WO2019192533A1

WO2019192533A1 - Estrogen receptor degrading agent for treating breast cancer

Info

Publication number: WO2019192533A1
Application number: PCT/CN2019/081314
Authority: WO
Inventors: 朱程刚; 杨铉; 徐良亮; 张朝春; 郭玉函
Original assignee: 深圳福沃药业有限公司
Priority date: 2018-04-04
Filing date: 2019-04-03
Publication date: 2019-10-10
Also published as: CN110343101A; CN111770924A; CN111770924B; CN110343101B

Abstract

The present invention relates to certain novel compounds or pharmaceutically acceptable salts thereof, wherein same have an anticancer activity and are therefore potentially useful in methods for treating the human body or animal bodies. The present invention also relates to methods for manufacturing the compounds, to pharmaceutical compositions comprising same and to the uses of same in therapeutic methods, for example, for manufacturing drugs for the prevention or treatment of cancers in warm-blooded animals such as humans, including for the prevention or treatment of cancers. The present invention also relates to compounds that are modulators for the selective down-regulation of estrogen receptors.

Description

Estrogen receptor degrading agent for treating breast cancer

Technical field

The present invention relates to certain novel compounds or pharmaceutically acceptable salts thereof which have anticancer activity and are therefore potentially useful in the treatment of the human or animal body. The invention also relates to methods for the manufacture of said compounds, pharmaceutical compositions containing them and their use in methods of treatment, for example for the manufacture of a medicament for the prevention or treatment of cancer in warm-blooded animals such as humans, including Used to prevent or treat cancer.

The invention also relates to compounds which are modulators of selective down-regulation of estrogen receptors.

Background technique

Estrogen receptor alpha (ERα, ESR1, NR3A) and estrogen receptor beta (ERβ, ESR2, NR3b) are steroid hormone receptors, and these steroid hormone receptors are members of a large nuclear receptor family. The structure is similar to all nuclear receptors, and ERα is composed of six functional domains (named AF) (Dahlman-Wright et al., Pharmacol. Rev., 2006, 58:773-781) and is classified as a ligand-dependent transcription factor because the complex binds to the estrogen after its association with the specific ligand (female sex steroid hormone 17b estradiol (E2)) The receptor element (ERE) genomic sequence, and interacts with a co-regulatory factor to regulate transcription of the target gene. The ERa gene is located on 6q25.1 and encodes the 595AA protein, and due to alternative splicing and translation initiation sites, multiple isoforms can be generated. In addition to the DNA binding domain (domain C) and the ligand binding domain (domain E), the receptor also comprises an N-terminal (A/B) domain, a hinge (D) domain linking the C and E domains, And a C-terminal extension (F domain). Although the C and E domains of ERa and ERb are fairly conserved (96% and 55% amino acid identity, respectively), the A/B, D and F domains are poorly conserved (less than 30% amino acid identity). Both receptors are involved in the regulation and development of the female reproductive tract and, in addition, play a role in the central nervous system, the cardiovascular system, and in bone metabolism. The genomic action of the ER occurs in the nucleus of the cell, at which point the receptor binds to the ERE either directly (direct activation or classical pathway) or indirectly (indirect activation or non-canonical pathway). In the absence of a ligand, the ER is associated with the heat shock proteins Hsp90 and Hsp70, and the associated chaperone machinery stabilizes the ligand binding domain (LBD) such that it is accessible to the ligand. Dissociation of the liganded ER from the heat shock protein results in a conformational change in the receptor, allowing dimerization, DNA binding, interaction with coactivators or co-repressors, and regulation of target gene expression. In the non-canonical pathway, AP-1 and Sp-1 are alternative regulatory DNA sequences used by the two isoforms of the receptor to regulate gene expression. In this example, ER does not interact directly with DNA, but by association with other DNA-binding transcription factors such as c-Jun or c-Fos (Kushner et al., Pure Applied Chemistry) ) 2003, 75: 1757-1769). The precise mechanism by which ER affects gene transcription is poorly understood, but appears to be mediated by multiple nuclear factors recruited by DNA-binding receptors. The recruitment of co-regulatory factors is mainly mediated by two protein surface AF2 and AF1, and AF2 and AF1 are located in the E-domain and A/B domain, respectively. AF1 is regulated by growth factors and its activity depends on the cell and promoter environment, whereas AF2 is completely dependent on ligand binding for activity. Although the two domains can function independently, the maximum ER transcriptional activity is through two domains (Tzukerman et al., Mol. Endocrinology, 1994, 8: 21- 30) The synergistic interaction is achieved. Although ERs are considered to be transcription factors, they can also function through non-genomic mechanisms, as evidenced by the rapid ER action in tissues in a time scale after E2 administration, which is considered too important for genomic effects. fast. Whether the receptor responsible for the rapid action of estrogen is the same nuclear ER or a different G-protein coupled steroid receptor remains unclear (Warner et al., Steroids, 2006, 71: 91-95), but an increasing number of E2 induction pathways have been identified, such as the MAPK/ERK pathway and activation of endothelial nitric oxide synthase and the PI3K/Akt pathway. In addition to the ligand-dependent pathway, ERα has also been shown to have ligand-independent activity through AF-1, through growth factor signaling such as insulin-like growth factor 1 (IGF-1-1) and epidermal growth factor (EGF), AF-1 It has been associated with stimulation of MAPK. The activity of AF-1 is dependent on the phosphorylation of Ser118 and an example of a cross talk between ER and growth factor signaling is phosphorylation of Ser118 by MAPK in response to growth factors such as IGF-1 and EGF (Kato ) et al., Science, 1995, 270: 1491-1494).

A large number of structurally different compounds have been shown to bind to the ER. Some compounds such as endogenous ligand E2 act as receptor agonists, while others competitively inhibit E2 binding and act as receptor antagonists. These compounds can be divided into two categories depending on their functional effects. Selective estrogen receptor modulators (SERMs) such as tamoxifen (the tamoxifen) have the ability to act as both receptor agonists and antagonists, depending on cell and promoter conditions along with ER isotype targeting . For example, tamoxifen acts as an antagonist in breast cancer but as a partial agonist in bone, cardiovascular system and uterus. All SERMs appear to act as AF2 antagonists and derive their partial agonist characteristics by AF1. The second group, with fulvestrant as an example, was classified as a complete antagonist and induced a unique conformational change in the compound-bound ligand binding domain (LBD) via complete inhibition of the AF1 and AF2 domains. (It causes the interaction between helix 12 and the rest of the LBD to be completely eliminated, thereby blocking recruitment of cofactors) to block estrogenic activity (Wakeling et al., Cancer Res., 1991). , 51:3867-3873; Pike et al., Structure, 2001, 9: 145-153).

The intracellular level of ERα is down-regulated by the ubiquitin/protein body (Ub/26S) pathway in the presence of E2. The polyubiquitination of the liganded ERa is catalyzed by at least three enzymes; the ubiquitin activated by the ubiquitin-activating enzyme E1 is conjugated to the lysine residue via E2 via the E3 ubiquitin ligase binding isopeptide. And then the polyubiquitinated ERa is directed to the protein body for degradation. Although ER-dependent transcriptional regulation and proteo-mediated degradation of ER are linked (Lonard et al., Mol. Cell, 2000, 5: 939-948), transcription It is not required for the degradation of ERa itself, and the assembly of the transcription initiation complex is sufficient to target ERa for the degradation of the nuclear proteasome. This E2-induced degradation process is thought to be necessary for its ability to rapidly activate transcription in response to requirements for cell proliferation, differentiation and metabolism (Stenoien et al., Molecular Cell Biology). (Mol. Cell Biol.), 2001, 21: 4404-4412). Fulvestrant is also classified as a subset of selective estrogen receptor down-regulators (SERDs), antagonists, which can also induce rapid down-regulation of ERa via the 26S proteasome pathway. In contrast, SERM such as tamoxifen can increase ERa levels, although the effect on transcription is similar to that seen for SERD. About 70% of breast cancers express ER and/or progesterone receptors, meaning that these tumor cells are dependent on hormones in terms of growth. Other cancers such as ovarian cancer and endometrial cancer are also thought to be dependent on ERa signaling in terms of growth. Therapies for such patients can inhibit ER signaling by antagonizing ligand binding to ER, such as tamoxifen, which is used to treat early and late ER positive in both premenopausal and postmenopausal settings. Breast cancer); antagonizes and down-regulates ERα, such as fulvestrant, which is used to treat breast cancer in women, although it has been treated with tamoxifen or aromatase inhibitors, but it still progresses; Hormone synthesis, such as aromatase inhibitors, is used to treat early and late ER-positive breast cancer. Although these therapies have a very positive impact on breast cancer treatment, a significant number of patients with tumor-expressing ER demonstrate de novo resistance to the presence of ER therapies or resistance to the development of these therapies over time. A number of different mechanisms have been described to explain resistance to first tamoxifen treatment, which primarily involves the conversion of tamoxifen from acting as an antagonist to acting as an agonist, which is a lower affinity through certain cofactors. Binding to the tamoxifen-ERα complex that is off-set by overexpression of these cofactors, or through the formation of a second site that promotes tamoxifen-ERα complexation The interaction of a substance with a cofactor that does not normally bind to the complex. The resulting resistance due to overgrowth of cells expressing a specific cofactor that drives tamoxifen-ERα activity can therefore occur. There is also the possibility that other growth factor signaling pathways directly activate the ER receptor or coactivator to drive cell proliferation independent of ligand signaling.

Recently, mutations in ESR1 have been identified as potential resistance mechanisms in frequency from 17%-25% in metastatic ER-positive patient-derived tumor samples and patient-derived xenograft models (PDX). These mutations are predominantly, but not exclusively, in the ligand binding domain that results in a mutant functional protein; examples of amino acid changes include Ser463Pro, Val543Glu, Leu536Arg, Tyr537Ser, Tyr537Asn, and Asp538Gly, wherein the changes at amino acids 537 and 538 constitute Most of the changes currently described. These mutations were not previously detected in primary breast genomic samples characterized by the Cancer Genome Atlas database. In the 390 primary breast cancer samples positive for ER expression, none of the single mutations detected in ESR1 (Cancer Genome Atlas Network, 2012 Nature, 490: 61-70). This ligand binding domain mutation is thought to have resistance to development in response to aromatase inhibitor endocrine therapy, as these mutant receptors exhibit substantial transcriptional activity in the absence of estradiol. The crystal structure of the ER mutated at amino acids 537 and 538 shows that the two mutants favor the agonist conformation of the ER by displacing the position of the helix 12 to allow coactivator recruitment and thereby mimic agonist activated wild-type ER. Published data have shown that endocrine therapies such as tamoxifen and fulvestrant can still bind to ER mutants and to some extent inhibit transcriptional activation, and fulvestrant can degrade Try537Ser, but higher doses may be required Complete receptor inhibition (Toy et al., Nat. Genetics, 2013, 45: 1439-1445; Robinson et al., Natural Genetics, 2013, 45: 144601451). Li, S (Li, S.) et al., Cell Rep., 4, 1116-1130 (2013)). It is therefore feasible that certain compounds of formula (I) or pharmaceutically acceptable salts thereof will be capable of downregulating and antagonizing mutant ER, although it is unknown at this time whether the ESR1 mutation is associated with altered clinical outcome.

Regardless of which resistance mechanism or combination mechanism of resistance mechanisms occurs, many still rely on ER-dependent activity, and removal of the receptor by the SERD mechanism provides the best way to remove ERa receptors from cells. Fulvestrant is currently the only approved product for clinical use by SERD, and despite its mechanismal properties, the pharmacological properties of the drug have limited efficacy due to the current monthly 500 mg dose limit, which results in in vitro mammary gland Complete down-regulation of receptors seen in cell line experiments is less than 50% of turnover in recipients in patient samples (Wardell et al., Biochem. Pharm., 2011, 82: 122-130). Therefore, there is a need for new ER targeting agents that have the desired pharmaceutical properties and SERD mechanisms to provide enhanced benefits in the context of early, metastatic, and acquired resistance.

Summary of the invention

The compounds of the present invention have been found to have potent anti-tumor activity and are useful for inhibiting uncontrolled cell proliferation caused by malignant diseases. These compounds of the invention provide anti-tumor effects by acting as a SERD (as a minimal).

According to another aspect of the invention there is provided a compound of formula I and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

among them:

Y ¹ is CR ^b or N;

Y ² is -(CH ₂ )-, -(CH ₂ CH ₂ )- or NR ^a ;

Y ³ is NR ^a or C(R ^b ) ₂ ;

Wherein one of Y ¹ , Y ² and Y ³ is N or NR ^a ;

R ^{a is} selected from the group consisting of H, C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, propargyl, C ₃ -C ₆ cycloalkyl and C ₃ -C ₆ heterocyclic, optionally selected Substituting one or more groups independently selected from the group consisting of F, Cl, Br, I, CN, OH, OCH ₃ and SO ₂ CH ₃ ;

R ^{b is} independently selected from H, -O(C ₁ -C ₃ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, propargyl, -(C ₁ -C ₆ alkanediyl) a -(C ₃ -C ₆ cycloalkyl) group, a C ₃ -C ₆ cycloalkyl group, and a C ₃ -C ₆ heterocyclic group, the group optionally substituted with one or more groups independently selected from the group consisting of: F, Cl, Br, I, CN, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, OH, OCH ₃ and SO ₂ CH ₃ ;

Z ^{1 is} selected from the group consisting of CR ^a R ^b , C(O) and a bond;

Cy is selected from the group consisting of C ₆ -C ₂₀ aryldiyl, C ₃ -C ₁₂ carbocyclic diyl, C ₂ -C ₂₀ heterocyclic diyl and C ₁ -C ₂₀ heteroaryldiyl;

Z ^{2 is} selected from the group consisting of O, S, NR ^a , C ₁ -C ₆ alkanediyl, C ₁ -C ₆ fluoroalkanediyl, O-(C ₁ -C ₆ alkanediyl), O-(C ₁ -C ₆ fluoroalkanediyl), C(O) and a bond;

R ¹ , R ² , R ³ and R ^{4 are} independently selected from the group consisting of H, F, Cl, Br, I, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH ( CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ OP(O)(OH) ₂ , -CH ₂ F, -CHF ₂ , -CH ₂ NH ₂ , -CH ₂ NHSO ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH(CH ₃ )CN, -C(CH ₃ ) ₂ CN, - CH ₂ CN, -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CONHCH ₂ CH ₃ , -CONHCH(CH ₃ ) ₂ , -CON(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -N( CH ₃ )COCH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , -NO ₂ , =O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ OCH ₃ , -OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OP(O) (OH) ₂ , -S(O) ₂ N(CH ₃ ) ₂ , -SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₃ H, cyclopropyl, cyclopropyl amide group, Cyclobutyl, Oxetane, azetidinyl, (1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, Azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, Olinone-methanone and morpholino;

R ^{5 is} selected from the group consisting of H, C ₁ -C ₉ alkyl, C ₃ -C ₉ cycloalkyl, C ₃ -C ₉ heterocyclic, C ₆ -C ₉ aryl, C ₆ -C ₉ heteroaryl, - (C ₁ -C ₆ alkanediyl)-(C ₃ -C ₉ cycloalkyl), -(C ₁ -C ₆ alkanediyl)-(C ₃ -C ₉ heterocyclic), C(O)R ^b And C(O)NR ^a , SO ₂ R ^a and SO ₂ NR ^a optionally substituted with one or more halogens, CN, OR ^a , N(R ^a ) ₂ , C ₁ -C ₉ alkyl, C _3- C ₉ cycloalkyl, C ₃ -C ₉ heterocyclic, C ₆ -C ₉ aryl, C ₆ -C ₉ heteroaryl, C(O)R ^b , C(O)NR ^a , SO ₂ R ^a and SO ₂ NR ^a ;

R ^{6 is} selected from the group consisting of H, F, Cl, Br, I, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ OP(O)(OH) ₂ , -CH ₂ F, -CHF ₂ , -CH ₂ NH ₂ , -CH ₂ NHSO ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ N (CH ₃ ) ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, -CH(CH ₃ )CN, -C(CH ₃ ) ₂ CN, -CH ₂ CN , -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CONHCH ₂ CH ₃ , -CONHCH (CH ₃ ) ₂ , -CON(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -N(CH ₃ ) COCH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , -NO ₂ , = O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ OCH ₃ , -OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OP(O)(OH) ₂ , -S(O) ₂ N(CH ₃ ) ₂ , -SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₃ H, cyclopropyl, cyclopropyl amide group, cyclobutyl Oxygen heterocycle Alkyl, azetidinyl, (1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin Alkyl-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methyl Ketone and morpholino;

Wherein the alkanediyl, fluoroalkanediyl, aryldiyl, carbocyclicdiyl, heterocyclic diyl and heteroaryldiyl are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ OP ( O) (OH) ₂ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, -CH(CH ₃ )CN, -C( CH ₃ ) ₂ CN, -CH ₂ CN, -CH ₂ NH ₂ , -CH ₂ NHSO ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CON(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -N(CH ₃ )COCH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , -NO ₂ , =O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ OCH ₃ ,- OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OP(O)(OH) ₂ , -S(O) ₂ N(CH ₃ ) ₂ , -SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₃ H, cyclopropyl, cyclopropyl amide group, cyclobutyl, oxetanyl, azetidine , (1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, Benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone and morpholino.

According to another aspect of the invention, there is provided a compound of Formula I and stereoisomers, tautomers, or a pharmaceutically acceptable salt thereof, wherein Y ¹ is N and Y ³ is C (R ^b) _2.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ^{a is} selected from the group consisting of H, C ₁ -C ₆ alkyl and C ₂ -C ₈ Alkenyl, said group optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, CN and OH.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ^{a is} selected from H and C ₁ -C ₆ alkyl, said group Optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, CN, and OH.

According to another aspect of the invention, there is provided a compound of Formula I and stereoisomers thereof, the tautomers thereof or a pharmaceutically acceptable salt thereof, wherein R ^a is H.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ^{b is} independently selected from H, -O(C ₁ -C ₃ alkyl), C ₁ -C ₆ alkyl, C ₂ -C ₈ alkenyl, propargyl, -(C ₁ -C ₆ alkanediyl)-(C ₃ -C ₆ cycloalkyl), said group optionally substituted There are one or more groups independently selected from the group consisting of F, Cl, Br, I, CN, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, OH, OCH ₃ and SO ₂ CH ₃ .

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ^{b is} independently selected from H, -O(C ₁ -C ₃ alkyl), C ₁ -C ₆ alkyl, said group optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I and OH.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ^b is C ₁ -C ₆ alkyl, the group optionally substituted One or more groups independently selected from the group consisting of F, Cl, Br, and I.

According to another aspect of the invention, there is provided a compound of Formula I and stereoisomers, tautomers, or a pharmaceutically acceptable salt thereof, wherein Y ² is - (CH ₂₎ -.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Cy is C ₆ -C ₂₀ aryldiyl or C ₁ -C ₂₀ heteroaryl base.

According to another aspect of the invention there is provided a compound of formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Cy is a C ₆ -C ₂₀ aryldiyl group.

According to another aspect of the invention there is provided a compound of formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Cy is a C ₆ -C ₁₀ aryldiyl group.

According to another aspect of the invention there is provided a compound of formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the C ₆ -C ₂₀ aryldiyl group is a phenyldiyl group.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein said C ₆ -C ₂₀ aryldiyl group is optionally substituted with one or more independent a group selected from the group consisting of F, Cl, Br, I, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ OH , -CH ₂ OCH ₃ , -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ OP(O)(OH) ₂ , -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, -CH(CH ₃ )CN, -C(CH ₃ ) ₂ CN, -CH ₂ CN, -CH ₂ NH ₂ , -CH ₂ NHSO ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CON(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -N(CH ₃ )COCH ₃ , -NHS(O) ₂ CH ₃ ,- N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , -NO ₂ , =O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ OCH ₃ , -OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OP(O)(OH) ₂ , -S(O) ₂ N(CH ₃ ) ₂ , -SCH ₃ , -S(O) ₂ CH ₃ and -S(O) ₃ H.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein said C ₆ -C ₂₀ aryldiyl group is optionally substituted with one or more independent a group selected from the group consisting of F, Cl, Br, I, -CN, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -NO ₂ , =O, -OH, -OCH ₃ , -OCH ₂ CH ₃ and -SCH ₃ .

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein said C ₆ -C ₂₀ aryldiyl group is optionally substituted with one or more independent A group selected from the group consisting of F, Cl, Br, I, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ and -CH ₂ CH ₂ F.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein said C ₆ -C ₂₀ aryldiyl group is optionally substituted with one or more independent A group selected from the group consisting of F, Cl, Br, and I.

According to another aspect of the invention there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the phenyldiyl group is optionally substituted with one or more groups independently selected from the group consisting of: F, Cl, Br and I.

According to another aspect of the invention there is provided a compound of formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the phenyldiyl group is substituted with one or more F.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ^{4 are} independently selected from H, F, Cl , Br, I, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ OP (O)(OH) ₂ , -CH ₂ F, -CHF ₂ , -CH ₂ NH ₂ , -CH ₂ NHSO ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH(CH ₃ )CN, -C(CH ₃ ) ₂ CN, -CH ₂ CN, -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CONHCH ₂ CH ₃ , -CONHCH(CH ₃ ) ₂ , -CON(CH ₃ ) ₂ , -C (CH ₃ ) ₂ CONH ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -N(CH ₃ )COCH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ ) C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , -NO ₂ , =O, -OH, -OCH ₃ , -OCH ₂ CH ₃ ,- OCH ₂ CH ₂ OCH ₃ , -OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OP(O) (OH) ₂ , -S(O) ₂ N(CH ₃ ) ₂ , -SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₃ H, cyclopropyl, cyclobutyl, oxacyclohexane Butane and azetidinyl.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ^{4 are} independently selected from H, F, Cl , Br, I, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH ₂ F, -CHF ₂ , -CH ₂ NH ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CN, - CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CONH ₂ , -CONHCH ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -NO ₂ , -OH, - OCH ₃ , -OCH ₂ CH ₃ , -SCH ₃ , -S(O) ₃ H, cyclopropyl and cyclobutyl.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ^{4 are} independently selected from H, F, Cl , Br, I, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OH, -CH ₂ F, -CHF ₂ , -CH ₂ NH ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CN, -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CONH ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NO ₂ , -OH , -OCH ₃ , -OCH ₂ CH ₃ , -SCH ₃ , cyclopropyl and cyclobutyl.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ^{4 are} independently selected from H, F, Cl , Br, I, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OH, -CH ₂ F, -CHF ₂ , -CH ₂ NH ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CN, -COCH ₃ , -NH ₂ , -NHCH ₃ , -OH, -OCH ₃ , -OCH ₂ CH ₃ , -SCH ₃ .

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ¹ , R ² , R ³ and R ^{4 are} independently selected from H, F, Cl , Br, I, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OH, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -COCH ₃ , - OH, -OCH ₃ , -OCH ₂ CH ₃ .

According to another aspect of the invention, there is provided a compound of Formula I and stereoisomers thereof, the tautomers thereof or a pharmaceutically acceptable salt thereof, ^wherein, R ¹ and R ² is H.

According to another aspect of the invention, there is provided a compound of Formula I and stereoisomers thereof, the tautomers thereof or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² is H.

According to another aspect of the invention, there is provided a compound of Formula I and stereoisomers, tautomers, or a pharmaceutically acceptable salt thereof, wherein R ³ is H and R ⁴ is -CH _3.

According to another aspect of the invention, there is provided a compound of Formula I and stereoisomers thereof, the tautomers thereof or a pharmaceutically acceptable salt thereof, wherein R ³ is -CH _3, and R ⁴ is H.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ^{5 is} selected from the group consisting of H, C ₁ -C ₉ alkyl, C ₃ -C ₉ Cycloalkyl, C ₃ -C ₉ heterocyclic, C ₆ -C ₉ aryl, C ₆ -C ₉ heteroaryl, -(C ₁ -C ₆ alkanediyl)-(C ₃ -C ₉ naphthenic) And -(C ₁ -C ₆ alkanediyl)-(C ₃ -C ₉ heterocycle) optionally substituted with one or more halogens, CN, OR ^a , N(R ^a ) ₂ , C ₁ a -C ₉ alkyl group, a C ₃ -C ₉ cycloalkyl group, a C ₃ -C ₉ heterocyclic ring, a C ₆ -C ₉ aryl group, and a C ₆ -C ₉ heteroaryl group.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ^{5 is} selected from H and C ₁ -C ₉ alkyl, optionally substituted One or more halogens, CN, OR ^a , N(R ^a ) ₂ , C ₁ -C ₉ alkyl, C ₃ -C ₉ cycloalkyl, C ₃ -C ₉ heterocycle, C ₆ -C ₉ aryl And C ₆ -C ₉ heteroaryl.

According to another aspect of the invention, there is provided a compound of Formula I and stereoisomers thereof, the tautomers thereof or a pharmaceutically acceptable salt thereof, wherein R ⁵ is optionally substituted with one or more halogen C ₁ -C ₉ alkoxy base.

According to another aspect of the invention, there is provided a compound of Formula I and stereoisomers thereof, the tautomers thereof or a pharmaceutically acceptable salt thereof, wherein R ⁵ is optionally substituted with one or more halogen C ₁ -C ₆ alkyl base.

According to another aspect of the invention, there is provided a compound of Formula I and stereoisomers thereof, the tautomers thereof or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from H, F, Cl, Br, I, -CN, -CH ₃ , -CF ₃ , -NO ₂ , -OH, -OCH ₃ and -SCH ₃ .

According to another aspect of the invention, there is provided a compound of Formula I and stereoisomers thereof, the tautomers thereof or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from H, F, Cl, Br, I, -CN, -CH ₃ , -CF ₃ , -OH and -OCH ₃ .

According to another aspect of the present invention, there is provided a compound of Formula I and stereoisomers thereof, the tautomers thereof or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from H, F, Cl, Br, I, -CH 3 and - OH.

According to another aspect of the invention, there is provided a compound of Formula I and stereoisomers thereof, the tautomers thereof or a pharmaceutically acceptable salt thereof, wherein R ⁶ is H.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Formula I is Formula Ia:

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Formula I is Formula Ib:

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Formula I is Formula Ic:

among them

R ⁷ is F, Cl, Br, I, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ OP(O)(OH) ₂ , -CH ₂ F, -CHF ₂ , -CH ₂ NH ₂ , -CH ₂ NHSO ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ N (CH ₃ ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH(CH ₃ )CN, -C(CH ₃ ) ₂ CN, -CH ₂ CN, -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CONHCH ₂ CH ₃ , -CONHCH(CH ₃ ) ₂ , -CON(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -N(CH ₃ )COCH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , -NO ₂ , =O, -OH, -OCH ₃ ,- OCH ₂ CH ₃ , -OCH ₂ CH ₂ OCH ₃ , -OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OP(O)(OH) ₂ , -S(O) ₂ N ( CH ₃ ) ₂ , -SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₃ H, cyclopropyl, cyclopropyl amide group, oxetanyl, azetidinyl ,(1- Methyl azetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxybenzene , pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone or morpholino;

n is selected from 0, 1, 2, 3, and 4;

R ⁸ is H or -CH ₃ .

According to another aspect of the present invention, there is provided a compound of Formula I and stereoisomers thereof, the tautomers thereof or a pharmaceutically acceptable salt thereof, wherein R ⁷ is F, Cl, Br, I, -CN, -CH 3, - CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ OP(O)(OH) ₂ , -CH ₂ F, -CHF ₂ , -CH ₂ NH ₂ , -CH ₂ NHSO ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH(CH ₃ )CN, -C(CH ₃ ) ₂ CN, -CH ₂ CN, -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH( OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CONHCH ₂ CH ₃ , -CONHCH(CH ₃ ) ₂ , -CON(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NH ₂ ,- NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -N(CH ₃ )COCH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N (CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , -NO ₂ , =O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ OCH ₃ , -OCH ₂ CH ₂ OH , -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OP(O)(OH) ₂ , -S(O) ₂ N(CH ₃ ) ₂ ,- SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₃ H, cyclopropyl, cyclobutyl, oxetanyl or azetidinyl.

According to another aspect of the present invention, there is provided a compound of Formula I and stereoisomers thereof, the tautomers thereof or a pharmaceutically acceptable salt thereof, wherein R ⁷ is F, Cl, Br, I, -CN, -CH 3, - CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH ₂ F, -CHF ₂ , -CH ₂ NH ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CN, -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CONH ₂ , -CONHCH ₃ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -NO ₂ , -OH, -OCH ₃ , -OCH ₂ CH ₃ , -SCH ₃ , -S(O) ₃ H, cyclopropyl or cyclobutyl.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R ⁷ is F, Cl, Br, I, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OH, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -COCH ₃ , -OH, -OCH ₃ or -OCH ₂ CH ₃ .

According to another aspect of the invention, there is provided a compound of Formula I and stereoisomers, tautomers, or a pharmaceutically acceptable salt thereof, wherein R ⁷ is F, Cl, Br or I.

According to another aspect of the invention, there is provided a compound of Formula I and stereoisomers thereof, the tautomers thereof or a pharmaceutically acceptable salt thereof, wherein R ⁷ is F.

According to another aspect of the invention there is provided a compound of formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein n is selected from 1, 2, 3 and 4.

According to another aspect of the invention there is provided a compound of formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein n is selected from the group consisting of 0, 1, 2 and 3.

According to another aspect of the invention there is provided a compound of formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein n is selected from 1, 2 and 3.

According to another aspect of the invention there is provided a compound of formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein n is selected from the group consisting of 1 and 2.

According to another aspect of the invention there is provided a compound of formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein n is selected from 2 and 3.

According to another aspect of the present invention, there is provided a compound of Formula I, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein n is 2, wherein Formula I is Formula Id:

According to another aspect of the invention there is provided a compound of formula (I) and (II) or a pharmaceutically acceptable salt thereof:

In another aspect of the invention there is provided a compound of formula (I) as defined above.

Compounds of formula (I), (II) have one, two or three chiral centers and the invention encompasses pure chiral forms or mixtures thereof in any ratio. The synthesis of the optically active form can be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of racemic forms. Similarly, the activities mentioned above can be assessed using standard laboratory techniques.

The specific enantiomers or diastereomers of the compounds described herein may be more active than the other enantiomers or diastereomers of the same compound.

According to another aspect of the present invention, there is provided a compound of the formula (I), (II) or a pharmaceutically acceptable salt thereof, which is an enantiomeric excess (ee%) ≥ 95%, ≥ 98% or ≥ 99 % of a single enantiomer. Suitably, the single enantiomer is present in an enantiomeric excess (ee%) > 99%.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the formula (I), (II), which is in an enantiomeric excess (ee%) ≥ 95%, ≥98% or ≥99% of a single enantiomer; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. Suitably, the single enantiomer is present in an enantiomeric excess (ee%) > 99%.

According to another aspect of the present invention, there is provided a compound of the formula (I), (II) or a pharmaceutically acceptable salt thereof, which is a diastereomeric excess (de%) ≥ 95%, ≥ 98% or ≥ 99 % of a single diastereomer. Suitably, the single diastereomer is present in a diastereomeric excess (de%) > 99%.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising a compound of the formula (I), (II), which is diastereomeric excess (de%) ≥ 95%, ≥98% or ≥99% of a single diastereomer; or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. Suitably, the single diastereomer is present in a diastereomeric excess (de%) > 99%.

Some of the compounds of formula (I), (II) may be crystalline and may have more than one crystal form. It will be appreciated that the present invention encompasses any crystalline or amorphous form or mixture thereof that has properties for SERD activity, and it is well known in the art how to determine the efficacy of crystalline or amorphous form for SERD activity by standard testing as described below.

It is generally known that conventional materials can be used to analyze crystalline materials such as X-ray powder diffraction (also known as XRPD) analysis, differential scanning calorimetry (also known as DSC), thermogravimetric analysis (also known as TGA), diffuse reflection. Infrared Fourier Transform (DRIFT) spectroscopy, near infrared (NIR) spectroscopy, solution and/or solid state nuclear magnetic resonance spectroscopy. The water content of these crystalline materials can be determined by Karl Fischer analysis.

In particular, the invention relates to the following:

1. A compound of the formula I and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof:

among them:

Y ¹ is CR ^b or N;

Y ² is -(CH ₂ )-, -(CH ₂ CH ₂ )- or NR ^a ;

Y ³ is NR ^a or C(R ^b ) ₂ ;

Wherein one of Y ¹ , Y ² and Y ³ is N or NR ^a ;

Z ^{1 is} selected from the group consisting of CR ^a R ^b , C(O) and a bond;

R ^{6 is} selected from the group consisting of F, Cl, Br, I, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ OP(O)(OH) ₂ , -CH ₂ F, -CHF ₂ , -CH ₂ NH ₂ , -CH ₂ NHSO ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ N(CH ₃ ) ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, -CH(CH ₃ )CN, -C(CH ₃ ) ₂ CN, -CH ₂ CN, - CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CONHCH ₂ CH ₃ , -CONHCH(CH ₃ ) ₂ , -CON(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -N(CH ₃ )COCH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , -NO ₂ , =O, -OH, -OCH ₃ , -OCH ₂ CH ₃ , -OCH ₂ CH ₂ OCH ₃ , -OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OP(O)(OH) ₂ , -S(O) ₂ N(CH ₃ ) ₂ , -SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₃ H, cyclopropyl, cyclopropyl amide group, cyclobutyl, oxygen Heterocyclic , azetidinyl, (1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidine -1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone And morpholino;

2. A compound of formula I according to item 1 and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

Y ¹ is N;

Y ² is -(CH ₂ )-;

Y ³ is C(R ^b ) ₂ ;

R ^{a is} selected from H and C ₁ -C ₆ alkyl, the group optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, CN and OH;

R ^b is C ₁ -C ₆ alkyl, the group optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br and I;

Z ^{1 is} selected from the group consisting of CR ^a R ^b , C(O) and a bond;

Cy is a C ₆ -C ₁₀ aryldiyl group optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br and I;

R ¹ , R ² , R ³ and R ^{4 are} independently selected from the group consisting of H, F, Cl, Br, I, -CH ₃ , -CH ₂ CH ₃ , -CH ₂ OH, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -COCH ₃ , -OH, -OCH ₃ , -OCH ₂ CH ₃ ;

R ^{5 is} selected from H and C ₁ -C ₉ alkyl optionally substituted with one or more halogens, CN, OR ^a , N(R ^a ) ₂ , C ₁ -C ₉ alkyl, C ₃ -C ₉ a cycloalkyl group, a C ₃ -C ₉ heterocyclic ring, a C ₆ -C ₉ aryl group, and a C ₆ -C ₉ heteroaryl group;

R ^{6 is} selected from the group consisting of H, F, Cl, Br, I, -CN, -CH ₃ , -CF ₃ , -NO ₂ , -OH, -OCH ₃ and -SCH ₃ ;

Wherein the alkanediyl, fluoroalkanediyl, aryldiyl, carbocyclicdiyl, heterocyclic diyl and heteroaryldiyl are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, -CN, -CH ₂ F, -CHF ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH ₂ CH ₂ F, -NH ₂ , -NHCH ₃ , -N ( CH ₃ ) ₂ , -NHCOCH ₃ , -NO ₂ , =O, -OH, -OCH ₃ , -OCH ₂ CH ₃ and -SCH ₃ .

3.

Item

1 or 2, Formula I compounds and stereoisomers, tautomers, or a pharmaceutically acceptable salt thereof, wherein Y ¹ is N and Y ³ is C (R ^b) _2.

4. The compound of formula I according to any one of items 1 to 3, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Y ² is -(CH ₂ )-.

5. The compound of formula I according to any one of items 1 to 4, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Cy is a C ₆ -C ₂₀ aryldiyl group.

6. The compound of formula I according to any one of items 1 to 5, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the C ₆ -C ₂₀ aryldiyl group is a phenyldiyl group.

The compound of formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, according to any one of items 1 to 6, wherein the phenyldiyl group is substituted with one or more F.

8. The item as claimed in any one of the compounds of Formula I and stereoisomers, tautomers, or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ² is H.

Item 9. The compound of formula 1-8 according to any one of the I and stereoisomers, tautomers, or a pharmaceutically acceptable salt thereof, wherein R ³ is H and R ⁴ is -CH _3.

The compound of formula I, or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, according to any one of items 1-9, wherein R ⁵ is C ₁ -C optionally substituted with one or more halogens ₆ alkyl.

11. Item 1 to 10 according to any one of the compounds of Formula I and stereoisomers, tautomers, or a pharmaceutically acceptable salt thereof, wherein R ⁶ is H.

12. The compound of formula I according to item 1, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein said formula I is of formula Ia:

13. The compound of formula I according to item 1, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein said formula I is formula Ib:

14. The compound of formula I according to item 1 and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein said formula I is of formula Ic:

among them

R ⁷ is F, Cl, Br, I, -CN, -CH ₃ , -CH ₂ CH ₃ , -CH(CH ₃ ) ₂ , -CH ₂ CH(CH ₃ ) ₂ , -CH ₂ OH, -CH ₂ OCH ₃ , -CH ₂ CH ₂ OH, -C(CH ₃ ) ₂ OH, -CH(OH)CH(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CH ₂ OH, -CH ₂ CH ₂ SO ₂ CH ₃ , -CH ₂ OP(O)(OH) ₂ , -CH ₂ F, -CHF ₂ , -CH ₂ NH ₂ , -CH ₂ NHSO ₂ CH ₃ , -CH ₂ NHCH ₃ , -CH ₂ N (CH ₃ ₂ , -CF ₃ , -CH ₂ CF ₃ , -CH ₂ CHF ₂ , -CH(CH ₃ )CN, -C(CH ₃ ) ₂ CN, -CH ₂ CN, -CO ₂ H, -COCH ₃ , -CO ₂ CH ₃ , -CO ₂ C(CH ₃ ) ₃ , -COCH(OH)CH ₃ , -CONH ₂ , -CONHCH ₃ , -CONHCH ₂ CH ₃ , -CONHCH(CH ₃ ) ₂ , -CON(CH ₃ ) ₂ , -C(CH ₃ ) ₂ CONH ₂ , -NH ₂ , -NHCH ₃ , -N(CH ₃ ) ₂ , -NHCOCH ₃ , -N(CH ₃ )COCH ₃ , -NHS(O) ₂ CH ₃ , -N(CH ₃ )C(CH ₃ ) ₂ CONH ₂ , -N(CH ₃ )CH ₂ CH ₂ S(O) ₂ CH ₃ , -NO ₂ , =O, -OH, -OCH ₃ ,- OCH ₂ CH ₃ , -OCH ₂ CH ₂ OCH ₃ , -OCH ₂ CH ₂ OH, -OCH ₂ CH ₂ N(CH ₃ ) ₂ , -OP(O)(OH) ₂ , -S(O) ₂ N ( CH ₃ ) ₂ , -SCH ₃ , -S(O) ₂ CH ₃ , -S(O) ₃ H, cyclopropyl, cyclopropyl amide group, oxetanyl, azetidinyl ,(1- Methyl azetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxybenzene , pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone and morpholino;

n is selected from 0, 1, 2, 3, and 4;

R ⁸ is H or -CH ₃ .

15. The compound of formula I according to item 1 and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein n is 2, wherein said formula I is of formula Id:

16. The compound of formula I according to item 1, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound of formula I is a compound of formula (I) or (II):

17. A pharmaceutical composition comprising a compound of any of items 1-16 and a pharmaceutically acceptable carrier, glidant, diluent or excipient.

18. A method of treating an estrogen receptor related disease in a patient comprising administering to the patient a therapeutically effective amount of a compound of any one of items 1-16.

19. The method of item 18, wherein the estrogen receptor-associated disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.

20. Use of a compound according to any one of items 1-16 for the manufacture of a medicament for the treatment of an estrogen receptor related disorder.

21. The use of claim 20, wherein the estrogen receptor-related disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.

Part of the structure of the structure

Figure 1. ¹ H-NMR spectrum of Compound 13;

Figure 2. ¹³ C-NMR spectrum of Compound 13;

Figure 3. High resolution spectrum of compound 13 (positive ion);

Figure 4. High resolution spectrum of compound 13 (negative ion);

Figure 5. ¹ H-NMR spectrum of Compound 16;

Figure 6. MS spectrum of compound 16.

Specific implementation

The invention is further illustrated by specific preparation examples and test examples.

Example 1

Synthetic route map:

1. Synthesis route of fragment aldehyde I:

Experimental operation section

2. Synthesis of fragment aldehyde I

Compound B: Compound A (0.50g, 2.67mmol) and Et ₃ N (0.74mL, 5.34mmol) was dissolved in 5mL CH _₂ Cl _2, cooled to 0 ℃, then slowly added dropwise MsCl (0.32mL, 4.01mmol) , the reaction is about 1 h. After the reaction was completed, 2 mL of 10% citric acid solution was added to the solution to quench it, and the organic phase was washed successively with 10% citric acid solution (2 mL), saturated NaHCO ₃ solution (2 mL x 2) and saturated NaCl (2 mL). aqueous Na ₂ SO ₄ dried, filtered, and concentrated under reduced pressure to give 0.53g compound B, the yellow oil, 75% yield, was used directly in the next step.

Compound C: Compound B (0.70 g, 2.67 mmol) was dissolved in TBAF (1M THF solution, 5 mL, 5 mmol) and refluxed for about 1 h. After the reaction was completed, it was cooled to EtOAc. EtOAc (EtOAc m.. liquid separation, the aqueous phase was extracted with EtOAc (2mL x 3), combined organic phases were washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered, and concentrated under reduced pressure, by column chromatography to obtain compound C 0.36g, as a pale yellow oil, The yield was 73%. ¹ H NMR (400MHz, CHLOROFORM -d) δ4.60 (d, J = 6.0Hz, 1H), 4.48 (d, J = 6.0Hz, 1H), 4.03 (td, J = 8.7,1.4Hz, 2H), 3.76 (dd, J = 8.8, 5.3 Hz, 2H), 2.95-2.79 (m, 1H), 1.45 (s, 9H).

Compound D: Compound C (0.42 g, <RTI ID=0.0></RTI></RTI><RTIID=0.0></RTI></RTI><RTIgt; After completion of the reaction, the water was concentrated and evaporated to give Compound Compound Compound Compound Compound Compound ^{1 H NMR (400MHz, DMSO-} d6) δ9.34 (s, 2H), 4.65 (d, J = 5.2Hz, 1H), 4.53 (d, J = 5.1Hz, 1H), 3.99 (td, J = 8.7 , 8.1, 3.8 Hz, 2H), 3.77 (dt, J = 11.1, 6.2 Hz, 2H), 3.23 - 3.04 (m, 1H).

Compound F: Compound E (0.51 g, 3.9 mmol), Cs ₂ CO ₃ (1.91 g, 5.85 mmol) and 2-bromoethanol (0.41 mL, 5.85 mmol) were dissolved in 10 mL DMF and warmed to 120 ° C for about 10 h. . After completion of the reaction was concentrated under reduced pressure, and then washed with water, saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered, and concentrated to obtain 0.49g compound F. To column chromatography, a colorless oil, yield 72%. ¹ H NMR (400 MHz, chloroform-d) δ 6.50-6.42 (m, 3H), 4.06 (dd, J=5.1, 3.6 Hz, 2H), 3.98 (dd, J=5.1, 3.6 Hz, 2H), 2.10 (dd, J = 24.4, 7.5 Hz, 1H).

Compound G: Compound F (0.66g, 3.8mmol) and Et ₃ N (0.72mL, 5.2mmol) was dissolved in 10mL CH _₂ Cl _2, cooled to 0 ℃, then slowly added dropwise MsCl (0.32mL, 4.01mmol) , the reaction is about 1 h. After the reaction was completed, 2 mL of 10% citric acid solution was added to the solution to quench it, and the organic phase was washed successively with 10% citric acid solution (2 mL), saturated NaHCO ₃ solution (2 mL x 2) and saturated NaCl (2 mL). aqueous Na ₂ SO ₄ dried, filtered, and concentrated under reduced pressure to give 0.86g of compound G as a pale yellow oil in 90% yield, was used directly in the next step.

Compound H: Compound G (0.22 g, 0.87 mmol), K ₂ CO ₃ (0.27 g, 1.92 mmol) and Compound D (0.11 g, 0.88 mmol) were dissolved in 10 mL CH ₃ CN and warmed to 85 ° C overnight. After completion of the reaction, the mixture was concentrated under reduced pressure. ¹ H NMR (400MHz, CHLOROFORM -d) δ6.43-6.36 (m, 3H) , 4.56 (d, J = 5.6Hz, 1H), 4.44 (d, J = 5.6Hz, 1H), 3.92 (t, J = 5.4 Hz, 2H), 3.49 (tt, J = 7.9, 1.9 Hz, 2H), 3.18-3.06 (m, 2H), 2.92-2.79 (m, 3H).

Compound I: Compound H (0.30g, 1.2mmol) was dissolved in 5mL dry THF, N ₂ protection, was cooled to -78 deg.] C, and then slowly added dropwise TMEDA (1.5mL, 10mmol) and n-BuLi (0.85mL, 1.3 Methyl), reacted at -78 ° C for about 0.5 h, then moved to room temperature, DMF (0.12 mL, 1.5 mmol) was slowly added dropwise, and allowed to react at room temperature for about 1 h. After completion of the reaction was slowly quenched with ice-water was added 5mL, 40mL EtOAc, the organic phase successively washed with water (20mL x 3), washed with saturated NaCl, dried over anhydrous Na ₂ SO _4, filtered, and concentrated under reduced pressure to give 0.17g compound I, a pale-yellow Oily, yield 51%. ¹ H NMR (400MHz, CHLOROFORM -d) δ10.18 (s, 1H) , 6.53-6.44 (m, 2H), 4.56 (d, J = 5.5Hz, 1H), 4.44 (d, J = 5.5Hz, 1H ), 4.00 (t, J = 5.4 Hz, 2H), 3.48 (td, J = 7.8, 1.5 Hz, 2H), 3.15 (dd, J = 7.7, 6.4 Hz, 2H), 2.85 (t, J = 5.4 Hz) , 3H).

references

[1]WO2014/205138

[2]WO2017059139A1

Target compound main course experimental operation part:

Compound 1 (15.0 g, 68.2 mmol) was dissolved in 102 mL of DMF, tert-butylamine (21 mL, 204.6 mmol, 3.0 eq) was added, and the reaction system was reacted at 45 ° C for 4 h, then the reaction was continued at room temperature for 10 h, and the reaction was completed. After adding 75 mL of water, stirring at room temperature for 1 h, adding 200 mL of ethyl acetate, and washing with water three times, the organic phase obtained was removed in vacuo to give 18.4 g (99%) of an orange-red solid. .

Compound 2 (18.4 g, 67.5 mmol) was dissolved in 170 mL of ethanol, 20 mL of an aqueous ammonium chloride solution (concentration: 1.0 mmol/0.6 mL) was added, and the reaction system was stirred at 90 ° C to add iron powder 19.0 g (337.5 mmol, 5.0 eq). After the reaction, the reaction system was reacted at 90 ° C for 3 h. After the reaction was completed, the mixture was filtered with suction, and the mixture was extracted with ethyl acetate. The organic phase was dried to afford 14.7 g (95%) as a solid. .

Compound 3 (14.7 g, 64.1 mmol) was dissolved in 100 mL of acetic acid, and 100 mL of a sodium nitrite aqueous solution (6.5 mmol/mL) was added. The reaction system was reacted at 90 ° C for 3 h. After the reaction was completed, 200 mL of ethyl acetate was added and washed three times with water. The organic phase was dried <RTI ID=0.0>; ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.82 (s, 9H), 7.48 (d, J = 8.6 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 8.18 (s, 1H).

11.1 mL (79.1 mmol, 1.3 eq) of diisopropylamine was dissolved in 10 mL of tetrahydrofuran, the reaction was cooled to -78 ° C, and n-butyl lithium 31.6 mL (2.5 M n-hexane solution, 1.3 eq) was added at -78 ° C. After stirring for 0.5 h, compound 4 was dissolved in 100 mL of tetrahydrofuran, cooled to -78 ° C, fresh LDA was added, and reacted at -78 ° C for 1 h, DMF 30 mL (400 mmol, 5.0 eq) was added, and the reaction was stirred at -78 ° C. After 3 h, all the reaction was carried out under a nitrogen atmosphere. After completion of the reaction, the mixture was stirred and evaporated. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.88 (s, 9H), 7.69 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 10.87 (s, 1H).

Compound 5 (15.6 g, 55 mmol) was dissolved in 55 mL of nitroethane, ammonium acetate (4.23 g, 55 mmol, 1.0 eq) was added, and the reaction was reacted at 118 ° C for 3 h. After completion of the reaction, spin dry, column chromatography Purification gave 13 g (70%) as a pale yellow solid. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.88 (s, 9H), 2.28 (d, J = 1.2 Hz, 3H), 7.68 (s, 1H), 8.19 (d, J = 0.8 Hz, 1H).

In a 100ml flask was added NaBH ₄ (216mg, 5.7mmol), in dry tetrahydrofuran 10ml, was slowly added at 0 ℃ _{_{BF 3 -Et 2 O (0.877ml,}} 7.1mmol), stirred at rt for 15min. Compound 6 (400 mg, 1.2 mmol) was dissolved in anhydrous tetrahydrofuran (3 ml) and added dropwise to the reaction, and the reaction was refluxed at 75 ° C for about 5.5 h (TLC detection reaction). After the reaction was completed, it was cooled to room temperature, and 18 ml of ice-water mixture was added slowly, and 1N HCl (18 ml) was added, and the mixture was stirred at 85 ° C for 2 h, cooled to room temperature, adjusted to pH with NaOH aqueous solution, and a small amount of solid NaCl was added. Methane extraction, dried over anhydrous sodium sulfate, EtOAc (EtOAc) Yield: 65%. ^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.59 (d, J = 8.8Hz, 1H), 7.49 (d, J = 8.8Hz, 1H), 3.59 (m, 1H), 3.46-3.33 (m, 2H) , 1.87 (s, 9H), 1.27 (d, J = 6.4 Hz, 3H). References: Syn. Commun, 1985, 15, 843-847.

Compound 7 (470mg, 1.0eq) was dissolved in 10ml CH _₂ Cl ₂ is dried, cooled to 0 deg.] C, was slowly added dry triethylamine (TEA, 0.274ml, 1.3eq), followed by addition of TsCl (376mg, 1.3eq ), stir to room temperature and continue to stir for about 20min. Starting material was complete by TLC the reaction, this reaction solution was added H ₂ O (5.0ml) was quenched, extracted three times with ₂ Cl ₂ CH, the organic layer was dried over anhydrous NaSO _4, the organic solvent was removed under reduced pressure, column chromatography ( CH ₂ Cl ₂ as an eluent) gave a solid compound (740 mg, yield 99%). ^{_{1 H NMR (400MHz, CDCl 3}} ) δ7.34 (d, J = 2.0Hz, 2H), 7.26 (d, J = 8.0Hz, 2H), 6.93 (d, J = 8.0Hz, 2H), 5.57 (d , J = 6.8 Hz, 1H), 3.88 - 3.81 (m, 1H), 3.43 (dd, J = 13.6 Hz, J = 10.0 Hz, 1H), 3.16 (dd, J = 13.8 Hz, J = 4.2 Hz, 1H ), 2.31 (s, 3H), 1.86 (s, 9H), 1.39 (d, J = 6.4 Hz, 3H).

Compound 8 (150 mg, 1.0 eq) was dissolved in 5 ml of dry THF under N ₂ and cooled to -78 ° C. t-BuLi (1.78 ml, 1.3 M, 1.4 eq) was slowly added and the reaction system became deep. Red, stirring was continued for 45 min at this temperature. The intermediate aldehyde I was dissolved in dry THF (1.0 ml), and then slowly added to the above reaction system, and the color of the reaction system was withdrawn when added. Stirring was continued at -78 °C for 20 min, then moved to room temperature and the reaction was continued for 30 min. 8 starting material the reaction was complete by TLC, was added to the reaction mixture was quenched with saturated NH ₄ Cl, the organic phase was extracted with ethyl acetate, the organic layer was dried over anhydrous NaSO _4, the organic solvent was removed under reduced pressure and column chromatography (CH ₂ Cl ₂ : MeOH = 40:1 as eluent. Among them, the compound 9 is doped with some impurities which cannot be separated (so the yield of the compound 9 is 20-30%), but does not affect the next reaction. References: Org. Lett., 2017, 19, 6460-6462.

Compound 9 (200mg, 1.0eq) was dissolved in 5ml of dry CH _₂ Cl _2, cooled to 0 deg.] C, was slowly added TfOH (0.5eq), stirring was continued at this temperature for 10min. When TLC detects that the reaction of the starting material 9 is complete, a small amount of aqueous ammonia is added to the reaction liquid, followed by quenching with a small amount of water, and the organic phase is extracted with CH ₂ Cl ₂ , the organic layer is dried over anhydrous NaSO ₄ , and the organic solvent is removed under reduced pressure. Analysis (CH ₂ Cl ₂ : MeOH = 30:1 as eluent) afforded Compound 10 (yel. Compound 10 is doped with some impurities that cannot be separated, but does not affect the next reaction. References: Tetrahedron Letters. 2017, 58, 294-297.

Solid naphthalene (615 mg, 5.0 mmol) was added to a 100 mL reaction flask, and the sodium block was sheared to dry sodium ether in dry petroleum ether, and then quickly weighed (drying the paper towel to remove the petroleum ether from the surface). , 5.0 mmol) was added to the original reaction flask and the nitrogen was replaced. 25 mL of the re-distilled THF was added to the reaction system with a syringe, and the mixture was stirred at room temperature for 1 h or more to obtain a fresh sodium naphthalene complex (0.2 M in THF), which was dark green. The other reaction flask containing 100 mg (0.156 mmol, 1.0 eq) of the reaction substrate compound 10 was replaced with nitrogen, and 3.9 mL (0.78 mmol, 5.0 eq) of the prepared sodium naphthalene complex solution was slowly added dropwise at -78 °C. After stirring at -78 ° C for 3 h, it was detected that most of the substrate had been consumed, and quenched by adding 2 mL of saturated ammonium chloride at -78 ° C, and the reaction color faded. After it was warmed to room temperature, it was extracted with EtOAc EtOAc (EtOAc m. The product was 30 mg as a colorless oil, yield 40%. References: Synthesis, 2012, 44, 297-303. ¹ H NMR (400 MHz, CDCl ₃ ) δ 1.38 (d, J = 6.4 Hz, 3H), 1.86 (s, 9H), 2.99 (m, 3H), 3.10 (dd, J = 16.8 Hz, J = 9.6 Hz , 1H), 3.36 (t, J = 6.8 Hz, 2H), 3.61-3.72 (m, 4H), 3.64 (dd, J = 17.2 Hz, J = 4.4 Hz, 1H), 4.03 (t, J = 5.2 Hz) , 2H), 4.47 (d, J = 4.8 Hz, 1H), 4.59 (d, J = 5.2 Hz, 1H), 5.76 (s, 1H), 6.44 (d, J = 10.4 Hz, 2H), 6.97 (d , J = 8.8 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H).

After adding 5 mL of methanol to a reaction flask containing Compound 11 (50 mg, 0.1 mmol), isobutyraldehyde (35 mg, 0.5 mmol, 5.0 eq) and sodium nitriloborohydride (13 mg, 0.2 mmol) were sequentially added under stirring. 2.0 eq) and catalytic amount of acetic acid (2-3 drops), stirred at room temperature for more than 4 h. The reaction was detected by TLC, and a small amount of isobutyraldehyde and sodium cyanoborohydride were added to continue the reaction. When the reaction is complete, a saturated NaHCO ₃ solution is added to adjust the pH to neutrality. Most of the solvent is dried and extracted with dichloromethane. The organic phase is combined and dried over anhydrous sodium sulfate. The aqueous phase is treated with an excess of ferric chloride. The organic phase was separated and purified by preparative thin-layer chromatography (DCM: MeOH=100mL: 5mL). The product was 41 mg as a colorless oil, yield 75%. ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.71 (d, J = 6.4 Hz, 3H), 0.84 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.4 Hz, 3H), 1.70 (m) , 1H), 1.85 (s, 9H), 2.04-2.10 (m, 2H), 2.47 (dd, J = 12.8 Hz, J = 5.6 Hz, 1H), 2.88 (m, 3H), 3.25 (t, J = 6.8 Hz, 2H), 3.36 (dd, J = 16.4 Hz, J = 3.2 Hz, 1H), 3.37 - 3.61 (m, 4H), 3.96 (t, J = 5.2 Hz, 2H), 4.46 (d, J = 5.2 Hz, 1H), 4.58 (d, J = 5.2 Hz, 1H), 5.16 (s, 1H), 6.38 (d, J = 9.6 Hz, 2H), 6.86 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 8.8 Hz, 1H).

30 mg (0.055 mmol) of compound 12 was placed in a 15 mL sealed tube, 1.5 mL of cyclohexane and 0.5 mL of trifluoromethanesulfonic acid were added, and the system was heated to 100 ° C to seal the tube for 12 hours or more. After TLC detection, the substrate reaction was completed, the pH was adjusted to neutral with saturated sodium bicarbonate, and the organic phase was combined and dried over anhydrous sodium sulfate. The organic phase was separated and purified by preparative thin-layer chromatography (DCM: MeOH: 17% aqueous ammonia = 100 mL: 15 mL: 2 mL). The product was a pale yellow powder of 16 mg in a yield of 60%. Reference: Tetrahedron, 1991, 47, 9449.

Final product 13 (Example 1) data:

Light yellow powder. Yield: 60%; ¹ H NMR (400 MHz, CDCl ₃ ) δ 0.67 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H), 1.66 (m, 1H), 2.04 (dd, J = 12.8 Hz, J = 8.0 Hz, 1H), 2.39 (dd, J = 12.8 Hz, J = 6.4 Hz, 1H), 2.91-3.00 (m, 3H), 3.09 (dd, J = 16.4 Hz, J = 4.0 Hz, 1H), 3.30 (t, J = 7.2 Hz, 2H), 3.38 (dd, J = 16.4 Hz, J = 4.8 Hz, 1H), 3.46 (q, J = 5.2 Hz, 1H), 3.63 - 3.68 (m, 2H), 3.88-3.97 (m, 2H), 4.44 (d, J = 5.2 Hz, 1H), 4.56 (d, J = 5.2 Hz, 1H), 5.15 (s, 1H), 6.18 (d, J = 10.4 Hz, 2H), 6.82 (d, J = 8.8 Hz, 1H), 7.45 (d, J = 8.4 Hz, 1H); δ 12.4, 20.4, 20.9, 26.5, 30.8, 31.3, 31.5, 47.8, 54.6, 56.2 (q, J = 3.8 Hz), 57.4, 57.6, 66.3, 82.8, 84.4, 98.4, 111.8, 113.0 (t, J = 15.7 Hz), 122.4, 125.8, 133.4, 138.4 (d, J = 213.7 Hz), 158.9 (t, J = 14.1 Hz), 162.3 (dd, J = 247.4 Hz, J = 11.2 Hz); HRMS m/z C ₂₆ H ₃₂ F ₃ N ₅ O [MH] ⁺ Calcd: 486.2486, Found: 486.2581; [M + H] +: 488.2632, Found: 488.2640.

Example 2

Synthetic route map:

Fragment

Synthesis of 7A

After compound 7-1 (8.00 g, 86.8 mmol) and 2,6-lutidine (11.2 g, 104 mmol) were dissolved in 100 mL of dichloromethane, Tf ₂ O (26.9 g, 95.5 mmol) was added at -10 °C. The reaction mixture was stirred at 0 ° C for 2 hours and LCMS showed the reaction was completed. The reaction mixture was washed with EtOAc EtOAc EtOAc EtOAc. ¹ H NMR (400 MHz CDCl ₃ ) δ 4.41 (d, J = 18.4 Hz, 2H), 1.45 (d, J = 20.8 Hz, 2H).

Synthesis of fragment 12-3A

Compound B: Compound A (16.7 g, 89.2 mmol) and triethylamine (10.8 g, 107 mmol) were dissolved in 160 mL of dichloromethane, and then slowly added dropwise 40 mL of MsCl (11.2 g, 98.1 mmol) at 0 ° C for 30 min. The methyl chloride solution was stirred at 25 ° C for 4 hours and LCMS showed the reaction was completed. The reaction mixture was washed with EtOAc (EtOAc) (EtOAc) The next step is to react.

Compound C: Compound B (25.0 g, 94.2 mmol) was dissolved in THF solution of TBAF (1.00 M, 400 mL), and stirred at 80 ° C for 6 hours. TLC showed the reaction was complete. After the reaction mixture was cooled to 20 ° C, 200 mL was added. After water, the THF was concentrated under reduced pressure. EtOAc (EtOAc)EtOAc. Compound C is obtained as a colorless oil from 0% to 15%. ¹ H NMR (400 MHz CDCl ₃ ) δ 4.57 (d, J = 6.0 Hz, 1H), 4.46 (d, J = 6.0 Hz, 1H), 4.03 - 3.99 (m, 2H), 3.76 - 3.72 (m, 2H) ), 2.89-2.81 (m, 1H), 1.43 (s, 9H).

Compound 12-3A: Compound C (11.5 g, 60.8 mmol) was dissolved in 100 mL dichloromethane, then TFA (35.5 g, 311 mmol) was added and the mixture was stirred at 20 ° C for 24 hours. The reaction mixture was concentrated to dryness to give crystals of Compounds 2-3 (23.5 g). ¹ H NMR (400 MHz CDCl ₃ ) δ 9.96 (s, 2H), 8.93-8.88 (m, 2H), 4.60 (d, J = 4.8 Hz, 1H), 4.49 (d, J = 4.8 Hz, 1H), 4.04-4.01 (m, 2H), 3.83-3.81 (m, 2H), 3.16-3.06 (m, 1H).

Synthesis of fragment 12A

Compound 12-2: Compound 12-1 (25.0 g, 192 mmol), 2-bromoethanol (36.0 g, 288 mmol), cesium carbonate (93.9 g, 288 mmol) was dissolved in 500 mL of DMF solution and stirred at 120 ° C for 16 hours. LCMS showed the reaction was complete. After concentration of DMF under reduced pressure, EtOAc (EtOAc) (EtOAc) 5%) Compound 12-2 (25.6 g, 73.9%) ¹ H NMR (400 MHz CDCl ₃ ) δ 6.47-6.42 (m, 3H), 4.05 - 4.03 (m, 2H), 3.95 (s, 2H), 2.11 (s, 1H).

Compound 12-3: After dissolving compound 12-2 (20.0 g, 115 mmol) and triethylamine (16.3 g, 161 mmol) in 200 mL of dichloromethane, MsCl (15.9 g, 138 mmol) was slowly added dropwise at 0 ° C. After stirring at 20 ° C for 16 hours, LCMS showed the reaction was completed. 100 mL of 10% citric acid was added to the reaction mixture, and the layers were separated. The organic phase was washed with 200 mL of 10% citric acid, 200 mL of a saturated aqueous sodium hydrogen carbonate solution, and 200 mL of brine. Dry, filter and concentrate to give a yellow solid (1. ¹ H NMR (400 MHz CDCl ₃ ) δ 6.49-6.42 (m, 3H), 4.57-4.55 (m, 2H), 4.22-4.20 (m, 2H), 3.09 (s, 3H).

Compound 12A: After dissolving compound 12-3A (23.0 g, 113 mmol) in 250 mL of acetonitrile, potassium carbonate (70.4 g, 509 mmol) was added, then compound 12-3 (28.5 g, 113 mmol) was added and the reaction mixture was reacted at 85 ° C 12 After an hour, LCMS showed complete reaction. The reaction mixture was diluted with 500 mL of water and concentrated. The aqueous phase was separated with 200 mL of dichloromethane. The organic phase was washed with 500 mL of brine, dried over anhydrous sodium sulfate The compound 12A (11.5 g, 31.9%) was obtained as a yellow oil. ¹ H NMR (400 MHz CDCl ₃ ) δ 6.42 - 6.37 (m, 3H), 4.56 (d, J = 5.6 Hz, 1H), 4.44 (d, J = 5.6 Hz, 1H), 3.92-3.89 (m, 2H) ), 3.50-3.46 (m, 2H), 3.15-3.12 (m, 2H), 2.83-2.80 (m, 3H).

Target compound main course experimental operation part:

Compound 7 (13.0 g, 41.8 mmol) and DIPEA (8.10 g, 62.7 mmol) were dissolved in 100 mL of 2,4-dioxane, and compound 7A (14.1 g, 62.7 mmol) was added, and the reaction mixture was stirred at 85 ° C for 48 hours. LCMS showed the reaction was complete. After cooling, the reaction mixture was combined with 100 mL of ethyl acetate and 200 mL of water, and the mixture was separated, and the aqueous phase was separated and extracted with 100 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated. A yellow gum compound 8 (12.2 g, 73.3%) was obtained from silica gel column chromatography (EtOAc/EtOAc). ¹ H NMR (400 MHz CDCl ₃ ) δ 7.54 (d, J = 8.8 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 3.50 - 3.47 (m, 1H), 3.33 - 3.28 (m, 2H) ), 2.86-2.76 (m, 2H), 1.84 (s, 9H), 1.33 (d, J = 3.2 Hz, 3H), 1.28 (d, J = 3.2 Hz, 3H), 1.10 (d, J = 6.0 Hz) , 3H).

After dissolving Compound 8 (12.0 g, 31.1 mmol) in 120 mL of THF, triethylamine (25.2 g, 249 mmol) was added at 0 ° C, then Boc ₂ O (27.2 g, 124 mmol) was added. The reaction mixture was reacted at 50 ° C for 12 hours and LCMS showed the reaction was completed. After cooling, the reaction mixture was combined with 100 mL of ethyl acetate and 200 mL of water, and the layers were separated. The aqueous phase was extracted with 100 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, filtered and evaporated. Column chromatography (EA/PE from 0% to 6%) afforded Compound 9 (14.3 g, 92.3%) as a white solid. ¹ H NMR (400 MHz CDCl ₃ ) δ 7.52 (d, J = 9.2 Hz, 1H), 7.43 (d, J = 8.8 Hz, 1H), 4.19 (s, 1H), 3.72-3.56 (m, 3H), 3.36-3.28 (m, 1H), 1.84 (s, 9H), 1.46-1.22 (m, 19H).

After dissolving compound 9 (14.3 g, 29.5 mmol) in 140 mL of methanol, Pd(dppf)Cl ₂ (23.7 g, 32.4 mmol) and sodium acetate (12.3 g, 150 mmol) were added, and the reaction was stirred at 80 ° C and CO for 169 hours. LCMS showed that 19.6% of compound 9 remained. After the reaction mixture was cooled to 20 ° C, EtOAc (EtOAc m.) ¹ H NMR (400 MHz CDCl ₃ ) δ 7.97 (d, J = 9.2 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 4.13-4.08 (m, 1H), 3.94 (s, 5H), 3.75-3.47 (m, 1H), 3.33-3.24 (m, 1H), 1.84 (s, 9H), 1.38-1.21 (m, 20H).

After compound 10 (4.30 g, 9.25 mmol) was dissolved in 50 mL of THF, LiBH ₄ (706 mg, 32.4 mmol) was added at -60 ° C, and the reaction mixture was stirred at -60 ° C for 1 hour, then heated to 20 ° C under stirring 47 After an hour, LCMS showed complete reaction. After the reaction mixture was cooled to 0 ° C, 80 mL of saturated ammonium chloride solution was slowly added dropwise, and the mixture was extracted with 40 mL of ethyl acetate. The aqueous phase was separated and extracted with 40 mL of ethyl acetate. The combined organic phase was washed with 200 mL of saturated salt. The mixture was washed with water, dried over anhydrous sodium sulfate. ¹ H NMR (400 MHz CDCl ₃ ) δ 7.61-7.45 (m, 2H), 4.85-4.76 (m, 2H), 4.57 (s, 0.5H), 4.04 (s, 0.6H), 3.70-3.43 (m, 3H), 3.21-3.11 (m, 1H), 1.85 (s, 9H), 1.45-1.16 (m, 19H).

After dissolving Compound 11 (4.00 g, 9.16 mmol) in 40 mL of dichloromethane, DMP (4.27 g, 10.1 mmol) was added at 20 ° C, and the reaction mixture was stirred at this temperature for 4 hr. After the reaction mixture was added to 60 mL of aq. NaHCO ₃ /Na ₂ S ₂ O ₃ (1:1), the mixture was extracted with 40 mL of dichloromethane, and the combined organic phases were washed with 200 mL of brine and dried over anhydrous sodium sulfate Filtration, concentration and EtOAc (EtOAc/EtOAc) ¹ H NMR (400 MHz CDCl ₃ ) δ 10.5 (s, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.64 (s, 1H), 4.17-3.92 (m, 3.5H), 3.60-3.21 ( m, 1.5H), 2.83-2.78 (m, 0.4H), 1.84 (s, 9H), 1.48-1.22 (m, 18H).

Compound 12A (6.60 g, 26.9 mmol) was dissolved in 40 mL of THF, EtOAc (EtOAc (EtOAc: EtOAc, EtOAc) After stirring for 40 minutes, a solution of compound 12 (3.90 g, 8.97 mmol) in 20 mL of THF was added to the reaction mixture and stirred at this temperature for 20 minutes, then warmed to 20 ° C and stirred for 5 hours, LCMS showed 26% of compound 12A remained The reaction mixture was added to a solution of EtOAc (EtOAc) (EtOAc). Compound /13 (2.00 g, 29.4%) was obtained as a yellow oil. ¹ H NMR (400 MHz CDCl ₃ ) δ 7.76-7.74 (m, 1H), 7.62-7.50 (m, 1H), 6.43 (d, J = 10.8 Hz, 2H), 4.55 (d, J = 6.0 Hz, 1H) ), 4.43 (d, J = 5.6 Hz, 1H), 3.91-3.88 (m, 2.7H), 3.58-3.35 (m, 4H), 3.14 (t, J = 6.4 Hz, 2.6H), 2.85-2.79 ( m, 2.7H), 1.84 (s, 9H), 1.48-1.25 (m, 15H), 0.97 (s, 3H).

After compound 13 (2.57 g, 3.78 mmol) was dissolved in dichloromethane (20 mL), DMP (1. After the reaction mixture was added to 60 mL of aq. NaHCO ₃ /Na ₂ S ₂ O ₃ (1:1), the mixture was extracted with 40 mL of dichloromethane, and the combined organic phases were washed with 150 mL of brine Filtration, concentration and EtOAc (EtOAc/EtOAc) ¹ H NMR (400 MHz CDCl ₃ ) δ 7.51 (s, 2H), 6.49 (d, J = 9.6 Hz, 2H), 4.56 (d, J = 5.2 Hz, 1H), 4.45 (d, J = 4.6 Hz, 1H), 3.99-3.91 (m, 4H), 3.51-3.48 (m, 3H), 3.18-3.14 (m, 3H), 2.92-2.79 (m, 3.6H), 1.84 (s, 9H), 1.40-1.23 (m, 18H).

After compound 14 (1.90 g, 2.80 mmol) was dissolved in 20 mL of dichloromethane, TFA (7.70 g, 67.5 mmol) was added, and the reaction mixture was stirred at 20 ° C for 4 hours, then stirred at 30 ° C for 1 hour, LCMS showed reaction complete. The reaction mixture was concentrated under reduced pressure to give Compound 15 (m.

Compound 15 (1.90g, 3.29mmol) was dissolved in 20mL of methanol was added TFA (7.70g, 67.5mmol) and _{NaBH 3 CN (4.13g, 65.8mmol)} , the reaction mixture was stirred at 20 ℃ 30 min, warmed to 50 deg.] C After stirring for 12 hours, LCMS showed the reaction was completed. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Column chromatography (MeOH/DCM from 0% to 5%) gave compound 15A (0.9 g) as a yellow oil. ¹ H NMR (400 MHz CDCl ₃ ) δ 7.35 (d, J = 8.4 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 6.36 (d, J = 10.4 Hz, 2H), 5.22 (s, 1H), 4.55 (d, J = 5.2 Hz, 1H), 4.44 (d, J = 4.8 Hz, 1H), 3.91-3.88 (m, 3H), 3.53-3.48 (m, 3H), 3.37-3.36 (m , 1H), 3.17-3.14 (m, 2H), 2.85-2.81 (m, 3H), 2.39-2.28 (m, 2H), 1.82 (s, 9H), 1.24-1.15 (m, 7H), 1.04 (d , J = 6.4 Hz, 3H).

Compound 15A (20 mg, 35.6 μmol) was dissolved in HCOOH (1.71 mg, 35.6 μmol), HCl (12M, 0.5 mL) was added, and the reaction mixture was stirred at 80 ° C for 96 hours. LCMS showed 23.8% target compound, reaction mixture The pH was adjusted to 8 with 5M NaOH and a saturated aqueous solution of sodium bicarbonate, and extracted with 100 mL of dichloromethane. The combined organic phase was washed with 50 mL of saturated brine, dried over anhydrous sodium sulfate, filtered and evaporated. Form TLC (DCM / MeOH = 10/1) afforded yellow solid 16 (15 mg). ¹ H NMR (400 MHz CDCl ₃ ) δ 7.42 (d, J = 8.8 Hz, 1H), 6.77 (d, J = 8.8 Hz, 1H), 6.19 (d, J = 10.8 Hz, 2H), 5.24 (s, 1H), 4.55 (d, J = 4.8 Hz, 1H), 4.44 (d, J = 4.8 Hz, 1H), 3.94 - 3.90 (m, 2H), 3.72-3.64 (m, 4H), 3.29 (t, J = 6.8 Hz, 2H), 3.13 - 2.88 (m, 5H), 2.37-2.26 (m, 1H), 1.17 (t, J = 22.8 Hz, 6H), 1.01 (d, J = 6.4 Hz, 3H).

Test Example 3 ERαTR-FRET test

Prepare 1X modified Tris-Hcl protein buffer, mix and use. The compound to be tested was tested to a final concentration of 10 μM, and was set to a concentration of 200 times the final concentration, that is, 2 mM. Dilute 3 times in sequence and dilute 10 concentrations. 100 μl of each diluted well was added to the reaction plate with

Echo

550, and 5 nl of estradiol (1.5 nM) was added to each well.

Preparation of 1x protein mixture: Prepare 2x GST-ERα-LBD/MAb anti-GST-Eu mixed solution according to the following table.

A 2x biotin-SRC1/streptavidin-XL665 mixed solution was configured.

Mix the above two 2x GST-NR-LBD/MAb anti-GST-Eu solution and 2x biotin-SRC2/streptavidin-XL665 solution by volume 1:1; add 1x protein mixed solution to 384-well plate. One well was added with 20 μl per well, and the 384-well plate was centrifuged at 1000 rpm for 10 seconds at room temperature, taken out and left at room temperature for 3 hours, and then read using an EnVision multi-function microplate reader.

The readings are 665 and 615 (nanometer) values, and the correction value is used as the 615 value. The final value is expressed as 665 value / 615 value; the inhibition rate is calculated according to the following formula:

X is the "665 value to 615 value" for each concentration. Min is the "665 value to 615 value" average with 0.2 mM positive control compound and 5 nl 3 nM (1.5 nM) estradiol. Max is the "665 value to 615 value" average of DMSO and 5 nl 3 nM (1.5 nM) estradiol. The data was imported into Graphpad Prism and the curve was simulated using Log(agonist) vs. response--variable slope. Fitting formula: Y=Bottom+(Top-Bottom)/(1+10^((LogEC ₅₀ -X)*HillSlope))

ERαTR-FRET experimental data

化合物Compound	IC ₅₀(nM) IC ₅₀ (nM)	最大抑制率Maximum inhibition rate
实施例1Example 1	2.32.3	101.3101.3
AZD9496AZD9496	4.44.4	99.8099.80
他莫昔芬Tamoxifen	142.9142.9	100.4100.4
氟维司群Fulvestrant	4.04.0	103.4103.4

Test Example 4 ERβTR-FRET test

Echo

550, and 5 nl of estradiol (1.5 nM) was added to each well.

Preparation of 1x protein mixture: Prepare 2x GST-ERβ-LBD/MAb anti-GST-Eu mixed solution according to the following table.

A 2x biotin-SRC1/streptavidin-XL665 mixed solution was configured.

Mix the above two 2x GST-NR-LBD/MAb anti-GST-Eu solution and 2x biotin-SRC2/streptavidin-XL665 solution by volume 1:1; add 1x protein mixed solution to 384-well plate For each well, add 20 μl per well, and place the 384-well plate in a centrifuge at 1000 rpm for 10 seconds. After removal, place it at room temperature for 3 hours and read using an EnVision multi-function microplate reader.

X is the "665 value to 615 value" for each concentration. Min is the "665 value to 615 value" average with 0.2 mM positive control compound and 5 nl 3 nM (1.5 nM) estradiol. Max is the "665 value to 615 value" average of DMSO and 5 nl 3 nM (1.5 nM) estradiol. The data was imported into Graphpad Prism and the curve was simulated using Log(agonist) vs. response--variable slope.

Fitting formula: Y=Bottom+(Top-Bottom)/(1+10^((LogEC ₅₀ -X)*HillSlope))

ERβTR-FRET experimental data

化合物Compound	IC ₅₀(nM) IC ₅₀ (nM)	最大抑制率Maximum inhibition rate
实施例1Example 1	80.280.2	100.3100.3

AZD9496AZD9496	167.1167.1	101.0101.0
他莫昔芬Tamoxifen	988.6988.6	99.499.4
氟维司群Fulvestrant	12.812.8	100.6100.6

Test Example 5 MCF-7 cell proliferation assay

MCF-7 was seeded in a 96-well plate (Chinese Academy of Sciences, Culture Collection Committee, TCHu74 cells, medium containing 10% FBS (Gibco, 10099-141), 1% pyruvate (sigma, S8636), 1% MEM (hyclone, SH30024.01B) medium of non-essential amino acids (sigma, M7145), seeding density of 4,000 cells/well, cells were cultured at 37 ° C, 5% CO ₂ . The compound was configured into a 20 mM stock solution. Diluted to a final concentration of 1000 with a gradient of 100% DMSO, and then diluted 20-fold with a medium containing 2% FBS. After 24 hours of culture, the medium was removed, and 90 μL of medium containing 2% FBS and 10 μL of drug were added to each well. Add 10 μL of DMSO and mix gently by shaking. The blank group contains only 100 μL of 2% FBS medium, and cultured in a 37 ° C, 5% CO ₂ incubator. After 72 hours, 50 μL of the mixed Cell Titer-Glo (Promega, G7571) is added. The mixture was shaken and allowed to stand at room temperature for 10 min to measure the chemiluminescence signal value, and the negative control was 0.5% DMSO well.

MCF-7 cell proliferation test experimental data

化合物Compound	IC ₅₀(nM) IC ₅₀ (nM)
实施例1Example 1	1.531.53
实施例2Example 2	6.166.16
AZD9496AZD9496	13.5313.53
化合物1* Compound 1*	2.682.68
他莫昔芬Tamoxifen	874.5874.5
氟维司群Fulvestrant	2.542.54

Remarks: *Compound 1 is from Example 1 of the patent PCT/EP2017/059234, WO 2017/182493 A1.

Test Example 6 In vitro human liver microsome stability test

In addition to the blank control group, 10 μL of the test compound at a concentration of 10 mM was added to each well of a 96-well plate, and 80 μL of the microsome solution (0.5 mg/mL of the microsomal protein solution prepared with 100 mM potassium phosphate solution) was added thereto, and Incubate at 37 ° C for 10 minutes. 10 μL of a 100 mM potassium phosphate buffer to NCF60 was added to NCF60, and allowed to stand at 37 ° C for 1 hour. After the test pretreatment, 10 μL of NADPH was added to each well to activate the reaction. The concentrations of the components of the reaction system are shown in the following table:

组分Component	终浓度Final concentration
微粒体Microsome	0.5mg蛋白/mL0.5mg protein/mL
待测化合物Test compound	1μΜ1μΜ
对照Control	1μΜ1μΜ
MeOHMeOH	0.99％0.99%
DMSODMSO	0.01％0.01%

Incubate and operate at 37 ° C as indicated in the table below:

300 μL of the reaction quenching solution ((cooled (4 ° C) in acetonitrile solution containing 100 ng/mL tolbutamide and Labetalol at a concentration of 100 ng/mL was added to each well. )) to terminate the reaction, the 96-well plate containing the sample to be tested was shaken on a shaker for about 10 minutes, and the 96-well plate was centrifuged at room temperature for 4000 minutes at room temperature for 20 minutes to prepare 8 new 96-well plates. And adding 300 μL of distilled water to each well, and then transferring 100 μL of the supernatant to be mixed, performing LC/MS/MS detection and analysis, and calculating according to the following formula:

In vitro microsomal stability experimental data

Test Example 7 Human liver microsome CYP inhibition experiment

Prepare the test compound at different concentrations of the test solution according to the following table:

Prepare positive control compounds according to the following table:

Prepare the substrate solution according to the following table:

Add 20 μL of substrate solution to the corresponding wells, add 20 μL of PB to the blank control group; add 2 μL of the test compound and positive control to the corresponding wells, add 2 μL of solvent to the group without added inhibitor or blank control Prepare HLM working solution (Human liver microsome human liver microsome solution (0.25 mg/mL microsomal protein solution prepared with 100 mM potassium phosphate solution), add 158 μL HLM working solution to each well, and preheat for 10 minutes at 37 °C Then, add 20 μL of NADPH solution, mix and incubate in a 37 ° C water bath for 10 minutes; add 400 μL of quenching solution, then centrifuge at room temperature for 4000 minutes at room temperature for 20 minutes, transfer 200 μL of the supernatant to 100 μL of HPLC water, and Mix for 10 minutes and samples are available for LC/MS/MS detection and analysis.

Human liver microsome CYP inhibition experimental data

Claims

Compounds of formula I and stereoisomers, tautomers or pharmaceutically acceptable salts thereof:

among them:

Y 1 is CR b or N;

Y 2 is -(CH 2 )-, -(CH 2 CH 2 )- or NR a ;

Y 3 is NR a or C(R b ) 2 ;

Wherein one of Y 1 , Y 2 and Y 3 is N or NR a ;

R a is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 8 alkenyl, propargyl, C 3 -C 6 cycloalkyl and C 3 -C 6 heterocyclic, optionally selected Substituting one or more groups independently selected from the group consisting of F, Cl, Br, I, CN, OH, OCH 3 and SO 2 CH 3 ;

R b is independently selected from H, -O(C 1 -C 3 alkyl), C 1 -C 6 alkyl, C 2 -C 8 alkenyl, propargyl, -(C 1 -C 6 alkanediyl) a -(C 3 -C 6 cycloalkyl) group, a C 3 -C 6 cycloalkyl group, and a C 3 -C 6 heterocyclic group, the group optionally substituted with one or more groups independently selected from the group consisting of: F, Cl, Br, I, CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, OH, OCH 3 and SO 2 CH 3 ;

Z 1 is selected from the group consisting of CR a R b , C(O) and a bond;

Cy is selected from the group consisting of C 6 -C 20 aryldiyl, C 3 -C 12 carbocyclic diyl, C 2 -C 20 heterocyclic diyl and C 1 -C 20 heteroaryldiyl;

Z 2 is selected from the group consisting of O, S, NR a , C 1 -C 6 alkanediyl, C 1 -C 6 fluoroalkanediyl, O-(C 1 -C 6 alkanediyl), O-(C 1 -C 6 fluoroalkanediyl), C(O) and a bond;

R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I, -CN, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH ( CH 3 ) 2 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -CH(OH)CH(CH 3 ) 2 , -C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 SO 2 CH 3 , -CH 2 OP(O)(OH) 2 , -CH 2 F, -CHF 2 , -CH 2 NH 2 , -CH 2 NHSO 2 CH 3 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CN, -C(CH 3 ) 2 CN, - CH 2 CN, -CO 2 H, -COCH 3 , -CO 2 CH 3 , -CO 2 C(CH 3 ) 3 , -COCH(OH)CH 3 , -CONH 2 , -CONHCH 3 , -CONHCH 2 CH 3 , -CONHCH(CH 3 ) 2 , -CON(CH 3 ) 2 , -C(CH 3 ) 2 CONH 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCOCH 3 , -N( CH 3 )COCH 3 , -NHS(O) 2 CH 3 , -N(CH 3 )C(CH 3 ) 2 CONH 2 , -N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , -NO 2 , =O, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 N(CH 3 ) 2 , -OP(O) (OH) 2 , -S(O) 2 N(CH 3 ) 2 , -SCH 3 , -S(O) 2 CH 3 , -S(O) 3 H, cyclopropyl, cyclopropyl amide group, Cyclobutyl Oxetane, azetidinyl, (1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, Azetidin-1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, Olinone-methanone and morpholino;

R 5 is selected from the group consisting of H, C 1 -C 9 alkyl, C 3 -C 9 cycloalkyl, C 3 -C 9 heterocyclic, C 6 -C 9 aryl, C 6 -C 9 heteroaryl, - (C 1 -C 6 alkanediyl)-(C 3 -C 9 cycloalkyl), -(C 1 -C 6 alkanediyl)-(C 3 -C 9 heterocyclic), C(O)R b And C(O)NR a , SO 2 R a and SO 2 NR a optionally substituted with one or more halogens, CN, OR a , N(R a ) 2 , C 1 -C 9 alkyl, C 3- C 9 cycloalkyl, C 3 -C 9 heterocyclic, C 6 -C 9 aryl, C 6 -C 9 heteroaryl, C(O)R b , C(O)NR a , SO 2 R a and SO 2 NR a ;

R 6 is selected from the group consisting of F, Cl, Br, I, -CN, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -CH(OH)CH(CH 3 ) 2 , -C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 SO 2 CH 3 , -CH 2 OP(O)(OH) 2 , -CH 2 F, -CHF 2 , -CH 2 NH 2 , -CH 2 NHSO 2 CH 3 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH(CH 3 )CN, -C(CH 3 ) 2 CN, -CH 2 CN, - CO 2 H, -COCH 3 , -CO 2 CH 3 , -CO 2 C(CH 3 ) 3 , -COCH(OH)CH 3 , -CONH 2 , -CONHCH 3 , -CONHCH 2 CH 3 , -CONHCH(CH 3 ) 2 , -CON(CH 3 ) 2 , -C(CH 3 ) 2 CONH 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCOCH 3 , -N(CH 3 )COCH 3 , -NHS(O) 2 CH 3 , -N(CH 3 )C(CH 3 ) 2 CONH 2 , -N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , -NO 2 , =O, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 N(CH 3 ) 2 , -OP(O)(OH) 2 , -S(O) 2 N(CH 3 ) 2 , -SCH 3 , -S(O) 2 CH 3 , -S(O) 3 H, cyclopropyl, cyclopropyl amide group, cyclobutyl, oxygen Heterocyclic butane , azetidinyl, (1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidine -1-ylmethyl, benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone And morpholino;

Wherein the alkanediyl, fluoroalkanediyl, aryldiyl, carbocyclicdiyl, heterocyclic diyl and heteroaryldiyl are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, -CN, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -CH(OH)CH(CH 3 ) 2 , -C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 SO 2 CH 3 , -CH 2 OP ( O) (OH) 2 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -CH(CH 3 )CN, -C( CH 3 ) 2 CN, -CH 2 CN, -CH 2 NH 2 , -CH 2 NHSO 2 CH 3 , -CH 2 NHCH 3 , -CH 2 N(CH 3 ) 2 , -CO 2 H, -COCH 3 , -CO 2 CH 3 , -CO 2 C(CH 3 ) 3 , -COCH(OH)CH 3 , -CONH 2 , -CONHCH 3 , -CON(CH 3 ) 2 , -C(CH 3 ) 2 CONH 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCOCH 3 , -N(CH 3 )COCH 3 , -NHS(O) 2 CH 3 , -N(CH 3 )C(CH 3 ) 2 CONH 2 , -N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , -NO 2 , =O, -OH, -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 OCH 3 ,- OCH 2 CH 2 OH, -OCH 2 CH 2 N(CH 3 ) 2 , -OP(O)(OH) 2 , -S(O) 2 N(CH 3 ) 2 , -SCH 3 , -S(O) 2 CH 3 , -S(O) 3 H, cyclopropyl, cyclopropyl amide group, cyclobutyl, oxetanyl, azetidine , (1-methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, Benzyloxyphenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone and morpholino.
A compound of the formula I according to claim 1 and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein:

Y 1 is N;

Y 2 is -(CH 2 )-;

Y 3 is C(R b ) 2 ;

R a is selected from H and C 1 -C 6 alkyl, the group optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, CN and OH;

R b is C 1 -C 6 alkyl, the group optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br and I;

Z 1 is selected from the group consisting of CR a R b , C(O) and a bond;

Cy is a C 6 -C 10 aryldiyl group optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br and I;

Z 2 is selected from the group consisting of O, S, NR a , C 1 -C 6 alkanediyl, C 1 -C 6 fluoroalkanediyl, O-(C 1 -C 6 alkanediyl), O-(C 1 -C 6 fluoroalkanediyl), C(O) and a bond;

R 1 , R 2 , R 3 and R 4 are independently selected from the group consisting of H, F, Cl, Br, I, -CH 3 , -CH 2 CH 3 , -CH 2 OH, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -COCH 3 , -OH, -OCH 3 , -OCH 2 CH 3 ;

R 5 is selected from H and C 1 -C 9 alkyl optionally substituted with one or more halogens, CN, OR a , N(R a ) 2 , C 1 -C 9 alkyl, C 3 -C 9 a cycloalkyl group, a C 3 -C 9 heterocyclic ring, a C 6 -C 9 aryl group, and a C 6 -C 9 heteroaryl group;

R 6 is selected from the group consisting of H, F, Cl, Br, I, -CN, -CH 3 , -CF 3 , -NO 2 , -OH, -OCH 3 and -SCH 3 ;

Wherein the alkanediyl, fluoroalkanediyl, aryldiyl, carbocyclicdiyl, heterocyclic diyl and heteroaryldiyl are optionally substituted with one or more groups independently selected from the group consisting of F, Cl, Br, I, -CN, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH 2 CH 2 F, -NH 2 , -NHCH 3 , -N ( CH 3 ) 2 , -NHCOCH 3 , -NO 2 , =O, -OH, -OCH 3 , -OCH 2 CH 3 and -SCH 3 .
A compound of formula I according to claim 1 or 2, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Y 1 is N and Y 3 is C(R b ) 2 .
A compound of formula I according to any one of claims 1 to 3, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Y 2 is -(CH 2 )-.
A compound of formula I according to any one of claims 1 to 4, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein Cy is a C 6 -C 20 aryldiyl group.
A compound of formula I according to any one of claims 1 to 5, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the C 6 -C 20 aryldiyl group is a phenyldiyl group.
A compound of formula I according to any one of claims 1 to 6, and stereoisomers, tautomers or pharmaceutically acceptable salts thereof, wherein the phenyldiyl group is substituted with one or more F.
Any compounds and stereoisomers of Formula I are 1-7 claims, tautomer or pharmaceutically acceptable salt thereof, wherein R 1 and R 2 is H.
Any compounds and stereoisomers of Formula I are 1-8 claims, tautomer or pharmaceutically acceptable salt thereof, wherein R 3 is H and R 4 is -CH 3.
A compound of formula I according to any one of claims 1-9, and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein R 5 is C 1 -C 6 optionally substituted with one or more halogens alkyl.
And any compound of Formula I stereoisomers of 1-10 claims, tautomer or pharmaceutically acceptable salt thereof, wherein R 6 is H.
A compound of the formula I according to claim 1 and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the formula I is of the formula Ia:
A compound of the formula I according to claim 1 and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the formula I is of the formula Ib:
A compound of the formula I according to claim 1 and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the formula I is of the formula Ic:

among them

R 7 is F, Cl, Br, I, -CN, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CH 2 OH, -CH 2 OCH 3 , -CH 2 CH 2 OH, -C(CH 3 ) 2 OH, -CH(OH)CH(CH 3 ) 2 , -C(CH 3 ) 2 CH 2 OH, -CH 2 CH 2 SO 2 CH 3 , -CH 2 OP(O)(OH) 2 , -CH 2 F, -CHF 2 , -CH 2 NH 2 , -CH 2 NHSO 2 CH 3 , -CH 2 NHCH 3 , -CH 2 N (CH 3 2 , -CF 3 , -CH 2 CF 3 , -CH 2 CHF 2 , -CH(CH 3 )CN, -C(CH 3 ) 2 CN, -CH 2 CN, -CO 2 H, -COCH 3 , -CO 2 CH 3 , -CO 2 C(CH 3 ) 3 , -COCH(OH)CH 3 , -CONH 2 , -CONHCH 3 , -CONHCH 2 CH 3 , -CONHCH(CH 3 ) 2 , -CON(CH 3 ) 2 , -C(CH 3 ) 2 CONH 2 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -NHCOCH 3 , -N(CH 3 )COCH 3 , -NHS(O) 2 CH 3 , -N(CH 3 )C(CH 3 ) 2 CONH 2 , -N(CH 3 )CH 2 CH 2 S(O) 2 CH 3 , -NO 2 , =O, -OH, -OCH 3 ,- OCH 2 CH 3 , -OCH 2 CH 2 OCH 3 , -OCH 2 CH 2 OH, -OCH 2 CH 2 N(CH 3 ) 2 , -OP(O)(OH) 2 , -S(O) 2 N ( CH 3 ) 2 , -SCH 3 , -S(O) 2 CH 3 , -S(O) 3 H, cyclopropyl, cyclopropyl amide group, oxetanyl, azetidinyl ,(1 -methylazetidin-3-yl)oxy, N-methyl-N-oxetan-3-ylamino, azetidin-1-ylmethyl, benzyloxy Phenyl, pyrrolidin-1-yl, pyrrolidin-1-yl-methanone, piperazin-1-yl, morpholinomethyl, morpholino-methanone and morpholino;

n is selected from 0, 1, 2, 3, and 4;

R 8 is H or -CH 3 .
A compound of the formula I according to claim 1 and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein n is 2, wherein said formula I is of the formula Id:
A compound of the formula I according to claim 1 and a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, wherein the compound of the formula I is a compound of the formula (I) or (II):
A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a pharmaceutically acceptable carrier, glidant, diluent or excipient.
A method of treating an estrogen receptor-associated disease in a patient, comprising administering to the patient a therapeutically effective amount of a compound of any of claims 1-16.
The method of claim 18, wherein the estrogen receptor-associated disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.
Use of a compound according to any one of claims 1 to 16 for the manufacture of a medicament for the treatment of an estrogen receptor related disorder.
The use according to claim 20, wherein the estrogen receptor-associated disease is a cancer selected from the group consisting of breast cancer, lung cancer, ovarian cancer, endometrial cancer, prostate cancer, and uterine cancer.