10.72(s,1H),12.12(br s,1H)。

Compound 259

N- (3, 5-difluoropyridin-2-yl) -3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 259 was synthesized by method a1 in 90% yield in THF during an overnight reaction time using the acid SM-XXVI and 2-amino-3, 5-difluoropyridine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.47(m,16H),2.80-2.94(m,2H),7.05-7.15(m,3H),7.26-7.28(m,1H)，7.98-8.03(m,1H)，8.34-8.35(m,1H),10.31(s,1H)。

Compound 260

N- (3, 5-Difluoropyridin-2-yl) -3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 260 was synthesized by method B from compound 259 in quantitative yield over a 4 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.62(m,13H),2.80-2.99(m,3H),7.03-7.15(m,3H),7.23-7.30(m,1H),7.55(s,1H),7.95-8.04(m,1H),8.32(d,1H),10.26(s,1H),10.98(br s,1H)。

Compound 261

N- (3, 5-Difluoropyridin-2-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 261 was synthesized by method C from compound 260 over a reaction time of 1 hour in 66% yield.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.36-2.50(m,13H),2.80-2.99(m,3H),7.03-7.15(m,3H),7.25-7.30(m,1H),7.44(s,1H),7.95-8.05(m,1H),8.34(d,1H),10.35(s,1H),12.14(br s,1H)。

Compound 262

N- (3-fluoropyridin-2-yl) -3- ((13S,15R) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 262 was synthesized by method a1 in 88% yield in THF using the acids SM-XXVI and 2-amino-3-fluoropyridine as starting materials in an overnight reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.30-2.47(m,16H),2.81-2.96(m,2H),7.05-7.16(m,3H),7.26-7.28(m,1H),7.30-7.37(m,1H),7.73-7.79(m,1H),8.23-8.25(m,1H),10.27(s,1H)。

Compound 263

N- (3-fluoropyridin-2-yl) -3- ((13S,15S, Z) -16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) propanamide

Compound 263 was synthesized by method B from compound 262 in quantitative yield over a 5 hour reaction time.

1H-NMR(400MHz,DMSO-d₆):1.00(s,3H),1.34-2.65(m,13H),2.80-2.99(m,3H),7.03-7.15(m,3H),7.20-7.30(m,1H),7.31-7.36(m,1H),7.57(s,1H),7.70-7.78(m,1H),8.20-8.24(m,1H),10.30(s,1H),11.01(br s,1H)。

Compound 264

N- (3-Fluoropyridin-2-yl) -3- ((8aS,12S) -8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) propanamide

Compound 264 was synthesized by method C from compound 263 in a reaction time of 1 hour with a yield of 40%.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.39-2.50(m,13H),2.80-2.99(m,3H),7.03-7.15(m,3H),7.25-7.30(m,1H),7.31-7.36(m,1H),7.45(s,1H),7.73-7.79(m,1H),8.22-8.26(m,1H),10.32(s,1H),12.13(br s,1H)。

Compound 265

3- ((13S,15R) -3-chloro-13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (3-fluoropyridin-2-yl) propanamide

Compound 265 was synthesized by method a1 in 81% yield in THF during an overnight reaction time using the acid SM-XVII and 2-amino-3-fluoropyridine as starting materials.

¹H-NMR(400MHz,DMSO-d₆):0.98(s,3H),1.30-2.47(m,16H),2.81-2.94(m,2H),7.15-7.16(m,2H),7.28-7.30m,1H),7.32-7.36(m,1H),7.73-7.79(m,1H),8.23-8.25(d,1H),10.27(s,1H)。

Compound 266

3- ((13S,15S, Z) -3-chloro-16- (hydroxymethylene) -13-methyl-17-oxo-7, 8,9,11,12,13,14,15,16, 17-decahydro-6H-cyclopenta [ a ] phenanthren-15-yl) -N- (3-fluoropyridin-2-yl) propanamide

Compound 266 was synthesized by method B from compound 265 in quantitative yield over a 4 hour reaction time.

¹H-NMR(400MHz,DMSO-d₆):0.99(s,3H),1.34-2.60(m,13H),2.80-2.99(m,3H),7.10-7.23(m,2H),7.25-7.35(m,2H),7.59(s,1H),7.70-7.79(m,1H),8.20-8.25(m,1H),10.34(br s,1H),11.01(br s,1H)。

Compound 267

3- ((8aS,12S) -4-chloro-8 a-methyl-1, 2,6b,7,8,8a,10,12,12a,12 b-decahydronaphthalene [2 ', 1': 4,5] indeno [1,2-c ] pyrazol-12-yl) -N- (3-fluoropyridin-2-yl) propanamide

Compound 267 was synthesized by method C from compound 266 in a reaction time of 1 hour with a yield of 58%.

¹H-NMR(400MHz,DMSO-d₆):1.11(s,3H),1.34-2.50(m,13H),2.80-2.99(m,3H),7.11-7.22(m,2H),7.25-7.37(m,2H),7.44(s,1H),7.70-7.79(m,1H),8.23-8.26(m,1H),10.32(s,1H),12.13(br s,1H)。

Pharmacological experiments

The following experiments are provided to demonstrate the invention in an illustrative manner and should not be construed as limiting the scope of the invention. Furthermore, the concentrations of the compounds in the assay are exemplary and should not be considered limiting. Pharmaceutically relevant concentrations can be defined by methods known in the art by those skilled in the art.

Inhibition of 17 beta-hydroxysteroid dehydrogenase type 1 enzyme

Production and isolation of 17 β -HSD 1: recombinant baculoviruses were generated by the "Bac to Bac expression system" (Invitrogen). Recombinant bacmid (bacmid) was transfected into Sd9 insect cells using "Cellfectin Reagent" (Invitrogen). Harvesting the cells after 60 hours; according to Puranen, t.j., Poutanen, m.h., Peltoketo, h.e., Vihko, p.t. and Vihko, R.K (1994) Site-directed mutagenesis of the reactive active Site of human 17 β -hydroxysteroid dehydrogenase type 1 (Site-directed mutagenesis of the putative active Site of 17 β -hydroxysteroid dehydrogenase type 1), biochem.j.304: 289-293 to isolate microsomal fractions. Aliquots were stored frozen until enzyme activity was measured.

Assay-inhibition of recombinant human 17 β -HSD 1: recombinant protein (1. mu.g/ml) was reacted with 30nM estrone (including 800000 cpm/ml) in KH2PO4 pH 7.4 at 20mM in the presence of potent inhibitors (potential inhibitors) at concentrations of 1. mu.M or 0.1. mu.M³H-estrone) and 1mM NADPH were incubated at Room Temperature (RT) for 30 minutes. Inhibitor stock solutions were prepared in DMSO. The final concentration of DMSO in all samples was adjusted to 1%. The enzyme reaction was stopped by the addition of 10% trichloroacetic acid (final concentration). The samples were centrifuged in a microtiter plate at 4000rpm for 10 minutes. The supernatant was applied to a Waters Symmetry C18 column equipped with a Waters Sentry Guard column for reverse phase HPLC. An isocratic HPLC run was performed at room temperature at a flow rate of 1ml/min with acetonitrile: water 48:52 as the running solvent. The radioactivity in the eluate was monitored by scintillation analyzer. The total radioactivity of estrone and estradiol in each sample was determined and the percent conversion of estrone to estradiol was calculated according to the following formula:

% conversion 100x { (estradiol cpm in inhibitor-containing samples) } based on

[ (estrone cpm in the inhibitor containing sample) + (estradiol cpm in the inhibitor containing sample) ] } {

{ [ (estradiol cpm in samples without inhibitor) } based { (based on the total amount of estradiol in the sample)

[ (estrone cpm in the sample without inhibitor) + (estradiol in the sample without inhibitor) cpm ] }.

Percent inhibition was calculated as follows: % inhibition is 100-% conversion.

The percent inhibition values for the exemplary compounds were determined and the results are summarized in table 2.

Inhibition of 17 beta-hydroxysteroid dehydrogenase type 2 enzyme

Production and isolation of 17 β -HSD 2: similar to 17 β -HSD1, recombinant baculovirus was generated by the "Bac to Bac expression System" (Invitrogen). Recombinant bacmid were transfected into Sd9 insect cells using "Cellfectin Reagent" (Invitrogen). After 60 hours the cells were harvested and the supernatant was separated by the following protocol:

the cells were dissolved in 40ml of A buffer (40mM TRIS, pH8.0, 20% glycerol, 20. mu.M NAD, 0.4mM PMSF, 150mM NaCl, 0.5% dodecyl-. beta. -maltoside + protease inhibitor cocktail)

Cells are sonicated

Incubation of the lysate on ice for 15 min

Centrifugation of lysate at 5000rpm for 15 min, +4 deg.C

Centrifugation of the supernatant at 180000 g for 30 min, +4 deg.C

Dissolving the pellet in 8ml of A buffer

Removal of the non-suspended material by centrifugation at 5000rpm at +4 ℃ for 15 minutes

The clarified supernatant was divided into 100 μ l aliquots and stored frozen until enzyme activity was determined.

The amount of 17 β -HSD2 was analyzed by immunoblotting and the total protein concentration of each extract batch was determined.

Assay-inhibition of recombinant human 17 β -HSD 2: recombinant protein (4. mu.g/ml) was incubated with 50nM estradiol (including 800000 cpm/ml) in 20mM KH2PO4 pH 8.5 in the presence of potent inhibitors at concentrations of 1. mu.M or 0.1. mu.M³H-estradiol) and 1mM NADH were incubated for 30 minutes at room temperature. Inhibitor stock solutions were prepared in DMSO. The final concentration of DMSO in all samples was adjusted to 1%. The enzyme reaction was stopped by the addition of 10% trichloroacetic acid (final concentration). The samples were centrifuged in a microtiter plate at 4000rpm for 10 minutes. The supernatant was applied to a Waters Symmetry C18 column equipped with a Waters Sentry Guard column for reverse phase HPLC. An isocratic HPLC run was performed at room temperature at a flow rate of 1ml/min with acetonitrile: water 48:52 as the running solvent. The radioactivity in the eluate was monitored by scintillation analyzer. The total radioactivity of estrone and estradiol in each sample was determined and the percent conversion of estradiol to estrone was calculated according to the following formula:

% conversion 100x { (estrone cpm in inhibitor-containing samples) { ({) } in inhibitor-containing samples) } in { (

[ (estradiol cpm in inhibitor-containing samples) + (estrone cpm in inhibitor-containing samples) ] }

/{ [ (estrone cpm in samples without inhibitor) } based on the presence of inhibitors

[ (estradiol cpm in the sample without inhibitor) + (estrone cpm in the sample without inhibitor) ] }.

Percent inhibition was calculated as follows: % inhibition is 100-% conversion.

The percent inhibition values for the exemplary compounds were determined and the results are summarized in table 2.

Inhibition of estrone conversion to estradiol in rabbit homogenate

The assay is based on an enzymatic reaction in which HSD1 enzyme expressed in rabbit placental tissue converts its natural substance, estrone (E1), to estradiol (E2) in the presence of the cofactor β -NADPH.

Homogenization of rabbit placental tissue: a piece of frozen tissue was weighed into a Precellys ck28 bead tube. Buffer solution (20mM KH) was added at a ratio of 1:2 (e.g., 300mg of tissue: 600. mu.l of reaction buffer solution)₂PO₄And 1mM EDTA, pH 7, 4). The bead tubes were inserted into a homogenizer and homogenized at 6000rpm for 2 × 30 seconds. Centrifuge at 2600rpm for 5 minutes at +4 ℃ and collect the supernatant. Aliquots of the homogenate were stored at-80 ℃.

Analysis-inhibition of E1 conversion to E2 in rabbit placental tissues: in a medium comprising an appropriate amount of a rabbit placenta homogenate, a cofactor (1 mM. beta. -NADPH), a substrate (30nM estrone), a labeled substrate (5nM, alpha., [ 2] as a tracer³H]-estrone), andbuffered solutions of potent inhibitors (20mM KH) at concentrations of 1. mu.M or 0.1. mu.M₂PO₄And 1mM EDTA, pH 7, 4). Inhibitor stock solutions were prepared in DMSO. The final concentration of DMSO in all samples was adjusted to 1%. During the 30 min incubation, part of the estrone was converted to estradiol. The reaction was stopped by lowering the pH to 1 with 10% trichloroacetic acid (TCA). The substrate and conversion products were analyzed by HPLC and scintillation counter analyzer. The total radioactivity of estrone and estradiol in each sample was determined and the percent conversion of estrone to estradiol was calculated according to the following formula:

% conversion 100x { (estradiol cpm in inhibitor-containing samples) } based on

[ (estrone cpm in inhibitor-containing samples) + (estradiol cpm in inhibitor-containing samples) ] }

/{ (estradiol cpm in samples without inhibitor) } based on

[ (estrone cpm in the sample without inhibitor) + (estradiol cpm in the sample without inhibitor) ] }.

Percent inhibition was calculated as follows: % inhibition was 100-% conversion. The percent inhibition values for the exemplary compounds were determined and the results are summarized in table 2.

Metabolic stability analysis

Stock solutions of compounds of the invention were prepared in DMSO. The final concentration of DMSO in all samples was adjusted to 1%. The in vitro metabolic stability of the compounds of the invention was determined for the exemplified compounds using human hepatocyte incubation; study compounds at a concentration of 1 μ M were incubated at 37 ℃ for 0, 10, 20, 40 and 60 minutes. Samples were collected at all time points and compounds were detected by LC-MS/MS analysis. The percentage of compound remaining was calculated by comparing the peak area of the parent compound at each time point to the time zero. The in vitro metabolic stability was determined as half-life (T1/2), which was determined by regression analysis of the percentage of maternal disappearance versus time curve. The results are summarized in table 2.

Results of pharmacological experiments

TABLE 2

Utility of the invention

The compounds of the present invention exhibit selective inhibitory potential against the 17 β -HSD1 enzyme and little or no inhibitory activity against the 17 β -HSD2 enzyme and are therefore useful in the treatment of steroid hormone dependent diseases or conditions, particularly in the treatment and prevention of several diseases and conditions including, but not limited to: breast cancer, prostate cancer, ovarian cancer, uterine cancer, endometrial hyperplasia, endometriosis, uterine fibroids, adenomyosis, polycystic ovary syndrome, dysmenorrhea, menorrhagia, uterine bleeding, infertility, prostadynia, benign prostatic hyperplasia, urinary dysfunction, lower urinary tract symptoms, chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), Systemic Lupus Erythematosus (SLE), multiple sclerosis, obesity, rheumatoid arthritis, Chronic Obstructive Pulmonary Disease (COPD), lung cancer, colon cancer, tissue wounds, skin wrinkles and cataracts.

In addition, the compounds of the present invention may be used to treat diseases and conditions associated with elevated estradiol levels and which may be prevented, treated and/or ameliorated by 17 β -HSD1 enzyme inhibitors.

As used herein, "treating or preventing" includes preventing or preventing as well as reducing the risk of acquiring the disorder or disease in an individual, or alleviating, ameliorating, eliminating or curing the disorder once confirmed.

The compounds of the invention may be administered in an effective amount in a dosage range of about 0.1 μ g/kg to about 300mg/kg, preferably 1.0 μ g/kg to 10mg/kg body weight. The compounds of the invention may be administered in a single daily dose, or their total daily dose may be administered in divided doses 2, 3 or 4 times daily.

An "effective amount" refers to the amount of a compound that confers a therapeutic effect on the subject being treated. The therapeutic effect may be objective (i.e. measurable by some experiment or marker) or subjective (i.e. the subject gives an indication or sensation of the effect). Such treatment does not necessarily completely ameliorate the condition of the disease. In addition, such treatment or prevention may be used in combination with other conventional treatments to alleviate conditions known to those skilled in the art.

The compounds of the present invention are most preferably used alone or in combination (i.e. administered simultaneously, separately or sequentially with the other active ingredients). The compounds of the present invention may be administered by various routes, for example, orally, parenterally, subcutaneously, intravenously, intraarticularly, intrathecally, intramuscularly, intraperitoneally, and by intradermal injection, as well as by the transdermal, rectal, buccal, oromucosal, nasal, ocular routes and by inhalation and by implantation.

The compounds may be formulated into suitable compositions; suitable administration forms include, for example, solutions, dispersions, suspensions, powders, capsules, tablets, pills, controlled release capsules, controlled release tablets and controlled release pills. In addition to the pharmacologically active compound, the pharmaceutical compositions of the compounds may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compound into preparations which can be used pharmaceutically.

Furthermore, the compounds of formula (I) may be used as synthetic intermediates for the preparation of other compounds, in particular other pharmaceutically active ingredients, which are obtainable from the compounds of formula (I), for example by introducing substituents or modifications of functional groups.

It is obvious to a person skilled in the art that with the advancement of technology, the inventive concept may be implemented in various ways. The invention and its embodiments are not limited to the examples described above but may vary within the scope of the claims.