Indazole derivative, preparation method thereof and application of indazole derivative in medicine

Abstract

The invention relates to an indazole derivative, a preparation method thereof and application of the indazole derivative in medicine. In particular, the disclosure relates to an indazole derivative as shown in general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and an application of the indazole derivative as an estrogen receptor modulator for preventing and / or treating estrogen receptor mediated or dependent diseases or symptoms, particularly breast cancer. Wherein each substituent in the general formula (I) is as defined in the specification. # imgabs0 #

Description

[0001] This application is a divisional application of the Chinese patent application with application number 202080038970.4, application date June 18, 2020, and invention name “Indazole derivatives, preparation methods thereof and their application in medicine”. Technical Field

[0002] The present disclosure belongs to the field of medicine, and relates to an indazole derivative, a preparation method thereof, and a medical application thereof. The present disclosure discloses the use of the indazole derivative as an estrogen receptor modulator to prevent and / or treat estrogen receptor-mediated or dependent diseases or conditions, and the disease is particularly preferably breast cancer. Background Art

[0003] Breast cancer is one of the most common malignant tumors in women. According to GLOBALCAN statistics in 2012 (CACANCER J CLIN 2015; 65:87-108), there are approximately 1.7 million new cancer cases and 520,000 deaths per year worldwide. Both the incidence and mortality rates of breast cancer rank first among malignant tumors in women.

[0004] About 70% of breast cancer patients have estrogen receptor (ER)-positive breast cancer. Endocrine therapy plays an important role in the treatment of this part of breast cancer patients. Endocrine therapy is mainly divided into three categories: aromatase inhibitor (AI), which can inhibit the conversion of androgens into estrogens and reduce the level of estrogen in the body; selective estrogen receptor modulator (SERM), which antagonizes the activity of estrogen receptors; and selective estrogen receptor degrader (SERD), which can not only antagonize the activity of estrogen receptors, but also promote the degradation of receptors (Pharmacol Ther. 2017Dec 28). Although endocrine therapy is the first choice for estrogen receptor-positive breast cancer, about 30% of patients who receive adjuvant therapy will relapse, and almost all patients with metastatic breast cancer will develop drug resistance and progress. The mechanisms of resistance to endocrine therapy can be divided into two categories. One category focuses on the estrogen receptor signaling pathway itself, including activating mutations, amplification, and fusion with other genes of the gene ESR1 encoding the estrogen receptor, and the dysregulation of estrogen receptor co-regulators and downstream cell cycle control factors. The other mechanism includes the activation of signaling pathways that cross-react with the estrogen receptor signaling pathway, such as the growth factor receptor pathway (Nat Rev Clin Oncol. 2015 Oct; 12(10): 573-83).

[0005] In 2013, two studies detected ESR1 gene mutations in 11-55% of estrogen receptor-positive metastatic breast cancer patients who had been treated with aromatase inhibitors. Further studies found that the mutated receptor can be phosphorylated independently of estrogen and exert transcriptional effects, making the estrogen-dependent MCF7-inoculated tumors no longer dependent on estrogen for growth in vivo. In addition, the mutated receptor reduces the activity of SERM tamoxifen and SERD fulvestrant. Therefore, ESR1 gene mutation may be one of the mechanisms of drug resistance in estrogen-positive breast cancer (Nat Rev Clin Oncol. 2015 Oct; 12 (10): 573-83 and Nat Genet 2013; 45: 1439-45). In subsequent studies, a certain proportion of ESR1 gene mutations were found in estrogen receptor-positive metastatic breast cancer patients, with the mutation ratio being about 30%. In the BOLERO-2 clinical trial, 29% of ctDNA of patients with estrogen receptor-positive metastatic breast cancer who progressed after AIs treatment contained ER Y537S and ER D538G mutations. In the exemestane monotherapy group, patients with mutations had shorter progression-free survival (PFS) and overall survival (OS) than those without mutations (Nat Genet 2013; 45: 1446-51).

[0006] In summary, ESR1 gene mutations mostly occur in patients with metastatic estrogen receptor-positive breast cancer that progress after AIs treatment. These patients are no longer sensitive to AIs treatment, so it is necessary to develop estrogen receptor antagonists targeting ESR1 gene mutations.

[0007] The first-in-class estrogen receptor covalent binding antagonist H3B-6545 developed by Eisai has strong inhibitory activity against both wild-type and mutant estrogen receptors, and can exert a longer-lasting drug effect through covalent binding to the receptor. It is currently undergoing phase I and II clinical trials. The currently disclosed patents for estrogen receptor antagonists targeting ESR1 gene mutations are WO2016196346 and WO2016196342. Summary of the invention

[0008] The object of the present disclosure is to provide a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof:

[0009]

[0010] in:

[0011] G is CH or N;

[0012] Z is selected from key, CR 5 R 6 , -O-(CH2)t- or -NR 7 -(CH2)t-;

[0013] Ring A is selected from cycloalkyl or heterocyclyl;

[0014] R a Selected from -CH2CH=CHC(O)NR 8 R 9 、-C(O)CH=CR 10 R 11 and -C(O)C≡CR 12 ;

[0015] R b is selected from a hydrogen atom or an alkyl group;

[0016] R 1 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0017] R 2 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, amino, cyano, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl, aryl and heteroaryl;

[0018] R 3 Each is the same or different and is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, NR 13 C(O)R 14 、C(O)NR 13 R 14 、SO2R 15 , cycloalkyl, heterocyclyl, aryl and heteroaryl;

[0019] R 4 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxyl group, an aldehyde group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0020] R 5 and R 6are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0021] R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0022] R 8 and R 9 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0023] Or, R 8 and R 9 Together with the nitrogen atom to which it is connected, it forms a heterocyclic group, wherein the heterocyclic group contains, in addition to one nitrogen atom, 1 to 2 identical or different heteroatoms selected from N, O and S, and the heterocyclic group is optionally substituted by one or more substituents selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0024] R 10 and R 11 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0025] R 12 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0026] R 13 and R 14 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0027] R 15 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0028] m is 0 or 1;

[0029] n is 0, 1, 2 or 3;

[0030] q is 0, 1, 2, 3, 4, or 5;

[0031] s is 0, 1, 2, or 3 and

[0032] t is 0, 1, 2, 3, 4, 5 or 6.

[0033] In a preferred embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from C3-C6 cycloalkyl, a 3- to 6-membered heterocyclic group; the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S.

[0034] In another preferred embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or piperidinyl.

[0035] In another preferred embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from Best

[0036] In a preferred embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or pharmaceutically acceptable salt thereof:

[0037]

[0038] in

[0039] Ring A, G, Z, R 1 , R 2 , R 3 , R 4 , R a , R b , n, m, s and q are as defined in the general formula (I).

[0040] In another preferred embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or pharmaceutically acceptable salt thereof:

[0041]

[0042] Among them: G, Z, R 1 , R 2 , R 3 , R 4 , R a , R b , n, m, s and q are as defined in the general formula (I).

[0043] In another preferred embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or pharmaceutically acceptable salt thereof, is a compound represented by general formula (IV) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or pharmaceutically acceptable salt thereof:

[0044]

[0045] in:

[0046] G, Z, R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , R b , n, s and q are as defined in the general formula (I);

[0047] Preferably, R 8 and R 9 Together with the connected nitrogen atom, a heterocyclic group is formed, wherein the heterocyclic group contains, in addition to 1 nitrogen atom, 1 to 2 identical or different heteroatoms selected from N, O and S, and the heterocyclic group is optionally substituted by one or more substituents selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic group, aryl and heteroaryl; more preferably, the heterocyclic group is optionally substituted by hydroxyl or hydroxyalkyl; further preferably, the heterocyclic group is optionally substituted by hydroxyl.

[0048] In another preferred embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is a N atom.

[0049] In another preferred embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or its pharmaceutically acceptable salt, wherein R 1 is selected from halogen or hydrogen atom.

[0050] In another preferred embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or its pharmaceutically acceptable salt, wherein R 2 It is a haloalkyl group, preferably a C1-C6 haloalkyl group, more preferably -CH2CF3.

[0051] In another preferred embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or its pharmaceutically acceptable salt, wherein R 3 Selected from hydrogen, halogen, alkyl, cyano, haloalkyl, NR 13 C(O)R 14 、C(O)NR 13 R 14 and SO2R 15 ; R 13 and R 14 are the same or different and are each independently selected from a hydrogen atom and an alkyl group; R 15 is selected from a hydrogen atom and an alkyl group.

[0052] In another preferred embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or its pharmaceutically acceptable salt, wherein R 4 The same or different, each independently selected from hydrogen atom, halogen, alkyl and alkoxy, preferably hydrogen atom.

[0053] In another preferred embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z is selected from a bond, -O-, -O-CH2- and -NH-.

[0054] In another preferred embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or its pharmaceutically acceptable salt, wherein R a Selected from -CH2CH=CHC(O)NR 8 R 9 、-C(O)CH=CR 10 R 11 and -C(O)C≡CR 12 ; R 8 and R 9 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group or a heterocyclic group; or R 8 and R9 Together with the nitrogen atom to which it is connected, it forms a heterocyclic group, wherein the heterocyclic group contains, in addition to one nitrogen atom, 1 to 2 identical or different heteroatoms selected from N, O and S, and the heterocyclic group is optionally substituted by one or more substituents selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 10 and R 11 are the same or different and are each independently a hydrogen atom or an alkyl group; R 12 is selected from a hydrogen atom or an alkyl group.

[0055] In another preferred embodiment of the present disclosure, the compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or its pharmaceutically acceptable salt, wherein R a Selected from -CH2CH=CHC(O)N(CH3)2, -CH2CH=CHC(O)NH(CH3), -CH2CH=CHC(O)NHC(CH3)3, -C(O)CH=CH2, -C(O)C≡CCH3,

[0056] Preferably, R a Selected from -CH2CH=CHC(O)N(CH3)2, -CH2CH=CHC(O)NH(CH3), -CH2CH=CHC(O)NHC(CH3)3, -C(O)CH=CH2, -C(O)C≡CCH3,

[0057]

[0058] Typical compounds of general formula (I) include, but are not limited to:

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068] or its tautomer, meso racemate, racemate, enantiomer, diastereomer or mixture form, or its pharmaceutically acceptable salt.

[0069] Another aspect of the present disclosure provides a compound represented by the general formula (IA) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0070]

[0071] It is an intermediate for synthesizing general formula (I),

[0072] in:

[0073] R w is an amino protecting group, preferably tetrahydropyranyl;

[0074] R is selected from -CH2CH=CHC(O)NR 8 R 9 、-C(O)CH=CR 10 R 11 or -C(O)C≡CR 12 ;

[0075] R 8 and R 9 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group;

[0076] Or, R 8 and R 9 Together with the nitrogen atom to which it is connected, it forms a heterocyclic group, wherein the heterocyclic group contains, in addition to one nitrogen atom, 1 to 2 identical or different heteroatoms selected from N, O and S, and the heterocyclic group is optionally selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, -COOR 16 -, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with one or more substituents;

[0077] R 10 and R 11 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl;

[0078] R 12is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

[0079] R 16 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group;

[0080] Ring A, G, Z, R 1 , R 2 , R 3 , R 4 , R b , n, m, s and q are as defined in the general formula (I).

[0081] Another aspect of the present disclosure provides a compound represented by general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0082]

[0083] It is an intermediate for synthesizing general formula (II),

[0084] in:

[0085] R w is an amino protecting group, preferably tetrahydropyranyl;

[0086] R is as defined in Formula (IA);

[0087] Ring A, G, Z, R 1 , R 2 , R 3 , R 4 , R b , n, m, s and q are as defined in the general formula (II).

[0088] Another aspect of the present disclosure provides a compound represented by general formula (IIIA) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0089]

[0090] It is an intermediate for synthesizing general formula (III),

[0091] in:

[0092] R w is an amino protecting group, preferably tetrahydropyranyl;

[0093] R is as defined in Formula (IA);

[0094] G, Z, R 1 , R2 , R 3 , R 4 , R b , n, s and q are as defined in the general formula (III).

[0095] Another aspect of the present disclosure provides a compound represented by the general formula (IVA) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof,

[0096]

[0097] It is an intermediate for synthesizing general formula (IV),

[0098] in:

[0099] R w is an amino protecting group, preferably tetrahydropyranyl;

[0100] G, Z, R 1 , R 2 , R 3 , R 4 , R b , R 8 , R 9 , n, s and q are as defined in the general formula (IV).

[0101] Typical compounds of general formula (IA) include, but are not limited to:

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112] or its tautomer, meso racemate, racemate, enantiomer, diastereomer or mixture form, or its pharmaceutically acceptable salt.

[0113] In another aspect, the present disclosure provides a method for preparing a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0114]

[0115] The compound or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt undergoes a deprotection reaction under acidic conditions to obtain a compound of formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt;

[0116] in:

[0117] R w is an amino protecting group, preferably tetrahydropyranyl or tert-butyloxycarbonyl;

[0118] R is as defined in Formula (IA);

[0119] Ring A, G, Z, R 1 , R 2 , R 3 , R 4 , R a , R b , n, m, s and q are as defined in the general formula (I).

[0120] In another aspect, the present disclosure provides a method for preparing a compound represented by general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0121]

[0122] The compound of the general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, undergoes a deprotection reaction under acidic conditions to obtain a compound of the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof;

[0123] in:

[0124] R w is an amino protecting group, preferably tetrahydropyranyl or tert-butyloxycarbonyl;

[0125] R is as defined in formula (IIA);

[0126] Ring A, G, Z, R 1 , R 2 , R 3 , R 4 , R a , R b , n, m, s and q are as defined in the general formula (II).

[0127] In another aspect, the present disclosure provides a method for preparing a compound represented by general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0128]

[0129] The compound of the general formula (IIIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, undergoes a deprotection reaction under acidic conditions to obtain a compound of the general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof;

[0130] in:

[0131] R w is an amino protecting group, preferably tetrahydropyranyl or tert-butyloxycarbonyl;

[0132] R is as defined in formula (IIIA);

[0133] G, Z, R 1 , R 2 , R 3 , R 4 , R a , R b , n, s and q are as defined in the general formula (III).

[0134] In another aspect, the present disclosure provides a method for preparing a compound represented by general formula (IV) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

[0135]

[0136] The compound of the general formula (IVA) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, undergoes a deprotection reaction under acidic conditions to obtain a compound of the general formula (IV) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof;

[0137] in:

[0138] R w is an amino protecting group, preferably tetrahydropyranyl or tert-butyloxycarbonyl;

[0139] G, Z, R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , R b , n, s and q are as defined in the general formula (IV).

[0140] Another aspect of the present disclosure relates to a pharmaceutical composition, which contains a therapeutically effective dose of the compound shown in each of the above general formulas (I) to (IV) or its tautomer, mesomorph, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt, and one or more pharmaceutically acceptable carriers, diluents or excipients. The present disclosure also relates to a method for preparing the above pharmaceutical composition, which comprises mixing the compound shown in each of the general formulas (I) to (IV) or its tautomer, mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier, diluent or excipient.

[0141] The present disclosure further relates to the use of compounds represented by general formula (I) to (IV) or their tautomers, mesomers, racemates, enantiomers, diastereomers or mixtures thereof, or their pharmaceutically acceptable salts or pharmaceutical compositions containing them in the preparation of estrogen receptor modulators.

[0142] The present disclosure further relates to the use of compounds represented by general formula (I) to (IV) or their tautomers, mesomers, racemates, enantiomers, diastereoisomers or mixtures thereof, or pharmaceutically acceptable salts thereof or pharmaceutical compositions comprising the same in the preparation of drugs for preventing and / or treating estrogen receptor-mediated or dependent diseases or conditions; wherein the estrogen receptor-mediated or dependent diseases or conditions are preferably cancer, more preferably breast cancer, ovarian cancer, endometrial cancer, prostate cancer or uterine cancer; further preferably breast cancer.

[0143] The present disclosure further relates to a compound represented by general formula (I) to (IV) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof for use as a drug.

[0144] The present disclosure further relates to a compound represented by the general formula (I) to (IV) of the present disclosure or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, which is used as a drug for treating estrogen receptor-mediated or dependent diseases or conditions; wherein the estrogen receptor-mediated or dependent diseases or conditions are preferably cancer, more preferably breast cancer, ovarian cancer, endometrial cancer, prostate cancer or uterine cancer; further preferably breast cancer.

[0145] The present disclosure further relates to a method for treating an estrogen receptor-mediated or dependent disease or condition, the method comprising administering to a patient in need thereof a therapeutically effective dose of a compound of the general formula (I) to (IV) of the present disclosure or its tautomer, mesomorph, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof. The method exhibits outstanding efficacy and fewer side effects. The estrogen receptor-mediated or dependent disease or condition is preferably cancer, more preferably breast cancer, ovarian cancer, endometrial cancer, prostate cancer or uterine cancer; breast cancer is further preferred.

[0146] The active compound may be formulated for administration by any appropriate route, preferably in a unit dosage form, or in a form in which the patient can self-administer a single dose. The unit dosage form of the compound or composition of the present invention may be tablets, capsules, cachets, bottled liquids, powders, granules, lozenges, suppositories, reconstituted powders or liquid preparations.

[0147] The dosage of the compound or composition used in the treatment method of the present invention will generally vary with the severity of the disease, the patient's weight and the relative efficacy of the compound. However, as a general guide, a suitable unit dosage may be 0.1 to 1000 mg.

[0148] The pharmaceutical composition of the present invention may contain one or more excipients in addition to the active compound, and the excipients are selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients, etc. Depending on the administration method, the composition may contain 0.1 to 99% by weight of the active compound.

[0149] The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Oral compositions may be prepared according to any method known in the art for preparing pharmaceutical compositions, and such compositions may contain one or more ingredients selected from the following: sweeteners, flavoring agents, colorants and preservatives to provide pleasing and palatable pharmaceutical preparations. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for preparing tablets for mixing. These excipients may be inert excipients; granulating agents and disintegrants; and lubricants. These tablets may be uncoated or may be coated by known techniques that mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained release effect over a longer period of time. For example, water-soluble taste masking substances may be used. Oral preparations may also be provided in soft gelatin capsules in which the active ingredient is mixed with an inert solid diluent, or in which the active ingredient is mixed with a water-soluble carrier.

[0150] Aqueous suspensions contain active substances and excipients suitable for preparing aqueous suspensions for mixing. Such excipients are suspending agents, dispersants or wetting agents. The active ingredient of the aqueous suspension can be a dispersible powder or granules. By adding water, the active ingredient is mixed with one or more dispersants, wetting agents or suspending agents. The aqueous suspension may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents and one or more sweeteners.

[0151] Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil or a mineral oil. The oil suspension may contain a thickener. The above-mentioned sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions may be preserved by adding an antioxidant.

[0152] Dispersible powders and granules suitable for preparing water suspensions can be provided with the active ingredient and a dispersant or wetting agent, a suspending agent or one or more preservatives for mixing by adding water. Suitable dispersants or wetting agents and suspending agents illustrate the examples above. Other excipients such as sweeteners, flavoring agents and coloring agents can also be added. These compositions can be preserved by adding antioxidants such as ascorbic acid.

[0153] The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil or a mineral oil or a mixture thereof. A suitable emulsifier may be a naturally occurring phospholipid. A sweetener may be used. Such preparations may also contain a demulcent, a preservative, a colorant, and an antioxidant.

[0154] The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. The sterile injectable formulation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. The injection or microemulsion may be injected into the patient's bloodstream by local mass injection. Alternatively, the solution and microemulsion may be preferably administered in a manner that maintains a constant circulating concentration of the disclosed compound. To maintain such a constant concentration, a continuous intravenous drug delivery device may be used. An example of such a device is the Deltec CADD-PLUS.TM.5400 intravenous injection pump.

[0155] Pharmaceutical compositions of the present disclosure can be in the form of sterile injection water or oil suspension for intramuscular and subcutaneous administration. Can be prepared by known technology with those suitable dispersants or wetting agents and suspending agents. Sterile injection preparations can also be sterile injection solutions or suspensions prepared in parenteral acceptable nontoxic diluents or solvents. In addition, sterile fixed oil can be used conveniently as solvent or suspension medium. In addition, fatty acids can also prepare injections.

[0156] The disclosed compounds may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and will therefore melt in the rectum to release the drug.

[0157] As is well known to those skilled in the art, the dosage of a drug depends on a variety of factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health status of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment method such as the mode of treatment, the daily dosage of the compound of formula (I) or the type of pharmaceutically acceptable salt can be verified according to traditional treatment plans.

[0158] Detailed description of the invention

[0159] Unless stated otherwise, the terms used in the specification and claims have the following meanings.

[0160] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, and more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-Dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0161] The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group having two residues derived from the same carbon atom or two different carbon atoms of a parent alkane by removing two hydrogen atoms, which is a straight or branched group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 carbon atoms, and more preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of alkylene include, but are not limited to, methylene (-CH2-), 1,1-ethylene (-CH(CH3)-), 1,2-ethylene (-CH2CH2)-, 1,1-propylene (-CH(CH2CH3)-), 1,2-propylene (-CH2CH(CH3)-), 1,3-propylene (-CH2CH2CH2-), 1,4-butylene (-CH2CH2CH2CH2-), and the like. The alkylene group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably independently selected from one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio and oxo.

[0162] The term "alkenyl" refers to an alkyl compound containing a carbon-carbon double bond in the molecule, wherein the alkyl group is as defined above. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0163] The term "alkynyl" refers to an alkyl compound containing a carbon-carbon triple bond in the molecule, wherein the definition of alkyl is as described above. Alkynyl may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from one or more substituents of hydrogen, alkyl, alkoxy, halogen, haloalkyl, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl and heteroaryl.

[0164] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl and cycloalkyl are defined as described herein. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0165] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12), and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused and bridged cycloalkyls.

[0166] The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (called a spiral atom) between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan (e.g., 6, 7, 8, 9, 10, 11, 12, 13, 14 yuan), more preferably 7 to 10 yuan. According to the number of spiral atoms shared between the rings, the spirocycloalkyl is divided into a single spiral cycloalkyl, a double spiral cycloalkyl or a multi-spirocycloalkyl, preferably a single spiral cycloalkyl and a double spiral cycloalkyl. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiral cycloalkyl. Non-limiting examples of spirocycloalkyl include:

[0167]

[0168] The term "condensed cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which each ring in the system shares a pair of adjacent carbon atoms with other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl, preferably a bicyclic or tricyclic, more preferably a 5-yuan / 5-yuan or 5-yuan / 6-yuan bicyclic alkyl. Non-limiting examples of condensed cycloalkyls include:

[0169]

[0170] The term "bridged cycloalkyl" refers to a 5 to 20-membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, and more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably a bicyclic, tricyclic or tetracyclic, and more preferably a bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

[0171]

[0172] The cycloalkyl ring includes the above-mentioned cycloalkyl (such as spirocycloalkyl, fused cycloalkyl and bridged cycloalkyl) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc. The cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, which are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0173] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen, S, S(O) or S(O)2, but excluding the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms (e.g., 1, 2, 3 and 4); more preferably, it contains 3 to 6 ring atoms (e.g., 3, 4, 5, 6). Non-limiting examples of monocyclic heterocyclyls include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably piperidinyl and pyrrolidinyl. Polycyclic heterocyclyls include spirocyclic, fused and bridged heterocyclyls.

[0174] The term "spiro heterocyclic group" refers to a polycyclic heterocyclic group in which one atom (called a spiral atom) is shared between 5 to 20 monocyclic rings, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, S, S(O) or S(O)2, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (e.g., 7, 8, 9 or 10 yuan). According to the number of shared spiral atoms between rings, the spiral heterocyclic group is divided into a single spiral heterocyclic group, a double spiral heterocyclic group or a multi-spiro heterocyclic group, preferably a single spiral heterocyclic group and a double spiral heterocyclic group. More preferably, it is a 4-yuan / 4-yuan, 4-yuan / 5-yuan, 4-yuan / 6-yuan, 5-yuan / 5-yuan or 5-yuan / 6-yuan single spiral heterocyclic group. Non-limiting examples of spiral heterocyclic groups include:

[0175]

[0176] The term "fused heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 20 members, each ring in the system shares a pair of atoms adjacent to other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, S, S(O) or S(O)2, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group, preferably a bicyclic or tricyclic group, more preferably a 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

[0177]

[0178] The term "bridged heterocyclic group" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, S, S(O) or S(O)2, and the remaining ring atoms are carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members (e.g., 7, 8, 9 or 10 members). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

[0179]

[0180] The heterocyclic ring includes the above-mentioned heterocyclic groups (such as spiro heterocyclic groups, fused heterocyclic groups and bridged heterocyclic groups) fused to aryl, heteroaryl or cycloalkyl rings, wherein the ring connected to the parent structure is a heterocyclic group, and its non-limiting examples include:

[0181]

[0182] The heterocyclyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0183] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings that share adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. The aryl ring includes the above aryl fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and its non-limiting examples include:

[0184]

[0185] The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate, preferably phenyl.

[0186] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5 to 10 yuan (e.g., 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidyl, thiadiazole, pyrazinyl, etc., preferably imidazolyl, pyrazolyl, pyrimidyl or thiazolyl; more preferably pyrazolyl or thiazolyl. The heteroaryl ring includes the above-mentioned heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and its non-limiting examples include:

[0187]

[0188] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0189] The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0190] The term "haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.

[0191] The term "deuterated alkyl" refers to an alkyl group substituted with a deuterium atom, wherein alkyl is as defined above.

[0192] The term "hydroxy" refers to an -OH group.

[0193] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0194] The term "amino" refers to -NH2.

[0195] The term "cyano" refers to -CN.

[0196] The term "nitro" refers to -NO2.

[0197] The term "carboxy" refers to -C(O)OH.

[0198] The term "aldehyde" refers to -CHO.

[0199] The term "carboxylate" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

[0200] The term "acyl halide" refers to a compound containing the group -C(O)-halogen.

[0201] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "a heterocyclic group optionally substituted with an alkyl group" means that an alkyl group may but need not be present, and the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0202] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in the group are replaced independently of each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the skilled person can determine (by experiment or theory) possible or impossible substitutions without undue effort. For example, amino or hydroxy groups with free hydrogens may be unstable when combined with carbon atoms with unsaturated (e.g. olefinic) bonds.

[0203] "Pharmaceutical composition" means a mixture containing one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or prodrugs and other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitate the absorption of the active ingredient, and thus exert biological activity.

[0204] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present disclosure, which are safe and effective when used in mammals and have the desired biological activity.

[0205] In the present disclosure, different terms such as “X is selected from A, B, or C”, “X is selected from A, B and C”, “X is A, B or C”, and “X is A, B and C” all express the same meaning, that is, X can be any one or more of A, B, and C.

[0206] The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivative" refers to a compound whose structure differs only in the presence of one or more isotopically enriched atoms. For example, a compound having a structure of the present disclosure except that hydrogen is replaced by "deuterium" or "tritium", or by 18 F-fluorine labeling ( 18F isotope) instead of fluorine, or with 11 C-, 13 C-, or 14 C-enriched carbon ( 11 C-, 13 C-, or 14 C-carbon labeling; 11 C-, 13 C-, or 14 Compounds in which a carbon atom is replaced by a C-isotope) are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as in vivo diagnostic imaging tracers for diseases, or as tracers for pharmacodynamics, pharmacokinetics or receptor studies. Deuterated compounds can generally retain activity comparable to that of undeuterated compounds, and when deuterated at certain specific sites, better metabolic stability can be achieved, thereby obtaining certain therapeutic advantages (such as increased half-life in vivo or reduced dosage requirements).

[0207] With respect to a drug or pharmacologically active agent, the term "therapeutically effective amount" refers to a sufficient amount of the drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, depending on the age and general condition of the subject, and also on the specific active substance. The appropriate effective amount in each case can be determined by a person skilled in the art based on routine experiments.

[0208] The present disclosure provides a novel estrogen receptor antagonist represented by the general structural formula (I), and it is found that the compounds of this type of structure have good in vitro activity. Compared with the prior art, the amide compounds of this type of structure containing α, β unsaturated bonds can inactivate the estrogen receptor by specifically binding to the cysteine ​​in the estrogen receptor ligand binding domain.

[0209] Synthesis method of the disclosed compound

[0210] In order to achieve the purpose of this disclosure, this disclosure adopts the following technical solutions:

[0211] Solution 1

[0212] The present invention discloses a method for preparing a compound represented by general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the following steps:

[0213]

[0214] The compound of the general formula (IA) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, undergoes a deprotection reaction under acidic conditions to obtain a compound of the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof;

[0215] in:

[0216] R w is an amino protecting group; R is as defined in the general formula (IA);

[0217] Ring A, G, Z, R 1 , R 2 , R 3 , R 4 , R a , R b , n, m, s and q are as defined in the general formula (I).

[0218] Solution 2

[0219]

[0220] The compound of the general formula (IIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, undergoes a deprotection reaction under acidic conditions to obtain a compound of the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof;

[0221] in:

[0222] R w is an amino protecting group;

[0223] R is as defined in formula (IIA);

[0224] Ring A, G, Z, R 1 , R 2 , R 3 , R 4 , R a , R b , n, m, s and q are as defined in the general formula (II).

[0225] Option 3

[0226]

[0227] The compound of the general formula (IIIA) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, undergoes a deprotection reaction under acidic conditions to obtain a compound of the general formula (III) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof;

[0228] in:

[0229] R w is an amino protecting group;

[0230] R is as defined in formula (IIIA);

[0231] G, Z, R 1 , R 2 , R 3 , R 4 , R a , R b , n, s and q are as defined in the general formula (III).

[0232] Option 4

[0233]

[0234] The compound of the general formula (IVA) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, undergoes a deprotection reaction under acidic conditions to obtain a compound of the general formula (IV) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof;

[0235] in:

[0236] R w is an amino protecting group;

[0237] G, Z, R 1 , R 2 , R 3 , R 4 , R 8 , R 9 , R b , n, s and q are as defined in the general formula (IV).

[0238] The reagents for providing acidic conditions in the above scheme include, but are not limited to, pyridine hydrobromide, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid or methanesulfonic acid, preferably hydrochloric acid.

[0239] The amino protecting group is selected from tetrahydropyranyl, tert-butoxycarbonyl, acetyl, benzyl, allyl and p-methoxybenzyl, preferably tetrahydropyranyl.

[0240] The above reaction is preferably carried out in a solvent, and the solvent used includes but is not limited to: acetic acid, methanol, ethanol, toluene, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, water, N,N-dimethylformamide or a mixed solvent thereof. DETAILED DESCRIPTION

[0241] The present disclosure is further described below in conjunction with embodiments, but these embodiments do not limit the scope of the present disclosure.

[0242] Example

[0243] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD) as the measuring solvent, and tetramethylsilane (TMS) as the internal standard.

[0244] MS was determined using Agilent 1200 / 1290DAD-6110 / 6120 Quadrupole MS LC / MS (manufacturer: Agilent, MS model: 6110 / 6120 Quadrupole MS); Waters ACQuity UPLC-QD / SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector / waters SQ Detector); THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

[0245] High performance liquid chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489.

[0246] Chiral HPLC analysis was performed using an Agilent 1260DAD high performance liquid chromatograph.

[0247] High performance liquid chromatography was performed using Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

[0248] Chiral preparations were performed using a Shimadzu LC-20AP preparative chromatograph.

[0249] The CombiFlash rapid preparation instrument used Combiflash Rf200 (TELEDYNE ISCO).

[0250] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The silica gel plate used in thin layer chromatography (TLC) adopts a specification of 0.15mm-0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm-0.5mm.

[0251] Silica gel column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier.

[0252] Average kinase inhibition rate and IC 50 The values ​​were determined using NovoStar microplate reader (BMG, Germany).

[0253] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, AccelaChemBio Inc, Darui Chemicals, and other companies.

[0254] Unless otherwise specified in the examples, the reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0255] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1L.

[0256] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0257] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or a HC2-SS hydrogenator.

[0258] The hydrogenation reaction is usually carried out by evacuating the vacuum, filling with hydrogen, and repeating the operation three times.

[0259] The microwave reaction was carried out using a CEM Discover-S 908860 microwave reactor.

[0260] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0261] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0262] The reaction progress in the embodiment is monitored by thin layer chromatography (TLC), the developing solvent used in the reaction, the eluent system of column chromatography used for purifying the compound and the developing solvent system of thin layer chromatography include: A: dichloromethane / methanol system, B: n-hexane / ethyl acetate system, C: petroleum ether / ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid can also be added for adjustment.

[0263] Example 1

[0264] (E)-1-morpholinyl-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 1

[0265]

[0266]

[0267] first step

[0268] tert-Butyl (1-(((5-iodopyridin-2-yl)oxy)methyl)cyclopropyl)carbamate 1c

[0269] Sodium hydride (0.4 g, 10.7 mmol) was dissolved in N,N-dimethylformamide (20 mL), and tert-butyl 1-(hydroxymethyl)cyclopropylcarbamate 1b (1.0 g, 5.3 mmol, prepared by the known method "Journal of Organic Chemistry, 2002, 67 (11), 3965-3968") was added at room temperature. After the addition was complete, 2-fluoro-5-iodopyridine 1a (1.8 g, 8.0 mmol) was slowly added. After stirring at room temperature for 2 hours, the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography using a developing solvent system B to obtain the title product 1c (2.4 g) with a yield of 86%.

[0270] MS m / z(ESI):391.0[M+1].

[0271] Step 2

[0272] (Z)-tert-Butyl (1-(((5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)carbamate 1f

[0273] 3-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,4-trifluorobut-1-yn-1-yl)-1H-indazole 1d (1.8 g, 5.5 mmol, prepared by the method disclosed in Example 3 on page 84 of the specification of patent application WO2018098305) was dissolved in methyltetrahydrofuran (40 mL), and bis-pinacol borate (1.7 g, 6.6 mmol) and tetrakistriphenylphosphine platinum (137 mg, 0.1 mmol) were added, argon was replaced 3 times, and the temperature was raised to 85 ° C and stirred for 3 hours. After cooling to room temperature, compound 1c (2.0 g, 5.2 mmol), bistriphenylphosphine palladium dichloride (741 mg, 1.1 mmol), cesium carbonate (3.6 g, 11.0 mmol) and water (1 mL) were added, and stirred at room temperature overnight. Add iodobenzene 1e (1.2 g, 6.1 mmol) and potassium hydroxide (1.5 g, 27.6 mmol), replace argon three times, heat to 85°C and stir for 2 hours, then cool to room temperature to stop the reaction. The reaction solution is concentrated under reduced pressure, and the residue is purified by thin layer chromatography with developing solvent system B to obtain the title product 1f (3.0 g), with a yield of 88%.

[0274] MS m / z(ESI):667.2[M+1].

[0275] Step 3

[0276] (Z)-(1-(((5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbutane-1-yl)-

[0277] (1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)-1-amine 1g

[0278] Compound 1f (1.8 g, 2.7 mmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (3 mL) was added, and the reaction was stirred at room temperature for 5 hours to stop the reaction. The reaction solution was concentrated under reduced pressure, and the reaction solution was adjusted to pH 8 with saturated sodium bicarbonate solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1 g crude product (1.4 g) of the title product, with a yield of 89%. The product was directly used for the next step without purification.

[0279] Step 4

[0280] (E)-1-morpholinyl-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 1i

[0281] Compound 1g (1.7g, 2.8mmol) was dissolved in N,N-dimethylformamide (20mL), diisopropylethylamine (1.1g, 8.5mmol) was added at room temperature, and then (E)-4-bromo-1-morpholinylbut-2-ene-1-one 1h (0.7g, 2.8mmol, prepared by the method disclosed in Example 15 on page 65 of the specification of patent application US2016347717) was added, and the reaction was stirred for 2 hours. The reaction was stopped and cooled, saturated sodium bicarbonate solution (15mL) was added, and extracted with ethyl acetate (50mL×2), the organic phases were combined, washed with saturated sodium chloride solution (50mL×4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with developing solvent system A to obtain the title product 1i (1.3g), with a yield of 65%.

[0282] MS m / z(ESI):720.2[M+1].

[0283] Step 5 (E)-1-morpholinyl-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 1

[0284] Compound 1i (2.0 g, 2.8 mmol) was dissolved in methanol (5 mL), and hydrochloric acid (12 N, 10 mL) was added and stirred for 3 hours. The reaction was stopped and cooled, the reaction solution was concentrated, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with dichloromethane (50 mL×4), the organic phases were combined, washed with water (30 mL×3), saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with developing solvent system A to obtain the title product 1 (1.3 g), with a yield of 73%.

[0285] MS m / z(ESI):636.2[M+1].

[0286] 1 H NMR(400MHz,CD3OD)7.65(d,2H),7.49(d,1H),7.30-7.22(m,7H),6.82-6.76( m,1H),6.60-6.52(m,2H),4.15(s,2H),3.62-3.39(m,12H),0.76-0.64(m,4H).

[0287] Example 2

[0288] (E)-1-(pyrrolin-1-yl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 2

[0289]

[0290]

[0291] first step

[0292] (E)-1-(pyrrolin-1-yl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 2b

[0293] The synthetic route of Example 1 was adopted, and the fourth step raw material 1h was replaced by (E)-4-bromo-1-(pyrrolidine-1-yl)but-2-en-1-one 2a (prepared by the method disclosed in Example 11 on page 58 of the specification of patent application US2016347717) to obtain the title compound 2b (51 mg) with a yield of 69%.

[0294] MS m / z(ESI):704.3[M+1].

[0295] Step 2

[0296] (E)-1-(pyrrolin-1-yl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 2

[0297] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 2b to obtain the title compound 2 (20 mg) with a yield of 65%.

[0298] MS m / z(ESI):620.3[M+1].

[0299] 1H NMR(400MHz,CD3OD)7.65(d,2H),7.50(d,1H),7.31-7.21(m,7H),6.84-6.80(m,1H),6.59( d,1H),6.38(d,1H),4.16(s,2H),3.61-3.39(m,8H),0.92-0.60(m,4H),0.72-0.64(m,4H).

[0300] Example 3

[0301] (E)-1-(piperidin-1-yl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0302] -1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 3

[0303]

[0304]

[0305] first step

[0306] (E)-1-(piperidin-1-yl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 3b

[0307] The synthetic route of Example 1 was adopted, and the fourth step raw material 1h was replaced by (E)-4-bromo-1-(piperidin-1-yl)but-2-en-1-one 3a (prepared by the method disclosed in Example 12 on page 58 of the specification of patent application US2016347717) to obtain the title compound 3b (40 mg) with a yield of 74%.

[0308] MS m / z(ESI):718.4[M+1].

[0309] Step 2

[0310] (E)-1-(piperidin-1-yl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0311] -1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 3

[0312] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 3b to obtain the title compound 3 (15 mg) with a yield of 61%.

[0313] MS m / z(ESI):634.3[M+1].

[0314] 1 H NMR (400MHz, CD3OD)7.65(d,2H),7.50(d,1H),7.30-7.21(m,7H),6.74-6.70(m,1H),6.60-6.55(m,2H),5.36-5. 35(m,1H),4.36(s,2H),3.56-3.53(m,5H),3.46-3.39(m,2H),2.05(s,1H),1.67-1.54(m,3H),0.92-0.68(m,6H).

[0315] Example 4

[0316] (E)-1-(piperazin-1-yl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbutyric acid

[0317] -1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 4

[0318]

[0319]

[0320] first step

[0321] tert-Butyl 4-((E)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-enoyl)piperazine-1-carboxylate 4b

[0322] The synthetic route of Example 1 was adopted, and the fourth step raw material 1h was replaced by (E)-4-(4-bromobut-2-enoyl)piperazine-1-carboxylic acid tert-butyl ester 4a (prepared by the method disclosed in Example 32 on page 129 of the specification of patent application WO2014160200) to obtain the title compound 4b (61 mg) with a yield of 72%.

[0323] MS m / z(ESI):819.4[M+1].

[0324] Step 2

[0325] (E)-1-(piperazin-1-yl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbutyric acid

[0326] -1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 4

[0327] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 4b to obtain the title compound 4 (20 mg) with a yield of 41%.

[0328] MS m / z(ESI):635.3[M+1].

[0329] 1 H NMR(400MHz,CD3OD)7.65(d,2H),7.50(d,1H),7.30-7.20(m,7H),6.82-6.77(m,1H),6.59-6.53( m,2H),4.15(s,2H),3.69-3.67(m,4H),3.53-3.41(m,4H),2.96-2.94(m,4H),0.72-0.62(m,4H).

[0330] Example 5

[0331] (E)-N,N-dimethyl-4-(methyl(1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbutane-1-yl)-

[0332] (cyclopropyl)amino)but-2-enamide 5-(4-(4-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-enamide

[0333]

[0334]

[0335] first step

[0336] Tert-butyl (1-(((5-iodopyridin-2-yl)oxy)methyl)cyclopropyl(methyl)carbamate 5a

[0337] Compound 1c (0.5 g, 1.3 mmol) was dissolved in N,N-dimethylformamide (25 mL), sodium hydride (0.1 g, 2.6 mmol) was added at room temperature, and iodomethane (0.3 g, 1.9 mmol) was slowly added after the addition was complete. The reaction was stopped after stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography using a developing solvent system B to obtain the title product 5a (0.5 g) with a yield of 87%.

[0338] MS m / z(ESI):405.1[M+1].

[0339] Step 2

[0340] (Z)-methyl(1-(((5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)carbamic acid tert-butyl ester 5b

[0341] The synthetic route of Example 1 was adopted, and the second step raw material 1c was replaced by compound 5a to prepare the title compound 5b (89 mg) with a yield of 85%.

[0342] MS m / z(ESI):681.3[M+1].

[0343] Step 3

[0344] (Z)-N-methyl-1-(((5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)-1-amine 5c

[0345] The synthetic route of Example 1 was adopted, and the raw material 1f in the third step was replaced by compound 5b to obtain the title compound 5c (60 mg) with a yield of 70%.

[0346] Step 4

[0347] (E)-N,N-dimethyl-4-(methyl(1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-enamide 5e

[0348] The synthetic route of Example 1 was adopted, and the raw material 1h in the fourth step was replaced by (E)-4-bromo-N,N-dimethylbut-2-enamide 5d (prepared by the method disclosed in Example 1 on page 39 of the specification of patent application US2016347717), and the raw material 1g was replaced by 5c to obtain the title compound 5e (60 mg) with a yield of 50%.

[0349] Step 5

[0350] (E)-N,N-dimethyl-4-(methyl(1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbutane-1-

[0351] (cyclopropyl)amino)but-2-enamide 5-(4-(4-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-enamide

[0352] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 5e to obtain the title compound 5 (15 mg) with a yield of 28%.

[0353] MS m / z(ESI):608.2[M+1].

[0354] 1 H NMR(400MHz, CDCl3)9.59(s,1H),7.65(d,2H),7.33(d,1H),7.28-7.23(m,6H),7.10(d,1H),6.79-6.75(m,1H),6. 46(d,1H),6.35(d,1H),4.22(s,2H),3.48(d,2H),3.38-3.35(m,2H),3.05(d,6H),2.38(s,3H),0.73-0.63(m,4H).

[0355] Example 6

[0356] (E)-4-(ethyl(1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridine

[0357] -2-yl)oxy)methyl)cyclopropyl)amino)-N,N-dimethylbut-2-enamide

[0358]

[0359] first step

[0360] Tert-butyl ethyl (1-(((5-iodopyridin-2-yl)oxy)methyl)cyclopropylcarbamate 6a

[0361] The synthetic route of Example 5 was adopted, and the first step reagent methyl iodide was replaced by ethyl iodide to prepare the title compound 6a (58 mg) with a yield of 88%.

[0362] Step 2

[0363] tert-Butyl (Z)-ethyl(1-(((5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)carbamate 6b

[0364] The synthetic route of Example 1 was adopted, and the second step raw material 1c was replaced by compound 6a to prepare the title compound 6b (85 mg) with a yield of 80%.

[0365] Step 3

[0366] (Z)-N-ethyl-1-(((5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)-1-amine 6c

[0367] The synthetic route of Example 1 was adopted, and the raw material 1f in the third step was replaced by compound 6b to obtain the title compound 6c (65 mg) with a yield of 76%.

[0368] Step 4 (E)-4-(ethyl(1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)-N,N-dimethylbut-2-enamide 6d

[0369] The synthetic route of Example 5 was adopted, and the raw material 5c in the fourth step was replaced by compound 6c to prepare the title compound 6d (70 mg) with a yield of 59%.

[0370] MS m / z(ESI):706.3[M+1].

[0371] Step 5

[0372] (E)-4-(ethyl(1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridine

[0373] -2-yl)oxy)methyl)cyclopropyl)amino)-N,N-dimethylbut-2-enamide

[0374] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 6d to obtain the title compound 6 (15 mg) with a yield of 28%.

[0375] MS m / z(ESI):622.3[M+1].

[0376] 1H NMR(400MHz, CDCl3)9.74(s,1H),7.66(d,2H),7.31(d,1H),7.28-7.25(m,6H),7.21(d,1H),6.86-6.82(m,1H),6.46-6.36( m,2H),4.19(s,2H),3.53(d,2H),3.35-3.30(m,2H),3.06(d,6H),2.73-2.70(m,2H),1.05-1.02(m,3H),0.73-0.61(m,4H).

[0377] Example 7

[0378] (E)-N,N-dimethyl-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene-1-

[0379] 2-(4-(4-yl)pyridin-2-yl)oxy)methyl)cyclopentyl)amino)but-2-enamide 7

[0380]

[0381]

[0382] first step

[0383] 1-(((5-iodopyridin-2-yl)oxy)methyl)cyclopentyl-1-amine 7b

[0384] Potassium tert-butoxide (0.4 g, 3.5 mmol) was dissolved in tetrahydrofuran (10 mL), and (1-aminocyclopentyl)methanol 7a (0.4 g, 3.5 mmol, prepared by the known method "Journal of the American Chemical Society, 2004, 126 (46), 15195-15201") was added at room temperature. After the addition was complete, compound 1a (0.8 g, 3.5 mmol) was slowly added. After stirring at room temperature for 2 hours, the reaction was stopped. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography using a developing solvent system B to obtain the title product 7b (0.7 g) with a yield of 66%.

[0385] MS m / z(ESI):319.1[M+1].

[0386] Step 2

[0387] (E)-4-((1-(((5-iodopyridin-2-yl)oxy)methyl)cyclopentyl)amino)-N,N-dimethylbut-2-enamide 7c

[0388] Compound 7b (100 mg, 0.3 mmol) was dissolved in N,N-dimethylformamide (10 mL), diisopropylethylamine (41 mg, 0.3 mmol) was added at room temperature, and then compound 5d (60 g, 0.3 mmol) was added, and the mixture was stirred for 2 hours. The reaction was stopped and cooled, and a saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with a saturated sodium chloride solution (50 mL×4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 7c (86 mg) with a yield of 67%.

[0389] Step 3

[0390] (E)-N,N-dimethyl-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0391] -5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopentyl)amino)but-2-enamide 7d

[0392] Compound 1d (50 mg, 0.2 mmol) was dissolved in methyltetrahydrofuran (20 mL), and bis-pinacol borate (47 mg, 0.2 mmol) and tetrakistriphenylphosphine platinum (10 mg, 0.01 mmol) were added. The argon was replaced 3 times, and the temperature was raised to 85 ° C and stirred for 3 hours. After cooling to room temperature, compound 7c (66 mg, 0.2 mmol), bistriphenylphosphine palladium dichloride (11 mg, 0.02 mmol), cesium carbonate (150 mg, 0.5 mmol) and water (0.2 mL) were added, and stirred at room temperature overnight. Compound 1e (63 mg, 0.3 mmol) and potassium hydroxide (26 mg, 0.5 mmol) were added, and the argon was replaced 3 times. The temperature was raised to 85 ° C and stirred for 2 hours, and then cooled to room temperature to stop the reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography with developing solvent system B to obtain the title product 7d (84 mg) with a yield of 78%.

[0393] Step 4

[0394] (E)-N,N-dimethyl-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene-1-

[0395] 2-(4-(4-yl)pyridin-2-yl)oxy)methyl)cyclopentyl)amino)but-2-enamide 7

[0396] Compound 7d (30 mg, 0.04 mmol) was dissolved in methanol (1 mL), and hydrochloric acid (12 N, 2 mL) was added and stirred for 3 hours. The reaction was stopped and cooled, the reaction solution was concentrated, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with dichloromethane (10 mL×4). The organic phases were combined, washed with water (10 mL×3), saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with developing solvent system A to obtain the title product 7 (10 mg), with a yield of 41%.

[0397] MS m / z(ESI):622.3[M+1].

[0398] 1 H NMR(400MHz, CDCl3)7.61-7.45(m,3H),7.29-7.01(m,7H),6.54-6.42(m,3H),3.95(s,2H),3.42-3.39(m,1H), 3.17-3.14(m,1H),2.91(s,1H),2.77(s,1H),2.62(s,3H),2.26(s,3H),1.63-1.52(m,4H),1.49-1.38(m,4H).

[0399] Example 8

[0400] (E)-N,N-dimethyl-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene-1-

[0401] 2-(4-(4-yl)pyridin-2-yl)oxy)methyl)cyclohexyl)amino)but-2-enamide 8

[0402]

[0403] first step

[0404] 1-(((5-iodopyridin-2-yl)oxy)methyl)cyclohexyl-1-amine 8b

[0405] The synthetic route of Example 7 was adopted, and the first step raw material 7a was replaced by (1-aminocyclohexyl)methanol 8a (prepared by a known method "Journal of Medicinal Chemistry, 2004, 47(18), 4613-4626") to obtain the title compound 8b (650 mg) with a yield of 68%.

[0406] MS m / z(ESI):333.1[M+1].

[0407] Step 2

[0408] (E)-4-((1-(((5-iodopyridin-2-yl)oxy)methyl)cyclohexyl)amino)-N,N-dimethylbut-2-enamide 8c

[0409] The synthetic route of Example 7 was adopted, and the second step raw material 7b was replaced by compound 8b to prepare the title compound 8c (500 mg) with a yield of 58%.

[0410] MS m / z(ESI):444.2[M+1].

[0411] Step 3

[0412] (E)-N,N-dimethyl-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0413] -5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclohexyl)amino)but-2-enamide 8d

[0414] The synthetic route of Example 7 was adopted, and the raw material 7c in the third step was replaced by compound 8c to prepare the title compound 8d (250 mg) with a yield of 94%.

[0415] MS m / z(ESI):720.4[M+1].

[0416] Step 4

[0417] (E)-N,N-dimethyl-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene-1-

[0418] 2-(4-(4-yl)pyridin-2-yl)oxy)methyl)cyclohexyl)amino)but-2-enamide 8

[0419] The synthetic route of Example 7 was adopted, and the raw material 7d in the fourth step was replaced by compound 8d to prepare the title compound 8 (80 mg) with a yield of 36%.

[0420] MS m / z(ESI):636.2[M+1].

[0421] 1H NMR(400MHz,CD3OD)7.72(d,1H),7.65(s,1H),7.49(dd,1H),7.33(dd,2H),7.31-7.24(m,5H),6.80(d,1H),6.68-6.65(m,2H),4.53 (s,2H),3.85(d,2H),3.46-3.38(m,2H),3.08(s,3H),2.98(s,3H),2.06(d,2H),1.75-1.64(m,3H),1.64-1.47(m,4H),1.31(m,1H).

[0422] Example 9

[0423] (E)-N,N-Dimethyl-4-(4-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 9

[0424]

[0425]

[0426] first step

[0427] tert-Butyl 4-((5-iodopyridin-2-yl)oxy)piperidine-1-carboxylate 9b

[0428] Sodium hydride (0.6 g, 14.9 mmol) was dissolved in N,N-dimethylformamide (30 mL), and tert-butyl 4-hydroxypiperidine-1-carboxylate 9a (1.0 g, 5.0 mmol, prepared by the known method "Journal of the American Chemical Society, 2018, 140 (1), 155-158") was added at room temperature. After the addition, compound 1a (2.2 g, 9.9 mmol) was slowly added. The reaction was stopped after stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography using a developing solvent system B to obtain the title product 9b (0.6 g) with a yield of 30%.

[0429] Step 2

[0430] (Z)-4-((5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-ene

[0431] -1-yl)pyridin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester 9c

[0432] Compound 1d (150 mg, 0.5 mmol) was dissolved in methyltetrahydrofuran (15 mL), and bis-pinacol borate (140 mg, 0.6 mmol) and tetrakistriphenylphosphine platinum (28 mg, 0.02 mmol) were added. The argon was replaced 3 times, and the temperature was raised to 85 ° C and stirred for 3 hours. After cooling to room temperature, compound 9b (167 mg, 0.4 mmol), bistriphenylphosphine palladium dichloride (31 mg, 0.05 mmol), cesium carbonate (300 mg, 0.9 mmol) and water (1 mL) were added, and stirred at room temperature overnight. Compound 1e (187 mg, 0.9 mmol) and potassium hydroxide (129 mg, 2.3 mmol) were added, and the argon was replaced 3 times. The temperature was raised to 85 ° C and stirred for 2 hours, and then cooled to room temperature to stop the reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography with developing solvent system B to obtain the title product 9c (210 mg) with a yield of 67%. MS m / z(ESI):681.3[M+1].

[0433] Step 3

[0434] (Z)-3-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,4-trifluoro-2-phenyl-1-(6-(piperidin-4-yloxy)pyridine-3-yl)-

[0435] (2-( ...

[0436] Compound 9c (120 mg, 0.2 mmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added, and the reaction was stirred at room temperature for 5 hours to stop the reaction. The reaction solution was concentrated under reduced pressure, and the reaction solution was adjusted to pH 8 with saturated sodium bicarbonate solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product of the title product 9d (100 mg), with a yield of 98%, and the product was directly used for the next step without purification.

[0437] Step 4 (E)-N,N-dimethyl-4-(4-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 9e

[0438] Compound 9d (100 mg, 0.2 mmol) was dissolved in N,N-dimethylformamide (5 mL), diisopropylethylamine (67 mg, 0.5 mmol) was added at room temperature, and then compound 5d (31 mg, 0.2 mmol) was added and stirred for 2 hours. The reaction was stopped and cooled, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2), the organic phases were combined, washed with saturated sodium chloride (20 mL×4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 9e (85 mg) with a yield of 71%.

[0439] Step 5 (E)-N,N-dimethyl-4-(4-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 9

[0440] Compound 9e (80 mg, 0.1 mmol) was dissolved in methanol (5 mL), and hydrochloric acid (12 N, 3 mL) was added and stirred for 3 hours. The reaction was stopped and cooled, the reaction solution was concentrated, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with dichloromethane (10 mL×4). The organic phases were combined, washed with water (10 mL×3), saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 9 (25 mg), with a yield of 36%.

[0441] MS m / z(ESI):608.4[M+1].

[0442] 1 H NMR(400MHz, CDCl3)9.91(br,1H),7.68(d,2H),7.45(d,1H),7.33(s,1H),7.24-7.15(m,5H),6.82(s,2H),6.47(d,1H),5 .31(s,1H),3.86(s,2H),3.49(s,2H),3.80-3.31(m,2H),3.15-3.12(s,3H),3.11(s,3H),3.05(s,3H),2.26-2.18(m,4H).

[0443] Example 10

[0444] (Z)-1-(4-((5-(4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-yn-1-one 10

[0445]

[0446]

[0447] The first step (Z)-1-(4-((5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbutane-1-

[0448] (2-(4-(4-(4-nitro-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-yn-1-one 10b

[0449] Compound 9d (60 mg, 0.1 mmol) was dissolved in N,N-dimethylformamide (3 mL), triethylamine (52 mg, 0.5 mmol), diacetylene acid 10a (17 mg, 0.2 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (30 mg, 0.2 mmol) and 1-hydroxybenzotriazole (24 mg, 0.2 mmol) were added at room temperature and stirred for 12 hours. The reaction was stopped and cooled, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 10b (45 mg) with a yield of 67%.

[0450] Step 2 (Z)-1-(4-((5-(4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-yn-1-one 10

[0451] Compound 10b (45 mg, 0.07 mmol) was dissolved in methanol (5 mL), and hydrochloric acid (12 N, 3 mL) was added and stirred for 3 hours. The reaction was stopped and cooled, the reaction solution was concentrated, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with dichloromethane (10 mL×4). The organic phases were combined, washed with water (10 mL×3), saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with developing solvent system A to obtain the title product 10 (15 mg), with a yield of 38%.

[0452] MS m / z(ESI):563.3[M+1].

[0453] 1H NMR(400MHz, CDCl3)9.67(br,1H),7.65(d,2H),7.45(d,1H),7.34(m,1H),7.21-7.17(m,4H),6.50(d,1H ),5.11(s,1H),3.94-3.92(m,1H),3.80-3.71(m,4H),3.37-3.29(m,2H),2.02(s,3H),1.94-1.75(m,4H).

[0454] Embodiment 11

[0455] (E)-N-methyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 11

[0456]

[0457] first step

[0458] (E)-4-Bromo-N-methylbut-2-enamide 11b

[0459] (E)-4-bromobut-2-enoic acid 11a (0.5 g, 3.0 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (0.3 g, 3.3 mmol), methylamine (0.1 g, 3.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.3 mmol), and 1-hydroxybenzotriazole (0.4 g, 3.3 mmol) were added at room temperature and stirred for 12 hours. The reaction was stopped and cooled, and saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 11b (0.4 g) with a yield of 77%.

[0460] Step 2

[0461] (R)-tert-Butyl 3-((5-iodopyridin-2-yl)oxy)piperidine-1-carboxylate 11d

[0462] The synthetic route of Example 1 was adopted, and the first step raw material 1b was replaced by (R)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester 11c (prepared by the known method "Tetrahedron, 2011, 67(7), 1485-1500") to obtain the title compound 11d (653 mg) with a yield of 91%.

[0463] Step 3

[0464] (3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbutyric acid

[0465] -1-en-1-yl)pyridin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester 11e

[0466] The synthetic route of Example 1 was adopted, and the second step raw material 1c was replaced by compound 11d to prepare the title compound 11e (200 mg) with a yield of 64%.

[0467] MS m / z(ESI):680.9[M+1].

[0468] Step 4

[0469] 3-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((Z)-4,4,4-trifluoro-2-phenyl-1-(6-(((R)-piperidin-3-yl)oxy)pyridin-3-yl)but-1-en-1-yl)-1H-indazole 11f

[0470] The synthetic route of Example 1 was adopted, and the raw material 1f in the third step was replaced by compound 11e to prepare the title compound 11f (170 mg) with a yield of 100%.

[0471] Step 5

[0472] (E)-N-methyl-4-((3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 11g

[0473] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 11f, and the raw material 1h was replaced by 11b, to obtain the title compound 11g (50 mg) with a yield of 86%.

[0474] Step 6 (E)-N-methyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 11

[0475] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 11g to obtain the title compound 11 (20 mg) with a yield of 45%.

[0476] MS m / z(ESI):594.2[M+1].

[0477] 1 H NMR (400MHz, CD3OD)7.65(d,2H),7.49(d,1H),7.31-7.19(m,6H),6.68-6.62(m,2H),6.30(d,1H),5.39(s,1H),3.88( s,2H),3.67(s,1H),3.48-3.38(m,3H),3.26-3.13(m,2H),3.01(s,1H),2.80(s,3H),2.06(s,2H),1.86-1.73(m,2H).

[0478] Example 12

[0479] (E)-1-morpholinyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene-1-

[0480] 1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-en-1-one 12

[0481]

[0482]

[0483] First Step (E)-1-Morpholinyl-4-((3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-en-1-one 12a

[0484] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 11f to prepare the title compound 12a (50 mg) with a yield of 79%.

[0485] Step 2

[0486] (E)-1-morpholinyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene-1-

[0487] 1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-en-1-one 12

[0488] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 12a to obtain the title compound 12 (20 mg) with a yield of 42%.

[0489] MS m / z(ESI):650.3[M+1].

[0490] 1 H NMR(400MHz, CDCl3)10.10(s,1H),7.67-7.62(m,3H),7.50(d,1H),7.27-7.11(m,6H),6.79(s,2H),6.48(s,1H) ,5.38(s,1H),3.93(s,2H),3.70(s,7H),3.55(s,2H),3.38-3.31(m,3H),3.09-2.82(m,2H),1.85-1.65(m,4H).

[0491] Embodiment 13

[0492] (E)-N-(tetrahydro-2H-pyran-4-yl)-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 13

[0493]

[0494]

[0495] first step

[0496] (E)-4-Bromo-N-(tetrahydro-2H-pyran-4-yl)but-2-enamide 13a

[0497] (E)-4-bromobut-2-enoic acid 11a (1.0 g, 6.1 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (1.8 g, 18.2 mmol), tetrahydropyran-4-amine (0.6 g, 6.1 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.3 g, 6.7 mmol) and 1-hydroxybenzotriazole (0.9 g, 6.7 mmol) were added at room temperature and stirred for 12 hours. The reaction was stopped and cooled, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (20 mL×4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 13a (1.2 g) with a yield of 79%.

[0498] Step 2

[0499] (E)-N-(tetrahydro-2H-pyran-4-yl)-4-((3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide

[0500] 13b

[0501] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 11f, and the raw material 1h was replaced by 13a, to prepare the title compound 13b (41 mg) with a yield of 81%.

[0502] Step 3 (E)-N-(tetrahydro-2H-pyran-4-yl)-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 13

[0503] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 13b to prepare the title compound 13 (20 mg) with a yield of 32%.

[0504] MS m / z(ESI):664.3[M+1].

[0505] 1 H NMR(400MHz,DMSO-d6)12.68(s,1H),7.92-7.90(d,1H),7.60-7.59(m,1H),7 .52-7.50(m,1H),7.23-7.14(m,6H),6.50-6.43(m,2H),5.97-5.93(d,1H),4 .86-4.79(m,1H),3.79-3.74(m,3H),3.47-3.38(m,2H),3.33-3.32(m,1H),3 .00-2.98(m,2H),2.80-2.78(m,1H),2.55-2.50(m,1H),2.00-1.24(m,12H).

[0506] Embodiment 14

[0507] (E)-N,N-Dimethyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0508] -1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 14

[0509]

[0510] First step (E)-N,N-dimethyl-4-((3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 14a

[0511] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 11f, and the raw material 1h was replaced by 5d to obtain the title compound 14a (80 mg) with a yield of 79%.

[0512] Step 2

[0513] (E)-N,N-Dimethyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0514] -1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 14

[0515] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 14a to obtain the title compound 14 (10 mg) with a yield of 27%.

[0516] MS m / z(ESI):608.3[M+1].

[0517] 1 H NMR(400MHz, CDCl3)9.77-7.75(br,1H),7.68-7.62(m,2H),7.46-7.43(m,1H),7.36-7.30(m,2H),7.27-7.18(d,5H),6.87-6. 76(m,2H),6.80-6.48(m,1H),5.42-5.28(m,1H),3.97-3.67(m,5H),3.38-3.31(m,2H),3.12-3.07(m,6H),2.31-1.69(m,4H).

[0518] Embodiment 15

[0519] (E)-1-(pyrrolin-1-yl)-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbutyl

[0520] -1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-en-1-one 15

[0521]

[0522]

[0523] first step

[0524] (E)-1-(pyrrolin-1-yl)-4-((3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-en-1-one 15a

[0525] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 11f, and the raw material 1h was replaced by 2a to obtain the title compound 15a (49 mg) with a yield of 72%.

[0526] Step 2

[0527] (E)-1-(pyrrolin-1-yl)-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbutyl

[0528] -1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-en-1-one 15

[0529] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 15a to obtain the title compound 15 (20 mg) with a yield of 47%.

[0530] MS m / z(ESI):634.3[M+1].

[0531] 1 H NMR (400MHz, CD3OD)7.63(d,2H),7.49(dd,1H),7.29-7.19(m,7H),6.79-6.74(m,1H),6.49-6.43(m,2H),5.02-4.98(m,1H),3.56-3. 54(m,2H),3.47-3.44(m,4H),3.25(d,2H),2.92(d,1H),2.65-2.64(m,1H),2.37-2.35(m,2H),1.94-1.85(m,6H),1.64-1.52(m,2H).

[0532] Example 16

[0533] (E)-N-(tert-butyl)-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0534] -1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 16

[0535]

[0536]

[0537] first step

[0538] (E)-4-Bromo-N-(tert-butyl)but-2-enamide 16a

[0539] Compound 11a (0.5 g, 3.0 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.4 g, 3.6 mmol), tert-butylamine (0.2 g, 3.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.7 g, 3.6 mmol) and 1-hydroxybenzotriazole (0.5 g, 3.6 mmol) were added at room temperature and stirred for 12 hours. The reaction was stopped and cooled, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (20 mL×4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 16a (0.3 g) with a yield of 39%.

[0540] Step 2

[0541] (E)-N-(tert-butyl)-4-((3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 16b

[0542] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 11f, and the raw material 1h was replaced by 16a to obtain the title compound 16b (47 mg) with a yield of 83%.

[0543] Step 3

[0544] (E)-N-(tert-butyl)-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0545] -1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 16

[0546] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 16b to obtain the title compound 16 (23 mg) with a yield of 28%.

[0547] MS m / z(ESI):636.5[M+1].

[0548] 1 H NMR (400MHz, CD3OD)7.67(d,2H),7.50(dd,1H),7.32-7.22(m,7H),6.64-6.55(m,2H),6.33(d,1H),5.40(s,1H),3.88(s, 2H),3.69(d,1H),3.52-3.41(m,3H),3.24(d,1H),3.02-2.99(m,1H),2.10-2.07(m,2H),1.87-1.75(m,2H),1.36(s,9H).

[0549] Embodiment 17

[0550] (E)-N-cyclopentyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene-1-

[0551] 1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 17

[0552]

[0553] first step

[0554] (E)-4-Bromo-N-cyclopentylbut-2-enamide 17a

[0555] Compound 11a (0.5 g, 3.0 mmol) was dissolved in dichloromethane (10 mL), triethylamine (0.4 g, 3.6 mmol), cyclopentylamine (0.3 g, 3.0 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.7 g, 3.6 mmol) and 1-hydroxybenzotriazole (0.5 g, 3.6 mmol) were added at room temperature, and the reaction was stirred for 12 hours. The reaction was stopped and cooled, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (20 mL×4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 17a (0.3 g) with a yield of 49%.

[0556] Step 2 (E)-N-cyclopentyl-4-((3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 17b

[0557] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 11f, and the raw material 1h was replaced by 17a to obtain the title compound 17b (42 mg) with a yield of 73%.

[0558] Step 3

[0559] (E)-N-cyclopentyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene-1-

[0560] 1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 17

[0561] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 17b to obtain the title compound 17 (21 mg) with a yield of 38%.

[0562] MS m / z(ESI):648.3[M+1].

[0563] 1 H NMR(400MHz,DMSO-d6)12.75-12.68(m,1H)7.88-7.86(d,1H),7.61-7.59(m,2 H),7.53-7.50(m,1H),7.23-7.15(m,6H),6.47-6.41(m,2H),5.96-5.93(d,1H ),4.85-4.79(m,1H),4.02-3.97(m,1H),3.47-3.39(m,2H),2.99-2.98(m,2H) ,2.80-2.79(m,1H),2.56-2.50(m,2H),2.30-2.25(m,1H),1.99-1.27(m,12H).

[0564] Embodiment 18

[0565] (E)-1-(piperazin-1-yl)-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbutane-1-yl)-

[0566] (1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-en-1-one 18

[0567]

[0568] first step

[0569] tert-Butyl 4-((E)-4-((3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enoyl)piperazine-1-carboxylate 18a

[0570] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 11f, and the raw material 1h was replaced by compound 4a to obtain the title compound 18a (51 mg) with a yield of 76%.

[0571] Step 2

[0572] (E)-1-(piperazin-1-yl)-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbutane-1-yl)-

[0573] (1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-en-1-one 18

[0574] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 18a to obtain the title compound 18 (21 mg) with a yield of 31%.

[0575] MS m / z(ESI):649.3[M+1].

[0576] 1 H NMR (400MHz, CD3OD)7.67(d,2H),7.50(d,1H),7.34-7.20(m,6H),6.92(d,1H),6.78-6.61(m,2H),5. 36(s,1H),3.94-3.88(m,5H),3.50-3.39(m,6H),3.28(s,2H),2.23-1.88(m,5H),1.34-1.30(m,3H).

[0577] Embodiment 19

[0578] (E)-N,N-Dimethyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-(4-fluorophenyl)butyl

[0579] -1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 19

[0580]

[0581] first step

[0582] (R)-5-iodo-2-(piperidin-3-yloxy)pyridine 19a

[0583] Compound 11d (1.0 g, 2.5 mmol) was dissolved in dichloromethane (15 mL), trifluoroacetic acid (3 mL) was added, and the reaction was stirred at room temperature for 5 hours to stop the reaction. The reaction solution was concentrated under reduced pressure, and the reaction solution was adjusted to pH 8 with saturated sodium bicarbonate solution (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product 19a (0.8 g), with a yield of 100%. The product was directly used for the next step without purification.

[0584] Step 2

[0585] (R,E)-4-(3-((5-iodopyridin-2-yl)oxy)piperidin-1-yl)-N,N-dimethylbut-2-enamide 19b

[0586] Compound 19a (752 mg, 2.5 mmol) was dissolved in N,N-dimethylformamide (20 mL), diisopropylethylamine (1.6 g, 12.4 mmol) was added at room temperature, and then compound 5d (470 mg, 2.5 mmol) was added and stirred for 2 hours. The reaction was stopped and cooled, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (50 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (50 mL×4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 19b (0.7 g) with a yield of 68%.

[0587] MS m / z(ESI):416.1[M+1].

[0588] Step 3 (E)-N,N-dimethyl-4-((3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-(4-fluorophenyl)but-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 19d

[0589] Compound 1d (50 mg, 0.2 mmol) was dissolved in methyltetrahydrofuran (10 mL), and bis-pinacol borate (47 mg, 0.2 mmol) and tetrakistriphenylphosphine platinum (4 mg, 0.003 mmol) were added. The argon was replaced 3 times, and the temperature was raised to 85 ° C and stirred for 3 hours. After cooling to room temperature, compound 19b (57 mg, 0.1 mmol), bistriphenylphosphine palladium dichloride (20 mg, 0.03 mmol), cesium carbonate (128 mg, 0.4 mmol) and water (0.5 mL) were added, and stirred at room temperature overnight. 4-Fluoroiodobenzene 19c (68 mg, 0.3 mmol) and potassium hydroxide (43 mg, 0.8 mmol) were added, and the argon was replaced 3 times. The temperature was raised to 85 ° C and stirred for 2 hours, and then cooled to room temperature to stop the reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography with developing solvent system B to obtain the title product 19d (50 mg) with a yield of 46%.

[0590] MS m / z(ESI):710.3[M+1].

[0591] Step 4

[0592] (E)-N,N-Dimethyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-(4-fluorophenyl)butyl

[0593] -1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 19

[0594] Compound 19d (50 mg, 0.07 mmol) was dissolved in methanol (2 mL), and hydrochloric acid (12 N, 1 mL) was added and stirred for 3 hours. The reaction was stopped and cooled, the reaction solution was concentrated, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with dichloromethane (10 mL×4). The organic phases were combined, washed with water (10 mL×3), saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 19 (15 mg) with a yield of 34%.

[0595] MS m / z(ESI):626.2[M+1].

[0596] 1H NMR(400MHz, CD3OD)7.70(s,1H),7.65(s,1H),7.52(dd,1H),7.32-7.26(m,4H),7.02-6.97(t,2H),6.91-6.87(m,1H),6.65-6.61(d, 2H),5.44(s,1H),3.94(s,3H),3.50-3.38(m,4H),3.14(s,3H),3.12-3.05(m,1H),3.01(s,3H),2.11-2.09(m,2H),1.89-1.77(m,2H).

[0597] Embodiment 20

[0598] (E)-4-((R)-3-((5-((Z)-2-(4-acetylaminophenyl)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)but-1-ene

[0599] -1-yl)pyridin-2-yl)oxy)piperidin-1-yl)-N,N-dimethylbut-2-enamide 20

[0600]

[0601] first step

[0602] (E)-4-((3R)-3-((5-((Z)-2-(4-acetylaminophenyl)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)-N,N-dimethylbut-2-enamide 20b

[0603] The synthetic route of Example 19 was adopted, and the third step raw material 19c was replaced by N-(4-iodophenyl)acetamide 20a (prepared by a known method "Journal of Organic Chemistry, 2018, 83(2), 930-938") to obtain the title compound 20b (70 mg) with a yield of 61%.

[0604] Step 2

[0605] (E)-4-((R)-3-((5-((Z)-2-(4-acetylaminophenyl)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)but-1-ene

[0606] -1-yl)pyridin-2-yl)oxy)piperidin-1-yl)-N,N-dimethylbut-2-enamide 20

[0607] The synthetic route of Example 19 was adopted, and the raw material 19d in the fourth step was replaced by compound 20b to obtain the title compound 20 (22 mg) with a yield of 41%.

[0608] MS m / z(ESI):665.2[M+1].

[0609] 1 H NMR(400MHz,CD3OD)7.67(d,2H),7.48-7.44(m,3H),7.28(dd,2H),7.18(d,2H),6.82(d,1H),6.67-6.59(m,2H),5.28(s,1H),3.76 (s,2H),3.49-3.39(m,4H),3.25(d,1H),3.10(s,3H),3.03(d,1H),2.99(s,3H),2.11(s,3H),1.99-1.94(m,2H),1.86-1.74(m,2H).

[0610] Embodiment 21

[0611] 4-((Z)-1-(6-(((R)-1-((E)-4-(dimethylamino)-4-oxobut-2-en-1-yl)piperidin-3-yl)oxy)pyridin-3-yl)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)but-1-en-2-yl)-N-methylbenzamide 21

[0612]

[0613] first step

[0614] 4-((Z)-1-(6-(((R)-1-((E)-4-(dimethylamino)-4-oxobut-2-en-1-yl)piperidin-3-yl)oxy)pyridin-3-yl)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-2-yl)-N-methylbenzamide 21b

[0615] The synthetic route of Example 19 was adopted, and the third step raw material 19c was replaced by 4-iodo-N-methylbenzamide 21a (prepared by a known method "Journal of the American Chemical Society, 2013, 135(12), 4628-4631") to obtain the title compound 21b (50 mg) with a yield of 44%.

[0616] Step 2

[0617] 4-((Z)-1-(6-(((R)-1-((E)-4-(dimethylamino)-4-oxobut-2-en-1-yl)piperidin-3-yl)oxy)pyridin-3-yl)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)but-1-en-2-yl)-N-methylbenzamide 21

[0618] The synthetic route of Example 19 was adopted, and the raw material 19d in the fourth step was replaced by compound 21b to obtain the title compound 21 (10 mg) with a yield of 32%.

[0619] MS m / z(ESI):665.3[M+1].

[0620] 1 H NMR (400MHz, CD3OD)7.71-7.69(m,4H),7.50(d,1H),7.36-7.29(m,4H),6.88(d,1H),6.65-6.58(m,2H),5.39(s,1H),3.97-3.91(m,2 H),3.69(d,1H),3.49-3.44(m,3H),3.06(s,3H),3.05-3.00(m,2H),2.99(s,3H),2.89(s,3H),2.10-2.03(m,2H),1.86-1.74(m,2H).

[0621] Embodiment 22

[0622] (E)-N,N-dimethyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-(4-(trifluoromethyl)

[0623] phenyl)but-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 22

[0624]

[0625] First Step (E)-N,N-Dimethyl-4-((3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-(4-(trifluoromethyl)phenyl)but-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 22b

[0626] The synthetic route of Example 19 was adopted, and the third step raw material 19c was replaced by 1-iodo-4-(trifluoromethyl)benzene 22a to prepare the title compound 22b (80 mg) with a yield of 69%.

[0627] Step 2 (E)-N,N-dimethyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-(4-(trifluoromethyl)

[0628] phenyl)but-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 22

[0629] The synthetic route of Example 19 was adopted, and the raw material 19d in the fourth step was replaced by compound 22b to prepare the title compound 22 (20 mg) with a yield of 31%.

[0630] MS m / z(ESI):676.2[M+1].

[0631] 1 H NMR(400MHz,CD3OD)7.70(dd,2H),7.57-7.55(m,3H),7.47(d,2H),7.32(dd,2H),6.88(d,1H),6.65-6.59(m,2H) ,5.37(s,1H),3.91(d,2H),3.50(q,2H),3.32(s,4H),3.12(s,3H),3.00(s,3H),2.09-2.04(m,2H),1.84(d,2H).

[0632] Embodiment 23

[0633] (E)-N,N-dimethyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-(4-(methylsulfonyl)phenyl)but-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 23

[0634]

[0635] First Step (E)-N,N-Dimethyl-4-((3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-(4-(methylsulfonyl)phenyl)but-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 23b

[0636] The synthetic route of Example 19 was adopted, and the third step raw material 19c was replaced by 1-iodo-4-(methylsulfonyl)benzene 23a (prepared by the known method "Organic Letters, 2014, 16(9), 2306-2309") to obtain the title compound 23b (60 mg) with a yield of 51%.

[0637] Step 2

[0638] (E)-N,N-dimethyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-(4-(methylsulfonyl)phenyl)but-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 23

[0639] The synthetic route of Example 19 was adopted, and the raw material 19d in the fourth step was replaced by compound 23b to prepare the title compound 23 (10 mg) with a yield of 28%.

[0640] MS m / z(ESI):686.2[M+1].

[0641] 1 H NMR(400MHz,CD3OD)7.83(d,2H),7.67(s,2H),7.53-7.50(m,3H),7.30(d,2H),6.89(dd,1H),6.66-6.59(m,2H),5.38(s,1H),3 .97-3.91(m,3H),3.70-3.65(m,1H),3.50(q,3H),3.28(d,1H),3.11(s,6H),2.99(s,3H),2.10-2.01(m,2H),1.94-1.86(m,2H).

[0642] Embodiment 24

[0643] (E)-4-((R)-3-((5-((Z)-2-(4-cyanophenyl)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)

[0644] Pyridin-2-yl)oxy)piperidin-1-yl)-N,N-dimethylbut-2-enamide 24

[0645]

[0646] first step

[0647] (E)-4-((3R)-3-((5-((Z)-2-(4-cyanophenyl)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)-N,N-dimethylbut-2-enamide 24b

[0648] The synthetic route of Example 19 was adopted, and the raw material 19c in the third step was replaced by 4-iodobenzonitrile 24a to prepare the title compound 24b (80 mg) with a yield of 73%.

[0649] Step 2 (E)-4-((R)-3-((5-((Z)-2-(4-cyanophenyl)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)but-1-en-1-yl)

[0650] Pyridin-2-yl)oxy)piperidin-1-yl)-N,N-dimethylbut-2-enamide 24

[0651] The synthetic route of Example 19 was adopted, and the raw material 19d in the fourth step was replaced by compound 24b to obtain the title compound 24 (20 mg) with a yield of 38%.

[0652] MS m / z(ESI):633.2[M+1].

[0653] 1 H NMR (400MHz, CD3OD)7.67-7.61(m,4H),7.47(d,1H),7.45(d,2H),7.33(d,2H),6.89(d,1H),6.66-6.61(m,2H),5.44(s,1H),3.94-3. 91(m,2H),3.71(d,1H),3.52-3.45(m,3H),3.25(d,1H),3.12(s,3H),3.05(d,1H),3.01(s,3H),2.11-2.04(m,2H),1.90-1.77(m,2H).

[0654] Embodiment 25

[0655] (R,Z)-1-(3-((5-(4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-yn-1-one 25

[0656]

[0657] first step

[0658] 1-((3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-yn-1-one 25a

[0659] The synthetic route of Example 10 was adopted, and the first step raw material 9d was replaced by compound 11f to obtain the title compound 25a (37 mg) with a yield of 83%.

[0660] Step 2

[0661] (R,Z)-1-(3-((5-(4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-yn-1-one 25

[0662] The synthetic route of Example 10 was adopted, and the second step raw material 10b was replaced by compound 25a to prepare the title compound 25 (4 mg) with a yield of 15%.

[0663] MS m / z(ESI):563.2[M+1].

[0664] 1 H NMR(400MHz, CDCl3)9.38(s,1H),7.68-7.65(m,2H),7.43-7.12(m,8H),6.46-6.39(m,1 H),5.02(d,1H),3.95-3.77(m,2H),3.33-3.00(m,4H),2.13-1.93(m,4H),1.69(d,3H).

[0665] Embodiment 26

[0666] (R,Z)-1-(3-((5-(4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)prop-2-en-1-one 26

[0667]

[0668] first step

[0669] 1-((3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)prop-2-en-1-one 26b

[0670] The synthetic route of Example 10 was adopted, and the first step raw material 9d was replaced by compound 11f, and the raw material 10a was replaced by acrylic acid 26a to obtain the title compound 26b (30 mg) with a yield of 73%.

[0671] Step 2

[0672] (R,Z)-1-(3-((5-(4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)prop-2-en-1-one 26

[0673] The synthetic route of Example 10 was adopted, and the second step raw material 10b was replaced by compound 26b to prepare the title compound 26 (3 mg) with a yield of 12%.

[0674] MS m / z(ESI):551.2[M+1].

[0675] 1 H NMR(400MHz, CDCl3)9.31(s,1H),7.68(d,2H),7.43(d,2H),7.29-7.27(m,5H),7.20-7.09(m,1H),6.40(d,1H),6.39-6. 20(m,1H),5.49-5.37(m,2H),4.95(s,1H),3.72(s,1H),3.68(d,2H),3.39(d,1H),3.36-3.31(m,2H),2.04-1.90(m,4H).

[0676] Embodiment 27

[0677] (E)-N,N-Dimethyl-4-((S)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0678] -1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 27

[0679]

[0680]

[0681] first step

[0682] (S)-tert-butyl 3-((5-iodopyridin-2-yl)oxy)piperidine-1-carboxylate 27b

[0683] The synthetic route of Example 1 was adopted, and the first step raw material 1b was replaced by (S)-3-hydroxypiperidine-1-carboxylic acid tert-butyl ester 27a (prepared by the known method "Tetrahedron, 2007, 63(2), 331-336") to obtain the title compound 27b (531 mg) with a yield of 92%.

[0684] Step 2

[0685] (3S)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbutyric acid

[0686] -1-en-1-yl)pyridin-2-yl)oxy)piperidine-1-carboxylic acid tert-butyl ester 27c

[0687] The synthetic route of Example 1 was adopted, and the second step raw material 1c was replaced by compound 27b to prepare the title compound 27c (190 mg) with a yield of 76%.

[0688] MS m / z(ESI):680.9[M+1].

[0689] Step 3

[0690] 3-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((Z)-4,4,4-trifluoro-2-phenyl-1-(6-(((S)-piperidin-3-yl)oxy)pyridin-3-yl)but-1-en-1-yl)-1H-indazole 27d

[0691] The synthetic route of Example 1 was adopted, and the raw material 1f in the third step was replaced by compound 27c to prepare the title compound 27d (85 mg) with a yield of 100%.

[0692] Step 4 (E)-N,N-dimethyl-4-((3S)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 27e

[0693] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 27d, and the raw material 1h was replaced by compound 5d to prepare the title compound 27e (65 mg) with a yield of 64%.

[0694] Step 5

[0695] (E)-N,N-Dimethyl-4-((S)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0696] -1-yl)pyridin-2-yl)oxy)piperidin-1-yl)but-2-enamide 27

[0697] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 27e to obtain the title compound 27 (15 mg) with a yield of 43%.

[0698] MS m / z(ESI):607.9[M+1].

[0699] 1 H NMR(400MHz, CDCl3)9.36(s,1H),7.69-7.67(m,1H),7.64-7.63(d,1H),7.45-7.43(m,1H),7.35 -7.32(d,1H),7.28-7.19(m,4H),7.08-7.06(d,1H),6.89-6.82(m,1H),6.46-6.41(m,1H),5.39- 5.36(m,1H),5.08-5.02(br,1H),3.38-3.30(m,2H),3.22-3.16(m,2H),3.05(s,3H),3.10(s,3H) ,2.92-2.86(m,1H),2.67-2.61(m,1H),2.34-2.24(m,2H),2.07-1.77(m,4H),1.53-1.48(m,1H).

[0700] Embodiment 28

[0701] (Z)-1-(4-((5-(4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)prop-2-en-1-one 28

[0702]

[0703] first step

[0704] (Z)-1-(4-((5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbutane-1-yl)-

[0705] 1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)prop-2-en-1-one 28a

[0706] The synthetic route of Example 10 was adopted, and the first step raw material 10a was replaced by compound 26a to obtain the title compound 28a (50 mg) with a yield of 63%.

[0707] Step 2 (Z)-1-(4-((5-(4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)piperidin-1-yl)prop-2-en-1-one 28

[0708] The synthetic route of Example 10 was adopted, and the second step raw material 10b was replaced by compound 28a to prepare the title compound 28 (10 mg) with a yield of 23%.

[0709] MS m / z(ESI):551.2[M+1].

[0710] 1 H NMR(400MHz, CDCl3)9.47(br,1H),7.60(d,2H),7.35(d,1H),7.28(d,1H),7.26-7.19(m,5H),6.59(dd,1H),6.49(d ,1H),6.29(d,1H),5.76(d,1H),5.14(m,1H),3.89-3.53(m,5H),3.34(t,2H),1.99-1.94(m,2H),1.77-1.66(m,2H).

[0711] Embodiment 29

[0712] (E)-N,N-Dimethyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0713] -1-yl)pyridin-2-yl)oxy)pyrrolin-1-yl)but-2-enamide 29

[0714]

[0715] first step

[0716] (R)-tert-butyl 3-((5-iodopyridin-2-yl)oxy)pyrroline-1-carboxylate 29b

[0717] The synthetic route of Example 1 was adopted, and the first step raw material 1b was replaced by (R)-3-hydroxypyrroline-1-carboxylic acid tert-butyl ester 29a to obtain the title compound 29b (0.9 g) with a yield of 86%.

[0718] Step 2

[0719] (3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbutyric acid

[0720] -1-en-1-yl)pyridin-2-yl)oxy)pyrroline-1-carboxylic acid tert-butyl ester 29c

[0721] The synthetic route of Example 1 was adopted, and the second step raw material 1c was replaced by compound 29b to prepare the title compound 29c (260 mg) with a yield of 37%.

[0722] Step 3

[0723] 3-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((Z)-4,4,4-trifluoro-2-phenyl-1-(6-(((R)-pyrrolin-3-yl)oxy)pyridin-3-yl)but-1-en-1-yl)-1H-indazole 29d

[0724] The synthetic route of Example 1 was adopted, and the raw material 1f in the third step was replaced by compound 29c to prepare the title compound 29d (93 mg) with a yield of 99%.

[0725] Step 4 (E)-N,N-dimethyl-4-((3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)pyrrolin-1-yl)but-2-enamide 29e

[0726] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 29d, and the raw material 1h was replaced by compound 5d to prepare the title compound 29e (60 mg) with a yield of 54%.

[0727] MS m / z(ESI):678.3[M+1].

[0728] Step 5

[0729] (E)-N,N-Dimethyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0730] -1-yl)pyridin-2-yl)oxy)pyrrolin-1-yl)but-2-enamide 29

[0731] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 29e to obtain the title compound 29 (15 mg) with a yield of 29%.

[0732] MS m / z(ESI):594.3[M+1].

[0733] 1 H NMR(400MHz, CDCl3)12.72(s,1H),7.70-7.65(m,2H),7.60-7.50(d,1H),7.2 5-7.20(m,5H),7.19-7.15(m,2H),6.55-6.45(m,3H),5.17-5.10(m,1H),3.50 -3.35(m,2H),3.15-3.10(m,2H),2.95(s,3H),2.83(s,3H),2.70-2.60(m,2H) ,2.50-2.45(m,1H),2.35-2.25(m,1H),2.15-2.05(m,1H),1.70-1.60(m,1H).

[0734] Embodiment 30

[0735] (E)-N,N-Dimethyl-4-((S)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0736] -1-yl)pyridin-2-yl)oxy)pyrrolin-1-yl)but-2-enamide 30

[0737]

[0738] first step

[0739] (S)-tert-butyl 3-((5-iodopyridin-2-yl)oxy)pyrroline-1-carboxylate 30b

[0740] The synthetic route of Example 1 was adopted, and the first step raw material 1b was replaced by (S)-3-hydroxypyrroline-1-carboxylic acid tert-butyl ester 30a to prepare the title compound 30b (0.5 g) with a yield of 50%.

[0741] Step 2

[0742] (3S)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbutyric acid

[0743] -1-en-1-yl)pyridin-2-yl)oxy)pyrroline-1-carboxylic acid tert-butyl ester 30c

[0744] The synthetic route of Example 1 was adopted, and the second step raw material 1c was replaced by compound 30b to prepare the title compound 30c (260 mg) with a yield of 85%.

[0745] Step 3

[0746] 3-Fluoro-1-(tetrahydro-2H-pyran-2-yl)-5-((Z)-4,4,4-trifluoro-2-phenyl-1-(6-(((S)-pyrrolin-3-yl)oxy)pyridin-3-yl)but-1-en-1-yl)-1H-indazole 30d

[0747] The synthetic route of Example 1 was adopted, and the raw material 1f in the third step was replaced by compound 30c to prepare the title compound 30d (100 mg) with a yield of 98%.

[0748] Step 4

[0749] (E)-N,N-Dimethyl-4-((3S)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)pyrrolin-1-yl)but-2-enamide 30e

[0750] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 30d, and the raw material 1h was replaced by compound 5d to prepare the title compound 30e (70 mg) with a yield of 62%.

[0751] MS m / z(ESI):678.3[M+1].

[0752] Step 5

[0753] (E)-N,N-Dimethyl-4-((S)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0754] -1-yl)pyridin-2-yl)oxy)pyrrolin-1-yl)but-2-enamide 30

[0755] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 30e to obtain the title compound 30 (10 mg) with a yield of 23%.

[0756] MS m / z(ESI):593.9[M+1].

[0757] 1H NMR(400MHz, CDCl3)9.58(s,1H),7.67-7.65(m,2H),7.46(d,1H),7.34-7.30(m,2H),7.27-7.16(m,4H),6.87-6.77( m,2H),6.59(d,1H),5.53(s,1H),4.14(s,1H),3.93(s,3H),3.39-3.31(m,2H),3.29-3.03(m,7H),2.41-2.28(m,4H).

[0758] Embodiment 31

[0759] (E)-N,N-Dimethyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0760] -1-yl)pyridin-2-yl)amino)piperidin-1-yl)but-2-enamide 31

[0761]

[0762]

[0763] first step

[0764] (R)-tert-butyl 3-((5-iodopyridin-2-yl)amino)piperidine-1-carboxylate 31b

[0765] The synthetic route of Example 1 was adopted, and the first step raw material 1b was replaced by (R)-3-aminopiperidine-1-carboxylic acid tert-butyl ester 31a to prepare the title compound 31b (0.8 g) with a yield of 57%.

[0766] Step 2

[0767] (3R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbutyric acid

[0768] -1-en-1-yl)pyridin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester 31c

[0769] The synthetic route of Example 1 was adopted, and the second step raw material 1c was replaced by compound 31b to obtain the title compound 31c (210 mg) with a yield of 75%.

[0770] Step 3

[0771] (R,Z)-N-(Piperidin-3-yl)-5-(4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridine

[0772] -2-Amine 31d

[0773] The synthetic route of Example 1 was adopted, and the raw material 1f in the third step was replaced by compound 31c to prepare the title compound 31d (42 mg) with a yield of 92%.

[0774] Step 4

[0775] (E)-N,N-Dimethyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0776] -1-yl)pyridin-2-yl)amino)piperidin-1-yl)but-2-enamide 31

[0777] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 31d, and the raw material 1h was replaced by compound 5d to obtain the title compound 31 (20 mg) with a yield of 39%.

[0778] MS m / z(ESI):607.3[M+1].

[0779] 1 H NMR(400MHz, CDCl3)9.26(s,1H),7.68(s,1H),7.55-7.54(m,1H),7.44-7.41(m,1H),7.36 -7.31(m,1H),7.28-7.23(m,4H),6.92-6.80(m,2H),6.45-6.41(m,1H),6.15-6.13(m,1H) ,5.39-5.37(m,1H),3.35-3.28(m,2H),3.17-3.15(m,2H),3.07(s,3H),3.02(s,3H),2.70 -2.68(m,1H),2.47-2.45(m,1H),2.47-2.45(m,1H),2.06-2.04(m,2H),1.34-1.29(m,4H).

[0780] Embodiment 32

[0781] (E)-1-morpholinyl-4-((R)-3-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene-1-

[0782] 1-yl)pyridin-2-yl)amino)piperidin-1-yl)but-2-en-1-one 32

[0783]

[0784] The synthetic route of Example 31 was adopted, and the raw material 5d in the fourth step was replaced by compound 1h to prepare the title compound 32 (8 mg) with a yield of 19%.

[0785] MS m / z(ESI):649.2[M+1].

[0786] 1 H NMR(400MHz, CDCl3)9.25(s,1H),7.68(s,1H),7.56-7.52(m,1H),7.45-7.40( m,1H),7.36-7.32(m,1H),7.28-7.21(m,4H),6.94-6.82(m,2H),6.44-6.37(m, 1H),6.15-6.07(m,1H),5.39-5.35(m,1H),3.76-3.46(m,8H),3.36-3.26(m,2H ),3.17-3.05(m,2H),2.99-2.92(m,1H),2.65-2.03(m,7H),0.95-0.87(m,1H).

[0787] Embodiment 33

[0788] (E)-N,N-dimethyl-4-(4-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)amino)piperidin-1-yl)but-2-enamide 33

[0789]

[0790] first step

[0791] tert-Butyl 4-((5-iodopyridin-2-yl)amino)piperidine-1-carboxylate 33b

[0792] The synthetic route of Example 1 was adopted, and the first step raw material 1b was replaced by 4-aminopiperidine-1-carboxylic acid tert-butyl ester 33a to prepare the title compound 33b (0.2 g) with a yield of 20%.

[0793] Step 2

[0794] (Z)-4-((5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-ene

[0795] -1-yl)pyridin-2-yl)amino)piperidine-1-carboxylic acid tert-butyl ester 33c

[0796] The synthetic route of Example 1 was adopted, and the second step raw material 1c was replaced by compound 33b to prepare the title compound 33c (80 mg) with a yield of 64%.

[0797] MS m / z(ESI):680.3[M+1].

[0798] Step 3

[0799] (Z)-N-(piperidin-4-yl)-5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-

[0800] Phenylbut-1-en-1-yl)pyridin-2-amine 33d

[0801] The synthetic route of Example 1 was adopted, and the raw material 1f in the third step was replaced by compound 33c to prepare the title compound 33d (68 mg) with a yield of 100%.

[0802] Step 4 (E)-N,N-dimethyl-4-(4-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)amino)piperidin-1-yl)but-2-enamide 33e

[0803] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 33d, and the raw material 1h was replaced by compound 5d to prepare the title compound 33e (70 mg) with a yield of 86%.

[0804] Step 5 (E)-N,N-dimethyl-4-(4-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)amino)piperidin-1-yl)but-2-enamide 33

[0805] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 33e to obtain the title compound 33 (15 mg) with a yield of 24%.

[0806] MS m / z(ESI):607.7[M+1].

[0807] 1H NMR(400MHz, CDCl3)7.63(s,1H),7.59(s,1H),7.38-7.32(m,4H),7.24(d,2H),7.23-7.02(m,2H),6.77(s,2H),6.47( d,1H),5.36(s,1H),3.93(s,1H),3.83(s,2H),3.39-3.29(m,6H),3.12(s,3H),3.09(s,3H),2.42(m,2H),2.07(s,2H).

[0808] Embodiment 34

[0809] (E)-N,N-Dimethyl-4-(((R)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0810] -1-yl)pyridin-2-yl)pyrrolin-3-yl)amino)but-2-enamide 34

[0811]

[0812]

[0813] first step

[0814] (R)-tert-Butyl (1-(5-iodopyridin-2-yl)pyrrolin-3-yl)carbamate 34b

[0815] The synthetic route of Example 1 was adopted, and the first step raw material 1b was replaced by (R)-tert-butyl pyrrolidine-3-ylcarbamate 34a to obtain the title compound 34b (0.8 g) with a yield of 70%.

[0816] Step 2

[0817] ((3R)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbutyl

[0818] -1-en-1-yl)pyridin-2-yl)pyrrolin-3-yl)carbamic acid tert-butyl ester 34c

[0819] The synthetic route of Example 1 was adopted, and the second step raw material 1c was replaced by compound 34b to prepare the title compound 34c (85 mg) with a yield of 83%.

[0820] MS m / z(ESI):665.9[M+1].

[0821] Step 3

[0822] (3R)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbutyric acid

[0823] -1-en-1-yl)pyridin-2-yl)pyrrolin-3-amine 34d

[0824] The synthetic route of Example 1 was adopted, and the raw material 1f in the third step was replaced by compound 34c to prepare the title compound 34d (60 mg) with a yield of 82%.

[0825] Step 4 (E)-N,N-dimethyl-4-(((3R)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)pyrrolin-3-yl)amino)but-2-enamide 34e

[0826] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 34d, and the raw material 1h was replaced by compound 5d to prepare the title compound 34e (45 mg) with a yield of 63%.

[0827] Step 5

[0828] (E)-N,N-Dimethyl-4-(((R)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0829] -1-yl)pyridin-2-yl)pyrrolin-3-yl)amino)but-2-enamide 34

[0830] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 34e to obtain the title compound 34 (9 mg) with a yield of 23%.

[0831] MS m / z(ESI):592.9[M+1].

[0832] 1 H NMR(400MHz, CDCl3)9.53(s,1H),7.67(s,2H),7.38(d,1H),7.30-7.22(m,6H),6.95-6.87(m,2H),6.45(d,1H),6.07(d,1H),3 .63-3.59(m,1H),3.54-3.48(m,3H),3.41-3.28(m,3H),3.23-3.19(m,1H),3.06(d,6H),2.27-2.14(m,2H),1.89-1.81(m,2H).

[0833] Embodiment 35

[0834] (E)-N,N-Dimethyl-4-(((S)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0835] -1-yl)pyridin-2-yl)pyrrolin-3-yl)amino)but-2-enamide 35

[0836]

[0837] first step

[0838] (S)-tert-Butyl (1-(5-iodopyridin-2-yl)pyrrolin-3-yl)carbamate 35b

[0839] The synthetic route of Example 1 was adopted, and the first step raw material 1b was replaced by (S)-tert-butyl pyrrolidine-3-ylcarbamate 35a to prepare the title compound 35b (0.8 g) with a yield of 69%.

[0840] Step 2

[0841] ((3S)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbutyric acid

[0842] -1-en-1-yl)pyridin-2-yl)pyrrolin-3-yl)carbamic acid tert-butyl ester 35c

[0843] The synthetic route of Example 1 was adopted, and the second step raw material 1c was replaced by compound 35b to prepare the title compound 35c (86 mg) with a yield of 84%.

[0844] MS m / z(ESI):666.3[M+1].

[0845] Step 3

[0846] (3S)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbutyric acid

[0847] -1-en-1-yl)pyridin-2-yl)pyrrolin-3-amine 35d

[0848] The synthetic route of Example 1 was adopted, and the raw material 1f in the third step was replaced by compound 35c to prepare the title compound 35d (55 mg) with a yield of 80%.

[0849] Step 4

[0850] (E)-N,N-dimethyl-4-(((3S)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)pyrrolin-3-yl)amino)but-2-enamide 35e

[0851] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 35d, and the raw material 1h was replaced by compound 5d to prepare the title compound 35e (40 mg) with a yield of 61%.

[0852] Step 5

[0853] (E)-N,N-Dimethyl-4-(((S)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene

[0854] -1-yl)pyridin-2-yl)pyrrolin-3-yl)amino)but-2-enamide 35

[0855] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 35e to obtain the title compound 35 (8 mg) with a yield of 23%.

[0856] MS m / z(ESI):592.9[M+1].

[0857] 1 H NMR(400MHz, CDCl3)9.47(s,1H),7.67(s,2H),7.39(dd,1H),7.34(dd,1H),7.28-7.22(m,5H),6.96-6.87(m,2H),6.45(dd,1H),6.07(d d,1H),3.63-3.59(m,1H),3.54-3.46(m,3H),3.41-3.28(m,3H),3.22-3.19(m,1H),3.07(d,6H),2.20-2.15(m,2H),1.88-1.81(m,2H).

[0858] Embodiment 36

[0859] (E)-N,N-dimethyl-4-((1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)piperidin-4-yl)amino)but-2-enamide 36

[0860]

[0861]

[0862] first step

[0863] Tert-butyl (1-(5-iodopyridin-2-yl)piperidin-4-yl)carbamate 36b

[0864] The synthetic route of Example 1 was adopted, and the first step raw material 1b was replaced by tert-butyl piperidin-4-ylcarbamate 36a to prepare the title compound 36b (0.3 g) with a yield of 28%.

[0865] Step 2

[0866] (Z)-(1-(5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-ene

[0867] -1-yl)pyridin-2-yl)piperidin-4-yl)carbamic acid tert-butyl ester 36c

[0868] The synthetic route of Example 1 was adopted, and the second step raw material 1c was replaced by compound 36b to prepare the title compound 36c (120 mg) with a yield of 74%.

[0869] MS m / z(ESI):679.9[M+1].

[0870] Step 3

[0871] (Z)-1-(5-(4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-ene

[0872] -1-yl)pyridin-2-yl)piperidin-4-amine 36d

[0873] The synthetic route of Example 1 was adopted, and the raw material 1f in the third step was replaced by compound 36c to prepare the title compound 36d (68 mg) with a yield of 100%.

[0874] Step 4 (E)-N,N-dimethyl-4-((1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)piperidin-4-yl)amino)but-2-enamide 36e

[0875] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 36d, and the raw material 1h was replaced by compound 5d to prepare the title compound 36e (70 mg) with a yield of 86%.

[0876] Step 5 (E)-N,N-dimethyl-4-((1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)piperidin-4-yl)amino)but-2-enamide 36

[0877] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 36e to obtain the title compound 36 (15 mg) with a yield of 24%.

[0878] MS m / z(ESI):607.7[M+1].

[0879] 1 H NMR(400MHz,CD3OD)7.70(s,1H),7.56-7.53(m,1H),7.48-7.42(m,1H),7 .35-7.32(m,1H),7.30-7.26(m,6H),7.00-6.98(d,1H),6.92-6.89(m,1H) ,6.72-6.64(m,1H),4.25-4.21(d,2H),3.92-3.90(d,2H),3.57-3.39(m,4 H),3.17-3.11(m,4H),3.01(s,3H),2.24-2.22(m,2H),1.67-1.67(m,2H).

[0880] Embodiment 37

[0881] (E)-N,N-dimethyl-4-(methyl((S)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbutyl

[0882] -1-en-1-yl)pyridin-2-yl)piperidin-3-yl)amino)but-2-enamide 37

[0883]

[0884] first step

[0885] (S)-tert-Butyl (1-(5-iodopyridin-2-yl)piperidin-3-yl)carbamate 37b

[0886] Potassium carbonate (1.5 g, 20.5 mmol) was dissolved in N,N-dimethylformamide (10 mL), and (S)-piperidin-3-ylcarbamic acid tert-butyl ester 37a (2.0 g, 10.0 mmol) was added at room temperature, and compound 1a (2.2 g, 10.0 mmol) was slowly added after the addition was complete. The reaction was stopped after heating to 100°C and stirring for 4 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography using a developing solvent system B to obtain the title product 37b (3.5 g) with a yield of 87%.

[0887] Step 2

[0888] (S)-tert-Butyl (1-(5-iodopyridin-2-yl)piperidin-3-yl)(methyl)carbamate 37c

[0889] Sodium hydride (12 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (10 mL), and compound 37b (100 mg, 0.2 mmol) was added at room temperature. After the addition was complete, iodomethane (28 mg, 0.2 mmol) was slowly added. The reaction was stopped after stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by thin layer chromatography using developing solvent system B to obtain the title product 37c (95 mg) with a yield of 92%.

[0890] MS m / z(ESI):418.1[M+1].

[0891] Step 3: Tert-butyl methyl((3S)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)piperidin-3-yl)carbamate 37d

[0892] The synthetic route of Example 1 was adopted, and the second step raw material 1c was replaced by compound 37c to prepare the title compound 37d (150 mg) with a yield of 71%.

[0893] MS m / z(ESI):694.4[M+1].

[0894] Step 4

[0895] (3S)-N-methyl-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-

[0896] Phenylbut-1-en-1-yl)pyridin-2-yl)piperidin-3-amine 37e

[0897] The synthetic route of Example 1 was adopted, and the raw material 1f in the third step was replaced by compound 37d to prepare the title compound 37e (80 mg) with a yield of 93%.

[0898] Step 5

[0899] (E)-N,N-dimethyl-4-(methyl((3S)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-

[0900] 1-(2-phenyl-1-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)piperidin-3-yl)amino)but-2-enamide 37f

[0901] The synthetic route of Example 1 was adopted, and the raw material 1g in the fourth step was replaced by compound 37e, and the raw material 1h was replaced by compound 5d, to prepare the title compound 37f (75 mg) with a yield of 79%.

[0902] Step 6

[0903] (E)-N,N-dimethyl-4-(methyl((S)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbutyric acid

[0904] -1-en-1-yl)pyridin-2-yl)piperidin-3-yl)amino)but-2-enamide 37

[0905] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 37f to obtain the title compound 37 (22 mg) with a yield of 25%.

[0906] MS m / z(ESI):621.2[M+1].

[0907] 1 H NMR(400MHz, CDCl3)10.51(s,1H),7.71(s,1H),7.62(s,1H),7.74-7.31(m,4H),7.29-7.21(m,4H),6.80(s,2H),6.65(dd,1H),4.71(dd ,1H),4.04(d,2H),3.87(d,2H),3.41(d,2H),3.35-3.31(m,2H),3.06(d,6H),2.84(s,3H),2.29(d,1H),2.02-1.92(m,2H),1.69(d,1H).

[0908] Embodiment 38

[0909] (E)-1-morpholinyl-4-(((S)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene-1-

[0910] 1-Aminyl)pyridin-2-yl)piperidin-3-yl)amino)but-2-en-1-one 38

[0911]

[0912]

[0913] first step

[0914] ((3S)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbutyric acid

[0915] -1-en-1-yl)pyridin-2-yl)piperidin-3-yl)carbamic acid tert-butyl ester 38a

[0916] The synthetic route of Example 1 was adopted, and the second step raw material 1c was replaced by compound 37b to prepare the title compound 38a (100 mg) with a yield of 80%.

[0917] MS m / z(ESI):680.4[M+1].

[0918] Step 2

[0919] (3S)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbutyric acid

[0920] -1-en-1-yl)pyridin-2-yl)piperidin-3-amine 38b

[0921] The synthetic route of Example 1 was adopted, and the raw material 1f in the third step was replaced by compound 38a to prepare the title compound 38b (35 mg) with a yield of 82%.

[0922] Step 3

[0923] (E)-1-morpholinyl-4-(((3S)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)piperidin-3-yl)amino)but-2-en-1-one 38c

[0924] The synthetic route of Example 1 was adopted, and the raw material 1g of the fourth step was replaced by compound 38b to obtain the title compound 38c (75 mg) with a yield of 79%.

[0925] Step 4

[0926] (E)-1-morpholinyl-4-(((S)-1-(5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene-1-

[0927] 1-Aminyl)pyridin-2-yl)piperidin-3-yl)amino)but-2-en-1-one 38

[0928] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 38c to prepare the title compound 38 (9 mg) with a yield of 25%.

[0929] MS m / z(ESI):649.3[M+1].

[0930] 1 H NMR(400MHz, CDCl3)9.92(s,1H),7.65(s,2H),7.37(d,1H),7.30-7.22(m,6H), 6.95-6.88(m,2H),6.40(d,2H),4.15(d,1H),3.76-3.49(m,7H),3.53-3.49(m, 4H),3.32-3.29(m,2H),3.00-2.95(m,1H),2.86-2.81(m,1H),2.73-2.69(m,1H ),1.99-1.94(m,1H),1.78-1.72(m,1H),1.58-1.48(m,1H),1.33-1.27(m,2H).

[0931] Embodiment 39

[0932] (E)-N,N-dimethyl-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene-1-

[0933] 1-(2-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-enamide 39

[0934]

[0935] first step

[0936] (E)-N,N-dimethyl-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[0937] -5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-enamide 39a

[0938] The synthetic route of Example 1 was adopted, and the raw material 1h in the fourth step was replaced by 5d to prepare the title compound 39a (53 mg) with a yield of 65%.

[0939] Step 2 (E)-N,N-dimethyl-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-ene-1-

[0940] 1-(2-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-ene-amide 39

[0941] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 39a to prepare the title compound 39 (24 mg) with a yield of 62%.

[0942] MS m / z(ESI):593.9[M+1].

[0943] 1 H NMR(400MHz,CD3OD)7.63(d,2H),7.41-7.08(m,8H),6.83-6.76(m,1H),6.48-6.36(m,2H),4. 12(s,2H),3.49-3.48(m,2H),3.36-3.31(m,2H),3.09(s,3H),3.03(s,3H),0.67-0.55(m,4H).

[0944] Embodiment 40

[0945] (E)-1-(3-hydroxyazetidin-1-yl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 40

[0946]

[0947]

[0948] first step

[0949] (E)-4-Bromo-1-(3-hydroxyazetidin-1-yl)but-2-en-1-one 40a

[0950] Compound 11a (0.5 g, 3.0 mmol) was dissolved in dichloromethane (5 mL), triethylamine (0.3 g, 3.3 mmol), 3-hydroxyazetidine (0.2 g, 3.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.3 mmol) and 1-hydroxybenzotriazole (0.4 g, 3.3 mmol) were added at room temperature, and the reaction was stirred for 12 hours. The reaction was stopped and cooled, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 40a (0.5 g) with a yield of 72%.

[0951] Step 2 (E)-1-(3-hydroxyazetidin-1-yl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-ene

[0952] -1-Keto 40b

[0953] The synthetic route of Example 1 was adopted, and the raw material 1h in the fourth step was replaced by 40a to prepare the title compound 40b (43 mg) with a yield of 51%.

[0954] Step 3 (E)-1-(3-hydroxyazetidin-1-yl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 40

[0955] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 40b to prepare the title compound 40 (27 mg) with a yield of 67%.

[0956] MS m / z(ESI):622.1[M+1].

[0957] 1H NMR (400MHz, CD3OD)7.71-7.66(m,2H),7.53-7.51(m,1H),7.35-7.21(m,8H),6.71-6.65(m,2H),4.63-4.48(m,2 H),4.43(s,2H),4.29-4.25(m,1H),4.05-4.00(m,3H),3.85-3.81(m,1H),3.48-3.33(m,2H),1.17-1.11(m,4H).

[0958] Embodiment 41

[0959] (E)-1-((S)-3-hydroxypyrrolidin-1-yl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 41

[0960]

[0961] first step

[0962] (S,E)-4-Bromo-1-(3-hydroxypyrrolidin-1-yl)but-2-en-1-one 41a

[0963] Compound 11a (0.5 g, 3.0 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (0.3 g, 3.3 mmol), (S)-3-hydroxypyrrolidine (0.2 g, 3.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.3 mmol) and 1-hydroxybenzotriazole (0.4 g, 3.3 mmol) were added at room temperature, and the reaction was stirred for 12 hours. The reaction was stopped and cooled, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated sodium chloride solution (20 mL×4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 41a (0.5 g) with a yield of 73%.

[0964] Step 2 (E)-1-((S)-3-hydroxypyrrolidin-1-yl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-ene

[0965] -1-Keto 41b

[0966] The synthetic route of Example 1 was adopted, and the raw material 1h in the fourth step was replaced by 41a to prepare the title compound 41b (41 mg) with a yield of 57%.

[0967] Step 3 (E)-1-((S)-3-hydroxypyrrolidin-1-yl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 41

[0968] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 41b to prepare the title compound 41 (37 mg) with a yield of 69%.

[0969] MS m / z(ESI):636.2[M+1].

[0970] 1 H NMR (400MHz, CD3OD)7.71-7.66(m,2H),7.53-7.51(m,1H),7.35-7.22(m,8H),6.71-6.66(m,2H),4.44( s,2H),4.07-4.00(m,2H),3.74-3.67(m,2H),3.55-3.51(m,5H),2.21-2.19(m,2H),1.19-1.13(m,4H).

[0971] Embodiment 42

[0972] (E)-1-((R)-2-(hydroxymethyl)morpholinyl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 42

[0973]

[0974] first step

[0975] (R,E)-4-Bromo-1-(2-(hydroxymethyl)morpholinyl)but-2-en-1-one 42a

[0976] Compound 11a (0.5 g, 3.0 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (0.3 g, 3.3 mmol), (R)-morpholin-2-ylmethanol (0.4 g, 3.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.6 g, 3.3 mmol) and 1-hydroxybenzotriazole (0.4 g, 3.3 mmol) were added at room temperature, and the reaction was stirred for 12 hours. The reaction was stopped and cooled, saturated sodium bicarbonate solution (15 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×2), the organic phases were combined, washed with saturated sodium chloride solution (20 mL×4), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography using a developing solvent system A to obtain the title product 42a (0.5 g) with a yield of 63%.

[0977] Step 2 (E)-1-((R)-2-(hydroxymethyl)morpholinyl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-yl

[0978] -1-Keto 42b

[0979] The synthetic route of Example 1 was adopted, and the raw material 1h in the fourth step was replaced by 42a to prepare the title compound 42b (31 mg) with a yield of 47%.

[0980] Step 3 (E)-1-((R)-2-(hydroxymethyl)morpholinyl)-4-((1-(((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)methyl)cyclopropyl)amino)but-2-en-1-one 42

[0981] The synthetic route of Example 1 was adopted, and the raw material 1i in the fifth step was replaced by compound 42b to prepare the title compound 42 (27 mg) with a yield of 59%.

[0982] MS m / z(ESI):666.1[M+1].

[0983] 1H NMR (400MHz, CD3OD)7.67-7.65(m,2H),7.52-7.50(m,1H),7.31-7.26(m,7H),6.81-6.77(m,1H),6.61-6.59(m,2 H),4.45-4.42(m,1H),4.30(s,2H),3.99-3.93(m,2H),3.61-3.42(m,9H),3.03-3.00(m,1H),0.81-0.72(m,4H).

[0984] Embodiment 43

[0985] (E)-1-morpholinyl-4-((2-((5-((Z)-4,4,4-trifluoro-1-(3-fluoro-1H-indazol-5-yl)-2-phenylbut-1-en-1-yl)pyridin-2-yl)oxy)ethyl)amino)but-2-en-1-one 43

[0986]

[0987] The synthetic route of Example 1 was adopted, and the raw material 1g of the fourth step was replaced by 43a (prepared by the method disclosed in Example 1 on page 77 of the specification of patent application WO2018098305) to obtain the title compound 43 (21 mg) with a yield of 42%.

[0988] MS m / z(ESI):610.2[M+1].

[0989] 1 H NMR(400MHz,CD3OD)7.69-7.67(m,2H),7.53-7.50(m,1H),7.32-7.20(m,7H),6.80-6.5 9(m,3H),4.36-4.34(m,2H),3.66-3.58(m,10H),3.48-3.40(m,3H),3.13-3.10(m,2H).

[0990] Biological evaluation

[0991] The present disclosure is further described and explained below in conjunction with test examples, but these embodiments are not intended to limit the scope of the present disclosure.

[0992] Test Example 1: Inhibitory effect of the disclosed compounds on estrogen receptor reporter gene activity

[0993] 1. Purpose of the experiment

[0994] The purpose of this experiment is to test the inhibitory effect of the disclosed compounds on the activity of the estrogen receptor reporter gene. 50Size evaluation of the in vitro activity of compounds.

[0995] 2. Experimental methods

[0996] MCF7 cells MCF7 / ERE-luc (ATCC, HTB-22) expressing the estrogen receptor response element-controlled luciferase reporter gene ERE-luc (synthesized by Jinweizhi Biotechnology Co., Ltd.) were cultured in MEM (GE Healthcare, SH30024.01) medium containing 10% fetal bovine serum and 500μg / ml G418. On the first day of the experiment, MCF7 / ERE-luc cells were seeded at a density of 30,000 cells / well in a 96-well plate using MEM incomplete medium containing 10% activated carbon-treated fetal bovine serum (BioSun, BS-0004-500), with 100μl of cell suspension per well, and placed in a cell culture incubator at 37°C, 5% CO2 for overnight culture. On the second day, 10 μl of β-estradiol (SIGMA, E2758-250MG) prepared with the above incomplete medium and different concentrations of the test compound were added to each well. The final concentration of β-estradiol was 0.1 nM. The final concentration of the compound was 9 concentration points of 10-fold gradient dilution starting from 10 μM. A blank control containing 0.5% DMSO was set up and placed in a cell culture incubator at 37°C and 5% CO2 for 20 hours. On the third day, the 96-well plate was taken out and 100 μl of ONE-Glo was added to each well. TM Luciferase Assay system (Promega, E6110) was used to detect the activity of luciferase. After the cells were placed at room temperature for 3 minutes to fully lyse, the luminescence signal value was read using a multi-label microplate reader (PerkinElmer, VICTOR 3). The IC value of the inhibitory activity of the compound was calculated based on the concentration and luminescence signal value of the compound using Graphpad Prism software. 50 value.

[0997] 3. Test results

[0998] The inhibitory effect of the compounds disclosed in the present invention on the activity of the estrogen receptor reporter gene was determined by the above test. The chemiluminescent signal value and the logarithmic concentration of the compound were plotted using Graphicpad Prism to obtain the IC 50 The values ​​are shown in Table 1 below.

[0999] Table 1 Inhibitory effect of the compounds disclosed herein on the activity of estrogen receptor reporter genes IC 50

[1000]

[1001]

[1002] Conclusion: The disclosed compounds have a significant inhibitory effect on the estrogen receptor reporter gene.

[1003] Test Example 2: Inhibitory effect of the disclosed compounds on MCF7 cell proliferation

[1004] 1. Purpose of the experiment

[1005] The purpose of this experiment is to determine the inhibitory activity of the disclosed compounds on MCF7 cell proliferation. 50 Size evaluation of the in vitro activity of compounds.

[1006] 2. Experimental methods

[1007] MCF7 cells (ATCC, HTB-22) were cultured with MEM (GE Healthcare, SH30024.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, MCF7 cells were seeded at a density of 3,000 cells / well in a 96-well plate using complete medium, with 100 μl of cell suspension in each well, and cultured overnight in a cell culture incubator at 37°C and 5% CO2. On the second day, the medium was aspirated and replaced with 135 μl of MEM incomplete medium containing 2% fetal bovine serum per well. At the same time, 15 μl of different concentrations of the test compound prepared with incomplete medium were added to each well. The final concentration of the compound was 9 concentration points with a 4-fold gradient dilution starting from 100 nM. A blank control containing 0.5% DMSO was set up and cultured in a cell culture incubator at 37°C and 5% CO2 for 144 hours. On the eighth day, the 96-well cell culture plate was taken out and 150 μl was added to each well. Luminescent Cell Viability Assay (Promega, G7573) was used. After standing at room temperature for 10 minutes, the luminescent signal value was read using a multi-label microplate reader (PerkinElmer, VICTOR 3). The IC value of the inhibitory activity of the compound was calculated based on the concentration and luminescent signal value using Graphpad Prism software. 50 value.

[1008] 3. Data Analysis

[1009] Graphpad Prism was used to plot the chemiluminescent signal value against the logarithmic concentration of the compound to obtain the IC value of the compound. 50 The results are shown in Table 2.

[1010] Table 2 IC values ​​of the inhibitory effects of the disclosed compounds on MCF7 cell proliferation 50

[1011]

[1012]

[1013] Conclusion: The disclosed compounds have a significant inhibitory effect on the proliferation of MCF7 cells.

[1014] Test Example 3: Inhibitory effect of the disclosed compounds on proliferation of MCF7 cells expressing ERα mutants

[1015] 1. Purpose of the experiment

[1016] The purpose of this experiment is to determine the inhibitory activity of the disclosed compounds on the proliferation of MCF7 cells expressing ERα mutants.

[1017] 2. Experimental methods

[1018] Site-directed mutagenesis and cell line construction

[1019] The mutants of human estrogen receptor α (ERα) protein ERαY537S and ERαD538G were obtained by site-directed mutagenesis using double primer PCR with the cDNA of wild-type ESR1 gene (Accession No. NM000125) as template. The primer sequences used for mutation are as follows (the nucleotides marked with underlines are the mutation sites):

[1020]

[1021] The cDNA of mutant ESR1 was cloned into the target lentiviral vector pCDH-CMV-MCS-EF1-Puro (SBI, CD510B-1). Then the lentiviral plasmid with mutant ESR1 gene sequence and lentiviral packaging plasmids pVSV-G and pCMV-dR8.91 (SBI, LV500A-1) were transfected into HEK-293T cells (ATCC, CRL-3216) by Lipofectamine 3000 Transfection Reagent (ThermoFisher Scientific, Cat#L3000075). 48 hours after transfection, the supernatant of DMEM high glucose medium (GE Healthcare, SH30243.01) containing 10% FBS with virus was filtered, ultracentrifuged to obtain virus precipitate, and resuspended and dissolved with an appropriate amount of MEM medium (GE Healthcare, SH30024.01) containing 10% FBS, non-essential amino acids (SIGMA, M7145-100ML), sodium pyruvate (SIGMA, S8636-100ML), and added to MCF7 cells (ATCC, HTB-22), and polybrene (SIGMA, H9268-5G) was added at a final concentration of 8 μg / ml and incubated overnight. Two days after transfection, 1 μg / ml of puromycin (invitrogen, A11138-03) was added to the cell culture medium for resistance screening, and about two weeks later, an MCF7 cell line capable of stably expressing ERαY537S and ERαD538G mutants was obtained.

[1022] Cell proliferation inhibition assay

[1023] MCF7 cells expressing ERα mutants were cultured with MEM (GE Healthcare, SH30024.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, cells were seeded in a 96-well plate at a density of 3,000 cells / well using complete medium, with 100 μl of cell suspension per well, and cultured overnight in a cell culture incubator at 37°C and 5% CO2. On the second day, the medium was aspirated and replaced with 135 μl of MEM incomplete medium containing 2% fetal bovine serum per well. At the same time, 15 μl of different concentrations of the test compound prepared with incomplete medium was added to each well. The final concentration of the compound was 9 concentration points with a 4-fold gradient dilution starting from 100 nM. A blank control containing 0.5% DMSO was set up and cultured in a cell culture incubator at 37°C and 5% CO2 for 144 hours. On the eighth day, the 96-well cell culture plate was removed and 150 μl was added to each well. Luminescent Cell Viability Assay (Promega, G7573) was used. After standing at room temperature for 10 minutes, the luminescent signal value was read using a multi-label microplate reader (PerkinElmer, VICTOR 3). The IC value of the inhibitory activity of the compound was calculated based on the concentration and luminescent signal value using Graphpad Prism software. 50 value.

[1024] Table 3 IC values ​​of the inhibitory effects of the disclosed compounds on the proliferation of MCF7 cells expressing ERα mutants 50

[1025]

[1026]

[1027] Conclusion: The disclosed compounds have a significant inhibitory effect on the proliferation of MCF7 cells expressing ERα mutants.

[1028] Test Example 4: Effect of the compounds of the present invention on Na v 1.5 Determination of inhibitory activity

[1029] The purpose of this study is to investigate the effects of compounds on Na V 1.5 Effects of ion channels. Na V 1.5 ion channel was stably expressed in HEK293 cells. V 1.5 After the current stabilizes, compare the Na before and after the application of the compound V 1.5 The magnitude of the current can be used to obtain the compound's Na V 1.5 Effects of ion channels.

[1030] 1 Experimental materials and instruments

[1031] 1) Patch clamp amplifier: patch clamp PC-505B (WARNER instruments)

[1032] 2) Digital to analog converter: Digidata 1440A (Axon CNS)

[1033] 3) Micromanipulator: MP-225 (SUTTER instrument)

[1034] 4) Inverted microscope: TL4 (Olympus)

[1035] 5) Glass microelectrode pulling instrument: PC-10 (NARISHIGE)

[1036] 6) Microelectrode glass capillary: B12024F (Wuhan Weitan Scientific Instrument Co., Ltd.)

[1037] 7) Dimethyl sulfoxide (DMSO): D2650 (Sigma-Aldrich)

[1038] 2 Experimental steps

[1039] 2.1 Compound preparation

[1040] All compounds used to prepare intracellular and extracellular fluids were purchased from Sigma (St. Louis, MO), except NaOH and KOH used for acid-base titration.

[1041] The extracellular solution was: NaCl, 137 mM; KCl, 4 mM; CaCl2, 1.8 mM; MgCl2, 1 mM; HEPES, 10; glucose 10 mM; pH 7.4 (NaOH titration).

[1042] The intracellular solution was: aspartic acid, 140 mM; MgCl2, 2 mM; EGTA 11 mM; HEPES, 10 mM; pH 7.2 (CsOH titration).

[1043] The test compound was stored at a concentration of 9 mM in dimethyl sulfoxide (DMSO). On the day of the test, it was redissolved in the extracellular fluid to prepare the required concentration.

[1044] 2.2 Manual patch clamp test process

[1045] 1) After the compound is prepared into a solution of specified concentration, the solution is added to each channel in order from high to low concentration, and each channel is marked.

[1046] 2) Transfer cells to perfusion tanks and perfuse with extracellular fluid. Store intracellular fluid in small batches at -80°C and thaw on the day of the experiment. Electrodes were made using PC-10 (Narishige, Japan). Whole-cell patch clamp recording was performed, and noise was filtered at one-fifth of the sampling frequency.

[1047] 3) All compounds were perfused using a perfusion system that utilized its own gravity. At least two cells were tested for each concentration. After the current stabilized (or for 5 minutes), the change in current magnitude before and after the compound was used was compared to calculate the blocking effect of the compound.

[1048] 4) Clean the perfusion tank. Rinse according to the concentration of the drug solution from high to low, and rinse for 20 seconds at each concentration. Finally, rinse with extracellular solution for 1 minute.

[1049] 2.3 Test voltage equation (resting state) and results

[1050] The cells were clamped at -80 mV and then depolarized to Vhalf with an 8-ms square wave, then hyperpolarized to -120 mV with a 20-ms square wave, and then depolarized to -10 mV with a 20-ms square wave to obtain Na V 1.5 current. This procedure was repeated every 15 seconds. The maximum current induced by -10mV square wave was detected, and after it stabilized, the test compound was perfused. When the response stabilized, the intensity of the blockade was calculated.

[1051] 3 Data analysis

[1052] Data were stored in a computer system for analysis. pCLAMP 10 (Molecular Devices, Union City, CA) was used for data acquisition and analysis. Current stability refers to the absolute average of the peak current of 4 consecutive scans exceeding 200 pA and the CV value is less than 10%, or the average of the peak current of 4 consecutive scans is between 200 pA and 50 pA and the CV value is less than 30%. The average of the last 4 current peaks after current stability is used to calculate the effect of the compound at this solubility.

[1053] The compounds of the present invention have an effect on Na v The inhibitory activity of 1.5 was determined by the above test, and the measured IC 50 The values ​​are shown in Table 4 below.

[1054] Table 4 The compounds of the present invention have an effect on Na v 1.5 IC of channel activity inhibition 50

[1055] Example No. <![CDATA[IC 50 (uM)]]> 1 >10 39 8.2 40 11.5 41 5.3 43 2.7

[1056] Conclusion: Compounds 1, 39-41 in the present invention have no significant effect on Na v The inhibitory effect on 1.5 channels is weaker than that of Example Compound 43, which shows that the risk of cardiac toxicity is significantly lower than that of Example Compound 43.

[1057] Pharmacokinetic evaluation

[1058] Test Example 5: BALB / C nude mouse pharmacokinetic test of the compounds of the present disclosure

[1059] 1. Summary

[1060] BALB / C nude mice were used as test animals, and the drug concentration in plasma at different time points after oral administration of the disclosed compound to BALB / C nude mice was determined by LC / MS / MS method. The pharmacokinetic behavior of the disclosed compound in BALB / C nude mice was studied, and its pharmacokinetic characteristics were evaluated.

[1061] 2. Experimental plan

[1062] 2.1 Experimental drugs and instruments

[1063] The compound of Example 1, the compound of Example 14, the compound of Example 15, and the compounds of Examples 39-42.

[1064] Instrument sources of LC / MS / MS: LC / MS / MS (API4000 triple quadrupole tandem mass spectrometer (No. 3) (Applied Biosystems, USA), Shimadzu LC-30AD ultra-high performance liquid chromatography system (Shimadzu, Japan).

[1065] 2.2 Experimental animals

[1066] 63 female BALB / C nude mice were equally divided into 7 groups, with 9 mice in each group, purchased from JCSJ Experimental Animal Co., Ltd., with animal production license number SCXK (Shanghai) 2013-0006.

[1067] 2.3 Drug preparation

[1068] For Example 14, an appropriate amount of sample was weighed, and 5% by volume of DMSO, 5% by volume of Tween 80 and 90% by volume of normal saline were added to prepare a 0.1 mg / mL colorless, clear and transparent liquid.

[1069] For Examples 1, 15, 39-42, appropriate amount of sample was weighed, and 9% volume of PEG400, 0.5% volume of Tween 80 and 90.5% volume of 0.5% CMC-Na were added to prepare a 1.5 mg / mL colorless clear liquid.

[1070] 2.4 Administration

[1071] After fasting overnight, the drugs were administered by gavage, with a volume of 0.2 ml / 10 g. The dosage of the compound of Example 14 was 2 mg / kg, and the dosage of the compound of Example 1, the compound of Example 15, and the compounds of Examples 39-42 was 30 mg / kg.

[1072] 3. Operation

[1073] Sixty-three female Balb / C nude mice were fasted overnight and then given the drug by gavage.

[1074] For Example Compounds 1 and 39, 0.1 ml of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration (3 animals at each time point), placed in a blood collection tube treated with heparin (Sinopharm Chemical Reagent Co., Ltd.), centrifuged at 3500 rpm for 10 minutes to separate the plasma, and stored at -20°C. Determination of the content of the test compound in the plasma of nude mice after oral administration of the drug: 25 μL of the plasma of nude mice at each time point after administration was taken, 30 μL (100 ng / mL) of the internal standard solution camptothecin (China National Institute for the Control of Biological Products) and 225 μL of acetonitrile were added, vortexed for 5 minutes, centrifuged for 10 minutes (3700-4000 rpm), and 0.1-0.5 μL of the supernatant of the plasma sample was taken for LC / MS / MS analysis.

[1075] For Example Compounds 14 and 15, 0.1 ml of blood was collected at 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration (3 animals at each time point), placed in a heparinized test tube, centrifuged at 3500 rpm for 10 minutes to separate the plasma, and stored at -20°C. Determination of the content of the test compound in the plasma of nude mice after oral administration of the drug: 25 μL of nude mouse plasma at each time point after administration was taken, 30 μL of internal standard solution camptothecin (100 ng / mL) and 200 μL of acetonitrile were added, vortexed for 5 minutes, centrifuged for 10 minutes (3700 rpm), and 0.25-1 μL of the supernatant of the plasma sample was taken for LC / MS / MS analysis.

[1076] For Example Compounds 40-42, 0.1 ml of blood was collected at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours after administration (3 animals at each time point), placed in an EDTA-K2 (Shanghai Titan Technology Co., Ltd.) anticoagulant tube, centrifuged at 10,000 rpm for 1 minute (4°C), and plasma was separated within 1 hour and stored at -20°C. The blood collection to centrifugation process was performed under ice bath conditions. Determination of the content of the test compound in the plasma of nude mice after oral administration of the drug: 25 μL of nude mouse plasma at each time point after administration was taken, 50 μL (100 ng / mL) of the internal standard solution camptothecin and 200 μL of acetonitrile were added, vortexed for 5 minutes, centrifuged for 10 minutes (3700 rpm), and 1 μL of the supernatant of the plasma sample was taken for LC / MS / MS analysis. 4. Results of pharmacokinetic parameters of BALB / C nude mice

[1077] The pharmacokinetic parameters of the compounds of the present invention are shown in Table 5.

[1078]

[1079] Conclusion: The pharmacokinetic absorption of the disclosed compounds is good and has obvious pharmacokinetic absorption effect.

[1080] Test Example 6: Biological evaluation of covalent modification of wild-type and Y537S mutant estrogen receptor ERα

[1081] 1. Experimental purpose

[1082] The purpose of this experiment is to determine the covalent modification effect of the disclosed compounds on the wild type and Y537S mutant types of the estrogen receptor ERα.

[1083] 2. Experimental methods

[1084] The ligand binding domain (LBD, aa296-554) of the estrogen receptor ERα wild type and ERαY537S mutant was expressed and purified from Escherichia coli. 2 μM ERα wild type or ERαY537S mutant protein and 10 μM compound were added to a buffer containing 50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM TCEP, and 5% glycerol, mixed, incubated at 4°C for 24 hours, and then detected by high-resolution mass spectrometry (Agilent Technologies, Agilent Q-tof 6530). Alternatively, 1 μM ERα wild type or ERαY537S mutant protein and 3 μM compound were added to a buffer containing 50 mM Tris-HCl, pH 7.5, 150 mM NaCl, 1 mM TCEP, and 5% glycerol, mixed, incubated at 37°C for 15 minutes, and then detected by high-resolution mass spectrometry. In the mass spectrometry detection results, the peak with a molecular weight equal to the sum of the protein and the compound is the covalently modified product. The percentage of covalent modification is calculated by calculating the ratio of unbound compound protein to total protein. The results are shown in Table 6 below.

[1085] Table 6 Covalent modification ratio of the disclosed compounds on wild-type and Y537S mutant estrogen receptor ERα after 24 hours of covalent modification

[1086]

[1087]

[1088] Conclusion: The test compounds have a good covalent modification effect on ERα wild-type or ERαY537S mutant proteins.

Claims

1. A compound represented by the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof: in: G is CH or N; Z is selected from key, CR 5 R 6 、-O-(CH2) t -or-NR 7 -(CH2) t -; Ring A is selected from cycloalkyl or heterocyclyl; R a Selected from -CH2CH=CHC(O)NR 8 R 9 、-C(O)CH=CR 10 R 11 and -C(O)C≡CR 12 ; R b is selected from a hydrogen atom or an alkyl group; R 1 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; R 2 is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, alkoxy, amino, cyano, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl, aryl and heteroaryl; R 3 Each is the same or different and is independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, NR 13 C(O)R 14 、C(O)NR 13 R 14 、SO2R 15 , cycloalkyl, heterocyclyl, aryl and heteroaryl; R 4 are the same or different and are each independently selected from a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, an alkoxy group, a cyano group, an amino group, a nitro group, a carboxyl group, an aldehyde group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R 5 and R 6 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 7 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R 8 and R 9 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; Or, R 8 and R 9 Together with the nitrogen atom to which it is connected, it forms a heterocyclic group, wherein the heterocyclic group contains, in addition to one nitrogen atom, 1 to 2 identical or different heteroatoms selected from N, O and S, and the heterocyclic group is optionally substituted by one or more substituents selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 10 and R 11 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 12 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R 13 and R 14 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 15 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; m is 0 or 1; n is 0, 1, 2 or 3; q is 0, 1, 2, 3, 4, or 5; s is 0, 1, 2, or 3 and t is 0, 1, 2, 3, 4, 5 or 6.

2. The compound of general formula (I) according to claim 1 or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from C3-C6 cycloalkyl or a 3- to 6-membered heterocyclic group; the heterocyclic group contains 1 to 3 heteroatoms selected from N, O or S; preferably, ring A is selected from cyclopropyl, cyclopentyl, cyclohexyl, tetrahydropyrrolyl or piperidinyl.

3. The compound of the general formula (I) according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein ring A is selected from 4. The compound of the general formula (I) according to claim 1 or 2, or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt, which is the compound of the general formula (II) or its tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or its pharmaceutically acceptable salt: in: Ring A, G, Z, R 1 , R 2 , R 3 , R 4 , R a , R b , n, m, s and q are as defined in claim 1.

5. A compound of the general formula (I) according to any one of claims 1 to 4, or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, which is a compound of the general formula (III) or a tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof: in: G, Z, R 1 , R 2 , R 3 , R 4 , R a , R b , n, s and q are as defined in claim 1.

6. A compound according to any one of claims 1 to 5, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is a nitrogen atom.

7. A compound according to any one of claims 1 to 6, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from halogen or hydrogen atom.

8. A compound according to any one of the general formula (I) of claim 1 or a tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a haloalkyl group, preferably a C1-C6 haloalkyl group, more preferably -CH2CF3.

9. A compound according to any one of the general formula (I) of claim 1 or a tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from hydrogen, cyano, halogen, alkyl, haloalkyl, NR 13 C(O)R 14 、C(O)NR 13 R 14 and SO2R 15 ; R 13 and R 14 are the same or different and are each independently selected from a hydrogen atom and an alkyl group; R 15 is selected from a hydrogen atom and an alkyl group.

10. A compound according to any one of the general formula (I) of claims 1 to 9, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R 4 The same or different, each independently selected from hydrogen atom, halogen, alkyl and alkoxy, preferably hydrogen atom.

11. A compound according to any one of claims 1 to 10, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein Z is selected from a bond, -O-, -O-CH2- and -NH-.

12. A compound according to any one of the general formula (I) of claims 1 to 11, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R a Selected from -CH2CH=CHC(O)NR 8 R 9 、-C(O)CH=CR 10 R 11 and -C(O)C≡CR 12 ; R 8 and R 9 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group or a heterocyclic group; or R 8 and R 9 Together with the nitrogen atom to which it is connected, it forms a heterocyclic group, wherein the heterocyclic group contains, in addition to one nitrogen atom, 1 to 2 identical or different heteroatoms selected from N, O and S, and the heterocyclic group is optionally substituted by one or more substituents selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 10 and R 11 are the same or different and are each independently a hydrogen atom or an alkyl group; R 12 is selected from a hydrogen atom or an alkyl group.

13. A compound according to any one of claims 1 to 12, or a tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R a Selected from -CH2CH=CHC(O)N(CH3)2, -CH2CH=CHC(O)NH(CH3), -CH2CH=CHC(O)NHC(CH3)3, -C(O)CH=CH2, -C(O)C≡CCH3, Preferably, R a Selected from -CH2CH=CHC(O)N(CH3)2, -CH2CH=CHC(O)NH(CH3), -CH2CH=CHC(O)NHC(CH3)3, -C(O)CH=CH2, -C(O)C≡CCH3, 14. A compound of the general formula (I) according to any one of claims 1 to 13, or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

15. A compound represented by the general formula (IA) or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, in: R w is an amino protecting group, preferably tetrahydropyranyl; R is selected from -CH2CH=CHC(O)NR 8 R 9 、-C(O)CH=CR 10 R 11 or -C(O)C≡CR 12 ; R 8 and R 9 are the same or different and are each independently selected from a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group; Or, R 8 and R 9 Together with the nitrogen atom to which it is connected, it forms a heterocyclic group, wherein the heterocyclic group contains, in addition to one nitrogen atom, 1 to 2 identical or different heteroatoms selected from N, O and S, and the heterocyclic group is optionally selected from alkyl, alkoxy, halogen, amino, cyano, nitro, hydroxyl, hydroxyalkyl, -COOR 16 -, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituted with one or more substituents; R 10 and R 11 are the same or different and are each independently selected from hydrogen, halogen, alkyl, haloalkyl, alkoxy, cyano, amino, nitro, carboxyl, aldehyde, hydroxyl, hydroxyalkyl, cycloalkyl, heterocyclic, aryl and heteroaryl; R 12 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; R 16 is selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group; Ring A, G, Z, R 1 , R 2 , R 3 , R 4 , R b , n, m, s and q are as defined in claim 1.

16. A compound of the general formula (IA) according to claim 15 or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

17. A method for preparing a compound of the general formula (I) according to any one of claims 1 to 14 or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising: The compound of the general formula (IA) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, undergoes a deprotection reaction under acidic conditions to obtain a compound of the general formula (I) or its tautomer, mesomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof; in: R w is an amino protecting group, preferably tetrahydropyranyl; R as defined in claim 15; Ring A, G, Z, R 1 , R 2 , R 3 , R 4 , R a , R b , n, m, s and q are as defined in claim 1.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the general formula (I) according to any one of claims 1 to 14 or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.

19. Use of a compound of the general formula (I) according to any one of claims 1 to 14 or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18 in the preparation of an estrogen receptor modulator.

20. Use of a compound of the general formula (I) according to any one of claims 1 to 14 or its tautomer, mesomer, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18 in the preparation of a medicament for preventing and / or treating estrogen receptor-mediated or dependent diseases or conditions.

21. The use according to claim 20, wherein the estrogen receptor-mediated or -dependent disease or condition is cancer, preferably breast cancer, ovarian cancer, endometrial cancer, prostate cancer or uterine cancer, more preferably breast cancer.

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