Chenodeoxycholic acid derivatives

Abstract

The present application discloses compounds represented by Formula I, Formula II, Formula III, Formula IV or Formula V, their tautomers, their stereoisomers or pharmaceutically acceptable salts thereof, and discloses their use in preparing drugs for treating FXR-related diseases.

Description

[0001] This application is a divisional application of the following application: Application date: April 29, 2016; Application number: 201680024495.9; Invention name: "Chenodeoxycholic acid derivatives". Field of the Invention

[0002] The present application relates to the field of medicine. Specifically, the present application relates to compounds represented by Formula I, Formula II, Formula III, Formula IV or Formula V, their tautomers, their stereoisomers or pharmaceutically acceptable salts thereof, and to their use in the preparation of drugs for treating FXR-related diseases. Background Art

[0003] Niacin X receptor (FXR) is an orphan nuclear receptor originally identified from a rat lung cDNA library (BM. Forman, et al., Cell 81: 687-693 (1995)), which is closely related to the insect ecdysone receptor. FXR is a member of the ligand-activated transcription factor nuclear receptor family that includes steroid, retinoid, and thyroid hormone receptors (DJ. Mangelsdorf, et al., Cell 83: 841-850 (1995)). Northern and in situ analysis showed that FXR is abundantly expressed in the lung, intestine, kidney, and adrenal gland (BM. Forman et al., Cell 81: 687-693 (1995) and W. Seol et al., Mol. Endocrinnol. 9: 72-85 (1995)). FXR forms a heterodimer with 9-cis retinoic acid receptor (RXR) and binds to DNA. FXR / RXR heterodimers preferentially bind to components consisting of two nuclear receptor half sites that share AG(G / T)TCA, which form inverted repeats and are separated by a single nucleotide (IR-1 motif) (BM. Forman, et al., Cell 81: 687-693 (1995)). However, these compounds fail to activate mouse and human FXR, leaving the naturalness of the endogenous FXR ligand uncertain. Some naturally occurring bile acids bind and activate FXR at physiological concentrations (PCT WO 00 / 37077, published June 29, 2000)). As described herein, bile acids that serve as FXR ligands include chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), and taurine and glycine conjugates of these bile acids.

[0004] WO-2005082925 discloses the use of INT747 in the preparation of a drug for treating FXR-related diseases.

[0005] SUMMARY OF THE INVENTION

[0006] One aspect of the present application provides a compound represented by formula I, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof:

[0007]

[0008] in,

[0009] R7, R8 and R9 are independently selected from H, halogen, OH, NH2, SH, CN, or C optionally substituted with 1, 2, 3, 4 or 5 R 1-3 Alkyl or C 1-3 Alkoxy, optionally, R8 and R9 can be linked together to form a 3-6 membered ring; or, R9 is selected from H, R7 and R8 and the carbon atom to which they are linked form a 5-6 membered heteroaromatic ring or C optionally substituted by 1, 2, 3, 4 or 5 R 3-6 Cycloalkyl;

[0010] The above R are independently selected from halogen, CN, OH, NH2, SH, or C optionally substituted by 1, 2, 3, 4 or 5 R'. 1-3 Alkyl, C 1-3 heteroalkyl;

[0011] The above R' is selected from halogen, CN, OH, NH2, SH, Me or trifluoromethyl;

[0012] Provided that R7, R8 and R9 are not H at the same time, and, when R8 is OH, R7 and R9 are not selected from H at the same time, and R8 or R9 is not selected from

[0013] Another aspect of the present application provides a compound represented by Formula II, Formula III or Formula IV, a tautomer thereof or a pharmaceutically acceptable salt thereof:

[0014]

[0015] in,

[0016] R1, R2, R3, and R5 are independently selected from H, halogen, OH, NH2, SH, CN, or C optionally substituted with 1, 2, 3, 4, or 5 R 1-3 Alkyl or C 1-3 Alkoxy;

[0017] When R2 is OH, R1 and R3 are not simultaneously selected from H;

[0018] Optionally, R2 and R3 may be linked together to form a 3-6 membered ring;

[0019] represents a single bond or a double bond;

[0020] Ring A is selected from a 5-6 membered heteroaromatic ring optionally substituted by 1, 2, 3, 4 or 5 R;

[0021] L is selected from: a single bond, -C(=O), -C(=O)S-, -C(=O)N(R L )S(=O)2(C(R L )2) 0-2 -、-C(=O)N(C(R L )3)S(=O)2-、-N(R L )C(=O)O(C(R L )2) 0-2 -、-N(R L )C(=O)N(R L )(C(R L )2) 0-2 -、-OC(=O)N(R L )-、-OS(=O)2N(R L )-、-N(R L )C(=S)N(R L )-、-N(R L )C(=S)-、-P(=O)(OR L )O-、-S(=O)2N(R L )-;

[0022] R L is selected from H, or is selected from C optionally substituted by 1, 2, or 3 R 1-3 alkyl;

[0023] R4 is selected from H, or is selected from C optionally substituted with 1, 2, 3, 4, or 5 R 1-3 Alkyl, C 3-10 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or 5- to 6-membered heteroaryl;

[0024] R is independently selected from halogen, CN, OH, NH2, SH, or optionally substituted with 1, 2, 3, 4, or 5 R': 1-3 Alkyl, C 1-3 Heteroalkyl; and / or

[0025] Optionally, any one R L can be linked together with R4 to form a 4- to 6-membered ring optionally substituted with 1, 2, 3, 4, or 5 Rs;

[0026] R' is selected from halogen, CN, OH, NH2, SH, Me, trifluoromethyl;

[0027] "Hetero" represents a heteroatom or a heteroatom group selected from -NH-, -O-, -S-, =O, =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)- and / or -S(=O)2-;

[0028] The number of "hetero" in each of the above-mentioned "hetero"-containing groups is 1, 2, 3, 4, or 5.

[0029] On the other hand, the present application provides a compound represented by formula V, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof:

[0030]

[0031] in,

[0032] R4 is selected from H, or C optionally substituted with 1, 2, 3, 4 or 5 R 1-3 Alkyl, C 3-10 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or 5- to 6-membered heteroaryl;

[0033] R5 is selected from H, halogen, OH, NH2, SH, CN, or C optionally substituted with 1, 2, 3, 4 or 5 R 1-3 Alkyl or C 1-3 Alkoxy;

[0034] R6 is selected from H or OH;

[0035] n is selected from 0, 1 or 2;

[0036] L is selected from: a single bond, -C(=O)-, -C(=O)S-, -C(=O)N(R L )S(=O)2(C(R L )2) 0-2 -、-C(=O)N(C(R L )3)S(=O)2-、-N(R L )C(=O)O(C(R L )2) 0-2 -、-N(R L )C(=O)N(R L )(C(R L )2) 0-2 -、-OC(=O)N(R L )-、-OS(=O)2N(R L )-、-N(R L )C(=S)N(R L )-、-N(R L )C(=S)-, -P(=O)(OEt)O-, -S(=O)2N(R L)-, -C(=O)NHS(=O)2NH-, -C(=O)NHS(=O)2NHCH2-, -C(=O)NHS(=O)2N(R L )-, -C(=O)NHS(=O)2NHC(=O)-, -NHS(=O)2-, -NHC(=O)C(=O)O- or -OP(=O)(OR L )O-;

[0037] The above R L is selected from H, or is selected from C optionally substituted by 1, 2, or 3 R 1-3 alkyl;

[0038] The above R are independently selected from halogen, CN, OH, NH2, SH, or optionally substituted by 1, 2, 3, 4 or 5 R': 1-3 Alkyl, C 1-3 Heteroalkyl and / or

[0039] Optionally, any one R L Together with R4, it forms a 4-6 membered ring optionally substituted with 1, 2, 3, 4, or 5 R;

[0040] The above R' is selected from halogen, CN, OH, NH2, SH, Me or trifluoromethyl;

[0041] Provided that, when R4 is selected from C 1-3 When it is an alkyl group, R is not selected from OH and NH2.

[0042] Another aspect of the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound as shown in Formula I, Formula II, Formula III, Formula IV or Formula V, its tautomers, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0043] On the other hand, the present application provides the use of compounds as shown in Formula I, Formula II, Formula III, Formula IV or Formula V, their tautomers, their stereoisomers or pharmaceutically acceptable salts or the above-mentioned pharmaceutical compositions in the preparation of prevention or treatment of diseases that benefit from FXR stimulation, wherein the diseases that benefit from FXR stimulation include cardiovascular diseases, liver / gallbladder system diseases, obesity, diabetes, lower urinary tract symptoms (nearby areas) and benign prostatic hyperplasia (BPH) or ureteral stones.

[0044] Another aspect of the present application provides a method for preventing or treating diseases that benefit from FXR stimulation, comprising administering to a patient a therapeutically effective amount of a compound as shown in Formula I, its tautomers, its stereoisomers or pharmaceutically acceptable salts thereof, or the above-mentioned pharmaceutical composition, wherein the diseases that benefit from FXR stimulation include cardiovascular diseases, liver / biliary system diseases, obesity, diabetes, lower urinary tract symptoms (nearby areas) and benign prostatic hyperplasia (BPH) or ureteral stones. DETAILED DESCRIPTION OF THE INVENTION

[0045] One aspect of the present application provides a compound represented by formula I, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof:

[0046]

[0047] in,

[0048] R7, R8 and R9 are independently selected from H, halogen, OH, NH2, SH, CN, or C optionally substituted with 1, 2, 3, 4 or 5 R 1-3 Alkyl or C 1-3 Alkoxy, optionally, R8 and R9 can be linked together to form a 3-6 membered ring; or, R9 is selected from H, R7 and R8 and the carbon atom to which they are linked form a 5-6 membered heteroaromatic ring or C optionally substituted by 1, 2, 3, 4 or 5 R 3-6 Cycloalkyl;

[0049] The above R are independently selected from halogen, CN, OH, NH2, SH, or C optionally substituted by 1, 2, 3, 4 or 5 R'. 1-3 Alkyl, C 1-3 heteroalkyl;

[0050] The above R' is selected from halogen, CN, OH, NH2, SH, Me or trifluoromethyl;

[0051] Provided that R7, R8 and R9 are not H at the same time, and, when R8 is OH, R7 and R9 are not selected from H at the same time, and R8 or R9 is not selected from

[0052] In one embodiment, in the compound of formula I, R7 is selected from H, F, Cl, Br, I, OH, NH2, SH, CN, Me, Et,

[0053] In one embodiment, in the compound of formula I, R7 is selected from H or

[0054] In one embodiment, in the compound represented by formula I, R8 and R9 are independently selected from H, F, Cl, Br, I, OH, NH2, SH, CN, Me, Et, Alternatively, R8 and R9 are connected together to form C 3-6 Cycloalkyl.

[0055] In one embodiment, in the compound represented by formula I, R8 and R9 are independently selected from H, F, OH, Me, Et, Alternatively, R8 and R9 are linked together to form a cyclopropyl group, and R8 and R9 are not H at the same time.

[0056] In one embodiment, in the compound represented by formula I, R9 is selected from H, and R7 and R8 together with the carbon atom to which they are attached form an imidazolyl, pyrazolyl, pyrrolyl, thienyl, oxazolyl, thiazolyl, furanyl or cyclopropyl group which is optionally substituted with 1 or 2 Rs.

[0057] In one embodiment, in the compound of formula I, R9 is selected from H, R7 and R8 form a group with the carbon atom to which they are attached which is optionally substituted with methyl or amino.

[0058] In one embodiment, in the compound of formula I, R9 is selected from H, R7 and R8 form a

[0059] Another aspect of the present application provides a compound represented by Formula II, Formula III or Formula IV, a tautomer thereof or a pharmaceutically acceptable salt thereof:

[0060]

[0061] in,

[0062] R1, R2, R3, and R5 are independently selected from H, halogen, OH, NH2, SH, CN, or C optionally substituted with 1, 2, 3, 4, or 5 R 1-3 Alkyl or C 1-3 Alkoxy;

[0063] When R2 is OH, R1 and R3 are not simultaneously selected from H;

[0064] Optionally, R2 and R3 may be linked together to form a 3-6 membered ring;

[0065] represents a single bond or a double bond;

[0066] Ring A is selected from a 5-6 membered heteroaromatic ring optionally substituted by 1, 2, 3, 4 or 5 R;

[0067] L is selected from: a single bond, -C(=O), -C(=O)S-, -C(=O)N(R L )S(=O)2(C(R L )2) 0-2 -、-C(=O)N(C(R L )3)S(=O)2-、-N(R L )C(=O)O(C(R L )2) 0-2 -、-N(R L )C(=O)N(R L )(C(R L )2) 0-2 -、-OC(=O)N(R L )-、-OS(=O)2N(R L )-、-N(R L )C(=S)N(R L )-、-N(R L )C(=S)-、-P(=O)(OR L )O-、-S(=O)2N(R L )-;

[0068] R L is selected from H, or is selected from C optionally substituted by 1, 2, or 3 R 1-3 alkyl;

[0069] R4 is selected from H, or is selected from C optionally substituted with 1, 2, 3, 4, or 5 R 1-3 Alkyl, C 3-10 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or 5- to 6-membered heteroaryl;

[0070] R is independently selected from halogen, CN, OH, NH2, SH, or optionally substituted with 1, 2, 3, 4, or 5 R': 1-3 Alkyl, C 1-3 Heteroalkyl; and / or

[0071] Optionally, any one R L can be linked together with R4 to form a 4- to 6-membered ring optionally substituted with 1, 2, 3, 4, or 5 Rs;

[0072] R' is selected from halogen, CN, OH, NH2, SH, Me, trifluoromethyl;

[0073] "Hetero" represents a heteroatom or a heteroatom group selected from -NH-, -O-, -S-, =O, =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O)- and / or -S(=O)2-;

[0074] The number of "hetero" in each of the above-mentioned "hetero"-containing groups is 1, 2, 3, 4, or 5.

[0075] In one embodiment of the present invention, the above R is selected from halogen, CN, OH, NH2, SH, or optionally substituted with 1, 2, 3, 4, or 5 R': 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylamino.

[0076] In one embodiment of the present invention, the above R is selected from F, Cl, Br, I, OH, CN, NH2, SH, Me, E t , CF3.

[0077] In one embodiment of the present invention, the above R1, R2, R3, and R5 are independently selected from H, halogen, OH, NH2, SH, CN, Me, Et,

[0078] In one embodiment of the present invention, the above R2 and R3 are connected together to form a cyclopropyl group.

[0079] In one embodiment of the present invention, the ring A is selected from imidazolyl, pyrazolyl, pyrrolyl, thienyl, oxazolyl, thiazolyl, furyl, which are optionally substituted with 1 or 2 Rs.

[0080] In one embodiment of the present invention, the ring A is selected from

[0081] In one embodiment of the present invention, the ring A is selected from

[0082] In one embodiment of the present invention, the above R4 is selected from H, or Me, Et,

[0083] In one embodiment of the present invention, the above R4 is selected from H, or selected from Me, Et,

[0084] In one embodiment of the present invention, the above R4 is selected from: H, Me, Et,

[0085] In one embodiment of the present invention, the above L is selected from: a single bond, -C(=O), -C(=O)S-, -C(=O)NHS(=O)2(CH2) 0-2-, -C(=O)N(CH3)S(=O)2-, -NHC(=O)O(CH2) 0-2 -、-NHC(=O)N(R L )(CH2) 0-2 -, -OC(=O)NH-, -OS(=O)2NH-, -NHC(=S)NH-, -NHC(=S)-, -P(=O)(OR L )O-, -S(=O)2NH-.

[0086] In one embodiment of the present invention, the above L is selected from: a single bond, -C(=O), -C(=O)S-, -C(=O)NHS(=O)2-, -C(=O)NHS(=O)2CH2-, -C(=O)NHS(=O)2(CH2)2-, -C(=O)N(CH3)S(=O)2-, -NHC(=O)O(CH2) 0-2 -, -NHC(=O)O-, -NHC(=O)OCH2-, -NHC(=O)O(CH2)2-, -NHC(=O)NH-, -NHC(=O)NHCH2-, -NHC(=O) NH(CH2)2-, -OC(=O)NH-, -OS(=O)2NH-, -NHC(=S)NH-, -NHC(=S)-, -P(=O)(OEt)O-, -S(=O)2NH-.

[0087] In one embodiment of the present invention, the above R L When the structural unit -L-R4 is connected together with R4 to form a 4- to 6-membered ring optionally substituted by 1, 2, 3, 4, or 5 R, the structural unit -L-R4 is selected from

[0088] In one embodiment of the present invention, the above R L When the structural unit -L-R4 is connected together with R4 to form a 4- to 6-membered ring optionally substituted by 1, 2, 3, 4, or 5 R, the structural unit -L-R4 is selected from

[0089] In one embodiment of the present invention, the structural unit -L-R4 is selected from:

[0090]

[0091] Another aspect of the present application provides a compound represented by formula V, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof:

[0092]

[0093] in,

[0094] R4 is selected from H, or C optionally substituted with 1, 2, 3, 4 or 5 R 1-3 Alkyl, C 3-10 Cycloalkyl, 3- to 6-membered heterocycloalkyl, 5- to 6-membered aryl or 5- to 6-membered heteroaryl;

[0095] R5 is selected from H, halogen, OH, NH2, SH, CN, or C optionally substituted with 1, 2, 3, 4 or 5 R 1-3 Alkyl or C 1-3 Alkoxy;

[0096] R6 is selected from H or OH;

[0097] n is selected from 0, 1 or 2;

[0098] L is selected from: a single bond, -C(=O)-, -C(=O)S-, -C(=O)N(R L )S(=O)2(C(R L )2) 0-2 -、-C(=O)N(C(R L )3)S(=O)2-、-N(R L )C(=O)O(C(R L )2) 0-2 -、-N(R L )C(=O)N(R L )(C(R L )2) 0-2 -、-OC(=O)N(R L )-、-OS(=O)2N(R L )-、-N(R L )C(=S)N(R L )-、-N(R L )C(=S)-, -P(=O)(OEt)O-, -S(=O)2N(R L )-, -C(=O)NHS(=O)2NH-, -C(=O)NHS(=O)2NHCH2-, -C(=O)NHS(=O)2N(R L )-, -C(=O)NHS(=O)2NHC(=O)-, -NHS(=O)2-, -NHC(=O)C(=O)O- or -OP(=O)(OR L )O-;

[0099] The above R L is selected from H, or is selected from C optionally substituted by 1, 2, or 3 R 1-3 Alkyl, preferably R L Select from H or C 1-3 alkyl;

[0100] The above R are independently selected from halogen, CN, OH, NH2, SH, or optionally substituted by 1, 2, 3, 4 or 5 R': 1-3 Alkyl, C 1-3 Heteroalkyl and / or

[0101] Optionally, any one R L Together with R4, it forms a 4-6 membered ring optionally substituted with 1, 2, 3, 4, or 5 R;

[0102] The above R' is selected from halogen, CN, OH, NH2, SH, Me or trifluoromethyl;

[0103] Provided that, when R4 is selected from C 1-3 When it is an alkyl group, R is not selected from OH and NH2.

[0104] In one embodiment, the stereoisomer of the compound represented by formula V is represented by the following formula V':

[0105]

[0106] In one embodiment, in the compound represented by formula V, the above R is selected from halogen, CN, OH, NH2, SH, or C optionally substituted with 1, 2, 3, 4 or 5 R' 1-3 Alkyl, C 1-3 Alkoxy or C 1-3 Alkylamino.

[0107] In one embodiment, in the compound represented by formula V, the above R is preferably selected from F, Cl, Br, I, OH, CN, NH2, SH, Me, Et, or CF3.

[0108] In one embodiment, in the compound represented by formula V, the above R is preferably selected from F, Cl, OH, NH2, SH, Me, Et, or CF3.

[0109] In one embodiment, in the compound represented by formula V, R5 is selected from H, F, Cl, Br, I, OH, NH2, SH, CN, Me, Et,

[0110] In one embodiment, in the compound represented by formula V, R5 is selected from H, Me or Et.

[0111] In one embodiment, in the compound represented by formula V, the above R4 is selected from H, or Me, Et, which is optionally substituted by 1, 2, 3, 4 or 5 R,

[0112] In one embodiment, in the compound represented by formula V, the above R4 is preferably selected from H, or selected from Me, Et,

[0113] In one embodiment, in the compound represented by formula V, the above R4 is more preferably selected from H, Me, Et,

[0114] In one embodiment, in the compound represented by formula V, the above L is selected from a single bond, -C(=O)-, -C(=O)S-, -C(=O)NHS(=O)2(CH2) 0-2 -, -C(=O)N(CH3)S(=O)2-, -NHC(=O)O(CH2) 0-2 -、-NHC(=O)N(R L )(CH2) 0-2 -, -OC(=O)NH-, -OS(=O)2NH-, -NHC(=S)NH-, -NHC(=S)-, -P(=O)(OEt)O-, -S(=O)2NH-, -C(=O)NHS(=O)2NH-, -C(=O)NHS(=O)2NHCH2-, -C(=O)NHS(=O)2N(R L )-, -C(=O)NHS(=O)2NHC(=O)-, -NHS(=O)2-, -NHC(=O)C(=O)O- or -OP(=O)(OR L )O-.

[0115] In one embodiment, in the compound represented by formula V, the above L is preferably selected from a single bond, -C(=O)-, -C(=O)S-, -C(=O)NHS(=O)2-, -C(=O)NHS(=O)2CH2-, -C(=O)NHS(=O)2(CH2)2-, -C(=O)N(CH3)S(=O)2-, -NHC(=O)O-, -NHC(=O)OCH2-, -NHC(=O)O(CH2)2-, -NHC(=O)NH-, -NHC(=O)NHCH2-, -NHC(=O)NH(C H2)2-, -OC(=O)NH-, -OS(=O)2NH-, -NHC(=S)NH-, -NHC(=S)-, -P(=O)(OEt)O-, -S(=O)2NH-, -C(=O)NHS(=O)2NH-, -C(=O)N HS(=O)2NHCH2-, -C(=O)NHS(=O)2N(CH3)-, -C(=O)NHS(=O)2NHC(=O)-, -NHS(=O)2-, -NHC(=O)C(=O)O- or -OP(=O)(OMe)O-.

[0116] In one embodiment, in the compound represented by formula V, the above R L When the structural unit -L-R4 is selected from the group consisting of:

[0117] In one embodiment, in the compound represented by formula V, the above R L When the structural unit -L-R4 is connected together with R4 to form a 4- to 6-membered ring optionally substituted by 1, 2, 3, 4 or 5 R, the structural unit -L-R4 is preferably selected from

[0118] In one embodiment, in the compound represented by formula V, the structural unit -L-R4 is selected from:

[0119]

[0120]

[0121] The following compounds:

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128]

[0129] Pharmaceutical composition

[0130] On the other hand, the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound as shown in Formula I, Formula II, Formula III, Formula IV or Formula V, its tautomers, its stereoisomers or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers or excipients.

[0131] The compound of the present application or its salt can be administered alone as an active substance, preferably in the form of a pharmaceutical composition.

[0132] On the other hand, the present application provides a pharmaceutical composition containing a compound represented by Formula I, Formula II, Formula III, Formula IV or Formula V or a pharmaceutically acceptable salt, solvate, polymorph, metabolite thereof as an active ingredient, and one or more pharmaceutically acceptable carriers.

[0133] The administration of the compound of the present application or its pharmaceutically acceptable salt can be carried out in pure form or in the form of a suitable pharmaceutical composition by providing any acceptable mode of administration of a medicine of similar use. The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with a suitable pharmaceutically acceptable carrier, diluent, medium or excipient. The pharmaceutical composition of the present application can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

[0134] Typical routes of administration of the compounds of the present application or their pharmaceutically acceptable salts or their pharmaceutical compositions include, but are not limited to, oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral, sublingual, vaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration, etc. The preferred route of administration is oral administration.

[0135] The pharmaceutical composition of the present application can be manufactured by methods known to those skilled in the art, such as conventional mixing methods, dissolution methods, granulation methods, sugar-coated pill making methods, grinding methods, emulsification methods, freeze-drying methods, etc.

[0136] In a preferred embodiment, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical composition can be prepared by mixing the active compound with a pharmaceutically acceptable carrier well known in the art. These carriers enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

[0137] Solid oral pharmaceutical compositions can be prepared by conventional mixing, filling or tableting methods. For example, they can be obtained by the following method: the active compound is mixed with a solid excipient, the resulting mixture is optionally milled, other suitable excipients are added if necessary, and then the mixture is processed into particles to obtain the core of a tablet or a sugar-coated agent. Suitable excipients include, but are not limited to, adhesives, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, etc. Such as microcrystalline cellulose, glucose solution, acacia gum, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol or dicalcium phosphate; silicon dioxide; cross-linked sodium carboxymethylcellulose, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose, cross-linked polyvinyl pyrrolidone, etc. The core of the sugar-coated agent can be optionally coated according to methods known in common pharmaceutical practice, especially using an enteric coating.

[0138] The pharmaceutical composition of the present application may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Appropriate excipients, such as fillers, buffers or surfactants, can be used.

[0139] The amount of compound or composition administered to a patient is not fixed and depends on the drug being administered, the purpose of administration, such as prevention or treatment; the patient's condition, the mode of administration, etc. In therapeutic applications, a patient already suffering from a disease may be administered a composition in an amount sufficient to cure or at least partially suppress the symptoms of the disease and its complications. The effective dose will depend on the disease state being treated and the judgment of the attending clinician, which depends on factors such as the severity of the disease, the patient's age, weight and general condition.

[0140] The composition administered to the patient may be in the form of a pharmaceutical composition as described above. These compositions may be sterilized by conventional sterilization techniques or by filtration sterilization. The aqueous solution may be packaged for use as is, or lyophilized, and the lyophilized preparation may be mixed with a sterile aqueous carrier before administration. The pH of the compound preparation is generally 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be appreciated that the use of some of the aforementioned excipients, carriers or stabilizers may result in the formation of a pharmaceutical salt.

[0141] Therapeutic Uses

[0142] The compounds of the present application are FXR agonists. The compounds of the present application can be used in a method for preventing or treating dyslipidemia or a disease associated with dyslipidemia, which comprises administering a therapeutically effective amount of the compounds of the present application to a patient in need of such treatment.

[0143] The compounds of the present application can be used to reduce total cholesterol levels, reduce LDL cholesterol levels, reduce VLDL cholesterol levels, increase HDL cholesterol levels, and / or reduce triglyceride levels. The reduction of triglyceride levels described in the present application refers to reducing the triglyceride levels in the subject in need of treatment to a level lower than the initial triglyceride level of the prevention or treatment subject before taking the compounds of the present application. For example, the compounds of the present application can reduce triglyceride production in the liver or reduce triglyceride secretion in the liver by reducing fat absorption. The compounds of the present application can also reduce serum triglycerides and liver triglycerides.

[0144] The compounds of the present application can be used to prevent or treat cardiovascular diseases associated with hypertriglyceridemia and / or hypercholesterolemia in a subject (e.g., a mammal, particularly a human), such as but not limited to atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, thrombosis, coronary artery disease, stroke or hypertension.

[0145] The compounds of the present application can be used to prevent or treat liver / biliary system diseases of a subject (e.g., a mammal, particularly a human), such as, but not limited to, cholestatic liver diseases, high HDL cholesterol diseases, high triglyceride diseases, or fibrotic diseases, specifically, such as, but not limited to, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstones, non-alcoholic cirrhosis, biliary atresia, cholestatic liver disease, chronic liver disease, hepatitis infection (type B or type C), alcoholic liver disease, or liver fibrosis.

[0146] The compounds of the present application can be used to prevent or treat obesity in a subject (eg, a mammal, particularly a human).

[0147] The compounds of the present application can be used to prevent or treat diabetes, or diseases related to insulin resistance and glucose intolerance in a subject (eg, mammal, particularly human).

[0148] The compounds of the present application can be used to prevent or treat lower urinary tract symptoms (nearby areas) and benign prostatic hyperplasia (BPH) or ureteral stones in a subject (eg, mammal, particularly human).

[0149] On the other hand, the present application provides the use of compounds as shown in Formula I, Formula II, Formula III, Formula IV or Formula V, their tautomers, their stereoisomers or pharmaceutically acceptable salts or the above-mentioned pharmaceutical compositions in the preparation of prevention or treatment of diseases that benefit from FXR stimulation, wherein the diseases that benefit from FXR stimulation include cardiovascular diseases, liver / gallbladder system diseases, obesity, diabetes, lower urinary tract symptoms (nearby areas) and benign prostatic hyperplasia (BPH) or ureteral stones.

[0150] Another aspect of the present application provides a method for preventing or treating diseases that benefit from FXR stimulation, comprising administering to a patient a therapeutically effective amount of a compound as shown in Formula I, Formula II, Formula III, Formula IV or Formula V, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition, wherein the diseases that benefit from FXR stimulation include cardiovascular diseases, liver / biliary system diseases, obesity, diabetes, lower urinary tract symptoms (nearby areas) and benign prostatic hyperplasia (BPH) or ureteral stones.

[0151] The cardiovascular disease includes cardiovascular disease related to hypertriglyceridemia and / or hypercholesterolemia. The cardiovascular disease further includes atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, thrombosis, coronary artery disease, stroke or hypertension. The liver / biliary system disease includes cholestatic liver disease, high HDL cholesterol disease, high triglyceride disease or fibrotic disease. The liver / biliary system disease further includes non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), gallstones, non-alcoholic cirrhosis, bile duct atresia, cholestatic liver disease, chronic liver disease, hepatitis infection (type B or type C), alcoholic liver disease or liver fibrosis.

[0152] Definition and Description

[0153] Unless otherwise stated, the following terms and phrases used in this application are intended to have the following meanings. A specific term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to the common meaning. When a trade name appears in this article, it is intended to refer to its corresponding commodity or its active ingredient. In the following description, some specific details are included to provide a comprehensive understanding of each disclosed embodiment. However, those skilled in the relevant art will recognize that, without adopting one or more of these specific details, embodiments can be realized in the case of adopting other methods, parts, materials, etc.

[0154] Unless otherwise required in this application, in the specification and claims, the word "comprise" and its English variations such as "comprises" and "comprising" should be interpreted as having an open and inclusive meaning, ie, "including but not limited to".

[0155] "One embodiment" or "an embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" mentioned throughout this specification means that at least one embodiment includes the specific referenced elements, structures or features described in the embodiment. Therefore, the phrases "one embodiment" or "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" appearing in different places throughout the specification do not necessarily all refer to the same embodiment. In addition, specific elements, structures or features can be combined in one or more embodiments in any appropriate manner.

[0156] It should be understood that the singular article "a", "an" and "the" used in the specification and the appended claims includes plural objects unless the context clearly dictates otherwise. Thus, for example, a reaction mentioned including "a catalyst" includes one catalyst, or two or more catalysts. It should also be understood that the term "or" is generally used in its sense including "and / or" unless the context clearly dictates otherwise.

[0157] The term "optional" or "optionally" means that the event or situation described subsequently may or may not occur, and the description includes the occurrence of the event or situation and the non-occurrence of the event or situation. For example, an ethyl group is "optionally" substituted with a halogen, meaning that the ethyl group may be unsubstituted (CH2CH3), monosubstituted (such as CH2CH2F), polysubstituted (such as CHFCH2F, CH2CHF2, etc.) or fully substituted (CF2CF3). It will be appreciated by those skilled in the art that for any group comprising one or more substituents, no substitution or substitution pattern that is sterically impossible to exist and / or cannot be synthesized will be introduced.

[0158] The C used in this paper m～n It means that there are m to n carbon atoms in this part. For example, "C 1-3 "Alkyl group" means that the alkyl group has 1 to 3 carbon atoms.

[0159] The numerical ranges herein refer to the individual integers in the given range. For example, "C 1-3 "Alkyl" means that the group can be selected from C1, C2 and C3 alkyl; "C 3-10 "Cycloalkyl" means that the group can be selected from C3, C4, C5, C6, C7, C8, C9 and C 10"3- to 6-membered heterocycloalkyl" means that the group can be selected from 3-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl.

[0160] The term "substituted" or "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is a keto group (i.e., =O), it means that two hydrogen atoms are replaced. Keto substitution does not occur on aromatic groups. The term "optionally substituted" means that it may be substituted or not substituted, and unless otherwise specified, the type and number of substituents can be arbitrary on the basis of chemical achievable.

[0161] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and / or variants thereof are permitted only if such combinations result in stable compounds.

[0162] When one of the variables is selected from a single bond, it means that the two groups it connects are directly connected. For example, when L in "ALZ" represents a single bond, it means that the structure A and Z are directly connected, which is actually AZ.

[0163] When a substituent's bond can cross-link to two atoms on a ring, the substituent can be bonded to any atom on the ring. When a substituent is listed without indicating the atom through which it is bonded to the compound included in the chemical formula but not specifically mentioned, the substituent can be bonded through any atom. Combinations of substituents and / or their variants are permitted only if such combinations result in stable compounds. For example, the structural unit It means that it can be substituted at any position on the cyclohexyl or cyclodiene, including

[0164] In some preferred embodiments of the present application, the right end of the L group is connected to R4. For example, L can be selected from -C(=O)S-. In some preferred embodiments of the present application, the right end of -C(=O)S- is connected to R4, that is, the S atom is connected to R4; for another example, L can be selected from -OC(=O)N(R L )-, in some preferred embodiments of the present application, -OC(=O)N(R L )- is connected to R4, that is, the N atom is connected to R4; for example, L can be selected from -N(R L )C(=O)N(RL )(C(R L )2) 0-2 -, in some preferred embodiments of the present application, -N(R L )C(=O)N(R L )(C(R L )2) 0-2 - is connected to R4, that is, "C(=O)N(R L )(C(R L )2) 0-2 The N atom in the " portion is connected to R4.

[0165]

[0043] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0166] The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, which is connected to the rest of the molecule by a single bond. Non-limiting examples of this term include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, -CH(CH3)2, -CH(CH3)(CH2CH3), -CH(CH2CH3)2, -C(CH3)3, -C(CH2CH3)3, -CH2CH(CH3)2, -CH2CH(CH3)(CH2CH3), and the like. The term "C 1～8 "Alkyl" refers to an alkyl group having 1 to 8 carbon atoms. 1～6 "Alkyl" refers to an alkyl group having 1 to 6 carbon atoms. 1～4 "Alkyl" refers to an alkyl group having 1 to 4 carbon atoms. 1～8 Alkyl", "C 1～6 Alkyl" or "C 1～4 The "alkyl" group may be unsubstituted or substituted by one or more substituents selected from hydroxy, halogen or amino.

[0167] The term "cycloalkyl" as used herein refers to a fully carbon cyclic saturated hydrocarbon group consisting only of carbon atoms and hydrogen atoms, including a monocyclic structure, a fused and parallel ring structure, a spirocyclic structure or a bridged ring structure, such as C 3-10 Cycloalkyl includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, The "cycloalkyl" may be unsubstituted or independently substituted by one or more substituents, including but not limited to alkyl, alkoxy, cyano, hydroxy, aryl, heteroaryl, amino, halogen, sulfonyl, sulfinyl, phosphoryl or hydroxy.

[0168] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated π electron system. For example, an aryl group may have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. "Aryl" includes, but is not limited to, phenyl, naphthyl, and anthracenyl, etc.

[0169] The term "hetero" refers to a heteroatom or a heteroatom group (i.e., an atomic group containing heteroatoms), including atoms other than carbon (C) and hydrogen (H) and atomic groups containing these heteroatoms, for example, including oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-, -S-, =O, =S, -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, and optionally substituted -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)- or -S(=O)N(H)-; the number of "hetero" in each of the above-mentioned "hetero"-containing groups can be optionally 1, 2, 3, 4 or 5.

[0170] The term "heteroalkyl" refers to a linear or branched saturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms, in which some of the carbon atoms and hydrogen atoms are replaced or substituted by the above-mentioned heteroatoms or heteroatomic groups. In some embodiments, the term "heteroalkyl" itself or in combination with another term represents a stable linear, branched hydrocarbon atom group or a combination thereof, which consists of a certain number of carbon atoms and at least one heteroatom. In a typical embodiment, the heteroatom is selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatom or heteroatomic group may be located at any internal position of the heteroalkyl group (including the position where the hydrocarbon group is attached to the rest of the molecule). Unless otherwise specified, the term "heteroalkyl" includes "alkoxy", "alkylamino" and "alkylthio". Examples of "heteroalkyl" include, but are not limited to, -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -CH2-CH=N-OCH3, and -CH=CH-N(CH3)-CH3, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -NHCH3, -NHCH2CH3, -NHCH2CH2CH3, -NHCH(CH3)2, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH(CH3)2. Up to two heteroatoms may be consecutive, for example, -CH2-NH-OCH3.

[0171] The term "heteroaryl" refers to a monocyclic or fused polycyclic system, which contains at least one ring atom structure selected from the above-mentioned heteroatom or heteroatom group, the remaining ring atoms are C, and has at least one aromatic ring. Preferably, the heteroaryl includes at least one ring atom selected from N, O, and S. Heteroaryl includes but is not limited to pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, 1,2,4-oxadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, isoquinolyl, tetrazolyl, triazolyl, triazine, benzofuranyl, benzothienyl, indolyl, isoindolyl, etc. The term "5-membered or 6-membered heteroaryl" refers to a heteroaryl having 5 to 6 ring atoms. The "heteroaryl" or "5-membered or 6-membered heteroaryl" may be unsubstituted or substituted by one or more selected from hydroxyl, halogen or C 1～4 The alkyl group is substituted with a substituent.

[0172] The term "heterocycloalkyl" refers to a non-aromatic monocyclic, fused polycyclic, bridged or spirocyclic ring system group, which contains at least one ring atom structure selected from the above-mentioned heteroatom or heteroatom group, and the remaining ring atoms are C. Preferably, the "heterocycloalkyl" includes at least one heteroatom selected from N, O, S, S(O)n (wherein n is 0, 1 or 2) as a ring atom structure, and the remaining ring atoms are C. Such a ring may be saturated or unsaturated (e.g., having one or more double bonds), but does not have a completely conjugated π-electron system. Non-limiting examples of “heterocycloalkyl” include oxirane, thioethanethiol, aziridinyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, oxazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothiophenyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, azepanyl, oxetanyl, thiepanyl, oxazabicyclo[2.2.1]heptyl, and azaspiro[3.3]heptyl, The term "5-membered or 6-membered heterocycloalkyl" refers to a heterocycloalkyl group having 5 to 6 ring atoms.

[0173] Unless otherwise specified, "ring" means cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. Wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are as defined above. Wherein, cycloalkenyl or cycloalkynyl refers to a ring atom structure of cycloalkyl including an alkenyl or alkynyl structure. Heterocycloalkenyl or heterocycloalkynyl refers to a ring atom structure containing at least one selected from the above heteroatom or heteroatom group in cycloalkenyl or cycloalkynyl, and the remaining ring atoms are C. Cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl are unsaturated (e.g., have one or more double bonds), but do not have a completely conjugated π-electron system.

[0174] The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0175] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application, prepared by a compound with a specific substituent found in the present application and a relatively nontoxic acid or base. When a relatively acidic functional group is contained in the compound of the present application, a base addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of base in a pure solution or a suitable inert solvent. When a relatively basic functional group is contained in the compound of the present application, an acid addition salt can be obtained by contacting a neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, and organic acid salts, and also include salts of amino acids (such as arginine, etc.), and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science 66: 1-19 (1977)). Certain specific compounds of the present application contain basic and acidic functional groups, and can be converted into any base or acid addition salt.

[0176] Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound. The parent form of the compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.

[0177] In addition to the form of salts, the compounds provided herein also exist in prodrug form. The prodrugs of the compounds described herein easily undergo chemical changes under physiological conditions to be converted into the compounds of this application. In addition, the prodrugs can be converted to the compounds of this application by chemical or biochemical methods in an in vivo environment.

[0178] Certain compounds of the present application may exist in unsolvated or solvated forms, including hydrate forms. Generally speaking, the solvated forms are equivalent to the unsolvated forms and are all included in the scope of the present application.

[0179] Certain compounds of the present application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the present application.

[0180] The notation for racemic, ambiscalemic and scalemic or enantiomerically pure compounds herein is from Maehr, J. Chem. Ed. 1985, 62: 114-120. 1985, 62: 114-120. Unless otherwise indicated, wedge-shaped bonds and dashed bonds are used to indicate the absolute configuration of a stereocenter. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they are intended to include both E and Z geometric isomers unless otherwise indicated. Likewise, all tautomeric forms are intended to be within the scope of this application.

[0181] The compounds of the present application may exist in specific geometric or stereoisomeric forms. The present application contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, all of which fall within the scope of the present application. Additional asymmetric carbon atoms may exist in substituents such as alkyl. All of these isomers and their mixtures are included within the scope of the present application.

[0182] Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by fractional crystallization or chromatography as is known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate is generated from an amine).

[0183] The compounds of the present application may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125( 125 I) or C-14( 14 C) All isotopic variations of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.

[0184] The term "pharmaceutically acceptable carrier" refers to any preparation or carrier medium that can deliver an effective amount of active substance of the present application, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oil, vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity enhancers, transdermal enhancers, etc. Their preparations are well known to those skilled in the art of cosmetics or topical drugs. For additional information about the carrier, reference can be made to Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.

[0185] The term "excipient" generally refers to a carrier, diluent and / or vehicle required to formulate an effective pharmaceutical composition.

[0186] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. For oral dosage forms in this application, an "effective amount" of an active substance in a composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. The determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, 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.

[0187] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0188] The term "patient" refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cows, sheep, horses or primates, and most preferably humans.

[0189] As used herein, the phrase "therapeutically effective amount" refers to the amount of an active compound or drug that elicits the biological or medical response that a researcher, veterinarian, physician or other clinician is seeking in a tissue, system, animal, individual or human, and includes one or more of the following:

[0190] (1) Prevention of disease: For example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not yet experienced or developed disease pathology or symptoms.

[0191] (2) Inhibiting a disease: eg, inhibiting a disease, disorder or condition in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition (ie, preventing further development of the pathology and / or symptoms).

[0192] (3) Disease alleviation: eg, ameliorating a disease, disorder or condition (ie, reversing the pathology and / or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder or condition.

[0193] The therapeutic dose of the compounds of the present application may be determined, for example, based on the specific use of the treatment, the method of administering the compound, the health and condition of the patient, and the judgment of the prescribing physician. The ratio or concentration of the compounds of the present application in the pharmaceutical composition may not be fixed, depending on a variety of factors, including dosage, chemical properties (e.g., hydrophobicity), and route of administration. For example, the compounds of the present application may be provided by a physiologically buffered aqueous solution containing about 0.1 to 10% w / v of the compound for parenteral administration. Some typical dosage ranges are about 1 μg / kg to about 1 g / kg body weight / day. In certain embodiments, the dosage range is about 0.01 mg / kg to about 100 mg / kg body weight / day. The dosage is likely to depend on such variables as the type and degree of development of the disease or condition, the general health status of the specific patient, the relative biological efficacy of the selected compound, the excipient formulation, and its route of administration. The effective dose can be obtained by extrapolation of a dose-response curve derived from an in vitro or animal model test system.

[0194] The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and equivalent substitution methods well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present application.

[0195] The chemical reactions of the specific embodiments of the present application are carried out in a suitable solvent, which must be suitable for the chemical changes of the present application and the reagents and materials required. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction processes based on the existing embodiments.

[0196] An important consideration in any synthetic route planning in this area is to select a suitable protecting group for a reactive functional group (such as the amino group in this application). For trained practitioners, Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1991) is an authority in this regard. All references cited in this application are incorporated herein in their entirety.

[0197] Reactions described herein may be monitored by any suitable method known in the art. For example, the monitoring may be performed by broad spectrum methods such as nuclear magnetic resonance spectroscopy (e.g. 1 H or 13C), infrared spectroscopy, spectrophotometry (eg, UV-visible), or mass spectroscopy, or by chromatography, such as high performance liquid chromatography (HPLC) or thin layer chromatography, to monitor product formation.

[0198] The solvents used in this application are commercially available. The following abbreviations are used in this application: aq represents water; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; EDC represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE represents petroleum ether; DIAD represents diisopropyl azodicarboxylate; DMF represents N,N-dimethylformamide; DMSO represents dimethyl sulfoxide; EtOAc represents ethyl acetate; EtOH represents ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, which is an amine protecting group; BOC represents tert-butylcarbonyl, which is an amine protecting group; HOAc represents acetic acid; NaCNBH3 represents sodium cyanoborohydride; rt represents room temperature; O / N represents overnight; THF represents tetrahydrofuran; Boc2O represents di-tert-butylcarbonyl; butyl dicarbonate; TFA stands for trifluoroacetic acid; TFAA stands for trifluoroacetic anhydride; DIPEA stands for diisopropylethylamine; SOCl2 stands for thionyl chloride; CS2 stands for carbon disulfide; TsOH stands for p-toluenesulfonic acid; NFSI stands for N-fluoro-N-(phenylsulfonyl)benzenesulfonamide; NCS stands for 1-chloropyrrolidine-2,5-dione; n-Bu4NF stands for tetrabutylammonium fluoride; iPrOH stands for 2-propanol; mp stands for melting point; LDA stands for lithium diisopropylamide; PTSA stands for p-toluenesulfonic acid; TMSCl stands for trimethylchlorosilane; BF3-Et2O stands for boron trifluoride etherate; Ac2O stands for acetic anhydride; DMAP stands for N,N-dimethylaminopyridine; EDCI stands for 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride; TEA stands for triethylamine; TBTU stands for O,N-dimethylhydroxylamine hydrochloride; MeMgBr stands for methylmagnesium bromide; Burgess reagent stands for Burgess reagent; Bu2OSn stands for dibutyltin oxide; TMSN3 stands for trimethylsilyl azide; DHP stands for 3,4-dihydropyran; PCC stands for pyridine chromate; AcCl stands for acetyl chloride; TMSCF3 stands for trimethyl trifluoromethylsilyl ether; TBAF stands for tetrabutylammonium fluoride; Pb(OAc)4 stands for lead tetraacetate; P(OEt)3 stands for triethylphosphite; Pyridine stands for pyridine; PPh3 stands for triphenylphosphine; Thiophosgene stands for thiophosgene; DAST stands for diethylaminosulfur trifluoride; Et2Zn stands for diethylzinc; Ph3PCH2OCH3Cl stands for methoxymethyltriphenylphosphonium chloride; n-BuLi stands for n-butyllithium; PhSO2Cl stands for phenylsulfonyl chloride; MsCl stands for methanesulfonyl chloride; TMSNCO stands for trimethylsilyl isocyanate.

[0199] Compounds are manually or The software names were used, and commercially available compounds were named using the supplier's catalog names. DETAILED DESCRIPTION

[0200] In order to illustrate the present invention in more detail, the following examples are given, but the scope of the present invention is not limited thereto.

[0201] Reference Example 1 Preparation of INT-747

[0202]

[0203] Reference example 1A

[0204]

[0205] To a solution of chenodeoxycholic acid (60.0 g, 152.8 mmol) in methanol / acetic acid / water / ethyl acetate (360 / 120 / 30 / 780 ml) were added tetrabutylammonium bromide (81.0 g, 251.3 mmol) and sodium bromide (9.0 g, 87.5 mmol) in portions, and sodium hypochlorite (210 ml, 3.4 mol) was added dropwise at 0°C over 30 minutes. After stirring at 28°C for 16 hours, a saturated sodium bisulfite solution (500 ml) was added to quench the mixture, and the aqueous layer was extracted with ethyl acetate (1000 ml×2). The combined organic layers were washed with water (1000 ml×5), dried over sodium sulfate, filtered and spin-dried, and the residue was recrystallized (dichloromethane, 200 ml) to give Reference Example 1A (yellow solid, 41.0 g, 69.0% yield). 1 H NMR (400MHz, METHANOL-d4) δ3.44-3.60(m,1H),2.99(dd,J=5.77,12.30Hz,1H),2.54(t,J=11.29Hz,1H),2.08-2.41(m ,3H),2.00-2.08(m,1H),1.75-1.96(m,6H),1.28-1.69(m,9H),1.09-1.27(m,8H),0.97(d,J=6.53Hz,3H),0.71(s,3H).

[0206] Reference Example 1B

[0207]

[0208] To a solution of the compound of Reference Example 1A (246.0 g, 629.9 mmol) in methanol (2 L) was added p-toluenesulfonic acid (10.9 g, 63.0 mmol) in one portion and reacted at 80 degrees Celsius for 4 hours. After cooling to room temperature, the mixture was evaporated to dryness, quenched with a saturated sodium bicarbonate solution (1500 ml), and the aqueous layer was extracted with ethyl acetate (1500 ml × 3). The combined organic layer was washed with brine (1000 ml × 3), dried over sodium sulfate, filtered and spin-dried, and the residue was recrystallized (ethyl acetate, 500 ml) to give Reference Example 1B (white solid, 202 g, 79% yield). 1 H NMR(400MHz,CHLOROFORM-d)δ3.66(s,3H),3.55-3.62(m,1H),2.85(dd,J=6.02,12.55Hz,1H),2.28-2.43(m,2H) ,2.13-2.26(m,2H),1.64-2.04(m,10H),1.19-1.51(m,11H),1.00-1.17(m,3H),0.86-0.97(m,3H),0.65(s,3H).

[0209] Reference Example 1C

[0210]

[0211] Under nitrogen protection at -78 degrees Celsius, lithium diisopropylamide (87.4 g, 815.6 mmol) was added dropwise to a solution of trimethylsilyl chloride (107.5 g, 989.5 mmol) in tetrahydrofuran (500.0 ml) and stirred for 40 minutes. A solution of the compound of Reference Example 1B (50 g, 123.6 mmol) in tetrahydrofuran (300 ml) was then added dropwise. After the addition was completed, stirring was continued at -78 degrees Celsius for 40 minutes. Triethylamine (182.5 g, 1.8 mol) was then added. After 1 hour, the mixture was quenched with saturated sodium bicarbonate (1000 ml) and the aqueous layer was extracted with ethyl acetate (1000 ml x 3). The combined organic layers were washed with water (100 ml x 6) and saturated brine (1000 ml x 2), and the organic layer was dried over sodium sulfate, filtered and spin-dried to obtain Reference Example 1C (brown oil, 68 g, yield 100%), which could be used directly in the next step without further purification. 1H NMR(400MHz,CHLOROFORM-d)δ4.75(dd,J=1.38,5.90Hz,1H),3.69(s,3H),3.48-3.59(m,1H),2.13-2.42(m,2H),1.52-2.04(m, 10H),1.29-1.48(m,7H),0.99-1.23(m,5H),0.95(d,J=6.53Hz,3H),0.85(s,3H),0.70(s,3H),0.17-0.20(m,9H),0.13(s,9H).

[0212] Reference example 1D

[0213]

[0214] Anhydrous acetaldehyde (10.1 g, 229.2 mmol) was added to a solution of the compound of Reference Example 1C (68.0 g, 123.9 mmol) in dichloromethane (500.0 ml). A solution of boron trifluoride-ether (64.4 g, 453.4 mmol) in dichloromethane (300 ml) was added dropwise under nitrogen protection at -78 degrees Celsius. The dropping speed was required to keep the internal temperature at -78 degrees Celsius. After stirring for 1 hour, the temperature was raised to 30 degrees Celsius and continued to stir for 2 hours. The above solution was quenched with saturated sodium bicarbonate (1000 ml), the aqueous layer was extracted with dichloromethane (1000 ml × 3), the combined organic layer was washed with saturated brine (1000 ml × 2), dried over sodium sulfate, filtered and spin-dried, and the residue was purified by column chromatography to obtain Reference Example 1D (yellow solid, 43.0 g, yield 81.0%). 1 H NMR(400MHz,CHLOROFORM-d)δ6.12(q,J=7.03Hz,1H),3.52-3.66(m,4H),2.54(dd,J=4.02,13.05Hz,1H),2.13-2.40(m ,5H),1.68-1.98(m,7H),1.65(d,J=7.03Hz,3H),1.00-1.52(m,11H),0.97(s,3H),0.89(d,J=6.53Hz,3H),0.61(s,3H).

[0215] Reference Example 1E

[0216]

[0217] To a solution of the compound of Reference Example 1D (212.0 g, 492.3 mmol) in methanol (500.0 ml) was added a solution of NaOH (39.4 g, 984.6 mmol) in water (50.0 ml), and the mixture was stirred at 50 degrees Celsius for 2 hours. After the solvent was dried, water (500.0 ml) was added, and the mixture was extracted with ethyl acetate (500.0 ml x 2), the aqueous phase was adjusted to pH 3 with dilute HCl, and then extracted with dichloromethane (600.0 ml x 2), the combined organic layers were concentrated, and the residue was purified by recrystallization (ethanol, 200.0 ml) to give Reference Example 1E (yellow solid, 147.0 g, yield 72.0%). 1 H NMR (400MHz, CHLOROFORM-d) δ6.19 (q, J=7.36Hz, 1H), 3.60-3.74 (m, 1H), 2.58 (dd, J=4.02, 13.05Hz, 1H), 2.40 (tt, J=5.02, 10.29Hz,3H),2.19-2.32(m,2H),1.61-2.06(m,10H),1.04-1.54(m,14H),1.01(s,3H),0.95(d,J=6.53Hz,3H),0.65(s,3H).

[0218] Reference Example 1F

[0219]

[0220] To a solution of the compound of Reference Example 1E (140.0 g, 336.1 mmol) in NaOH (0.5 mol) aqueous solution (600.0 ml) was added 10% Pd-C (19.9 g, 134.4 mmol) at once, hydrogen was introduced at 15 psi, and the mixture was reacted at 100 degrees Celsius for 16 hours. The mixture was filtered, the pH of the filtrate was adjusted to 3 with dilute hydrochloric acid, the aqueous layer was extracted with dichloromethane (1500.0 ml×3), the combined organic layer was washed with brine (1000.0 ml×3), dried over sodium sulfate, filtered and spin-dried to obtain Reference Example 1F (white solid, 101.0 g, yield 72.0%), which was directly used in the next step without further purification. 1 H NMR(400MHz,CHLOROFORM-d)δ3.49-3.60(m,1H),2.70(q,J=6.02Hz,1H),2.12-2.45(m,4H),1.65-2.02(m ,9H),1.29-1.52(m,6H),1.05-1.24(m,8H),0.93(d,J=6.53Hz,5H),0.81(t,J=7.53Hz,3H),0.66(s,3H).

[0221] Reference example 1INT-747

[0222]

[0223] To a solution of the compound of Reference Example 1F (16.0 g, 38.2 mmol) in sodium hydroxide (2 mol, 100.0 ml) was added sodium borohydride (8.7 g, 229.3 mmol) in portions, and the mixture was stirred at 100 degrees Celsius for 2 hours. After cooling to room temperature, a saturated aqueous ammonium chloride solution (150.0 ml) was added, and the pH was adjusted to 3 with dilute hydrochloric acid. The aqueous layer was extracted with dichloromethane (300.0 ml × 3), and the combined organic layer was washed with brine (200.0 ml × 3), dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography to give Reference Example 1 (white solid, 14.5 g, yield 90.0%). 1 H NMR(400MHz,CHLOROFORM-d)δ3.71(br.s,1H),3.36-3.48(m,1H),2.18-2.47(m ,2H),1.56-2.01(m,10H),1.06-1.54(m,15H),0.86-0.97(m,9H),0.66(s,3H).

[0224] Route 1

[0225]

[0226] Example 1

[0227]

[0228] Example 1A

[0229]

[0230] Under nitrogen protection, acetic anhydride (1.0 g, 9.5 mmol) was added to a pyridine solution (10.0 ml) of the compound of Reference Example 1 (1.0 g, 2.4 mmol) and N,N-dimethylaminopyridine (30.0 mg, 0.2 mmol). After stirring at 40 °C for 12 hours, water (100.0 ml) was added to quench the mixture. The aqueous layer was extracted with ethyl acetate (100.0 ml x 2), and the organic layer was washed with 1 molar aqueous hydrochloric acid solution and saturated brine in turn. The combined organic layers were dried over sodium sulfate, filtered and spin-dried, and the residue was purified by column chromatography to give the compound of Example 1A (1.1 g, 92.0% yield).

[0231] Example 1B

[0232]

[0233] A mixture of Example 1A compound (0.1 g, 0.2 mmol) and carbonyldiimidazole (60.0 mg, 0.4 mmol) in acetonitrile (3 ml) was reacted at 25 degrees Celsius for 0.5 hours, then sodium hydrosulfide (40.0 mg, 0.8 mmol) was added and the reaction was continued at 25 degrees Celsius for 12 hours. After concentration under reduced pressure, the mixture was diluted with water (80.0 ml), and the pH was adjusted to 3 with dilute hydrochloric acid. The aqueous layer was extracted with ethyl acetate (100.0 ml x 2), and the combined organic layer was washed with water (100.0 ml) and brine (100.0 ml), dried over sodium sulfate, filtered and spin-dried, and the residue was purified by preparative TLC plate to give the title Example 1B compound (40.0 mg, yield 39.0%). 1 H NMR(400MHz,DMSO-d6)δ4.98(br.s.,1H),4.52-4.34(m,1H),2.38-2.13(m,2H),2.04-1.85(m,7H ),1.84-1.49(m,9H),1.38(d,J=8.5Hz,5H),1.26-0.99(m,10H),0.95-0.71(m,9H),0.60(s,3H).

[0234] Example 1

[0235]

[0236] Under nitrogen protection, potassium hydroxide (0.5 g, 8.9 mmol) was added to a mixture of water (2.0 ml) and ethanol (2.0 ml) of the compound of Example 1B (30.0 mg, 0.06 mmol). After stirring at 80 degrees Celsius for 24 hours, it was neutralized with 1 molar hydrochloric acid and the aqueous layer was extracted with ethyl acetate (100 ml x 4). The combined organic layers were dried over sodium sulfate, filtered and dried by spin drying, and the residue was purified by preparative TLC plate to give the compound of Example 1 (20.0 mg, yield 62.0%). 1 H NMR(400MHz,CHLOROFORM-d)δ3.70(br.s.,1H),3.48-3.35(m,1H),2.47-2.33(m,1H),2.30-2.17(m,1H),2. 00-1.72(m,7H),1.70-1.55(m,3H),1.52-1.26(m,11H),1.22-1.10(m,3H),1.04-0.86(m,10H),0.65(s,3H).

[0237] Route 2

[0238]

[0239] Example 2

[0240]

[0241] Example 2A

[0242]

[0243] Under nitrogen protection, perchloric acid (6.0 g, 60.0 mmol) was added to tetrahydrofuran (40 ml) of the compound of Reference Example 1 (2.7 g, 6.4 mmol) and formic acid (0.3 g, 6.4 mmol). After stirring at 55 degrees Celsius for 6 hours, the mixture was concentrated under reduced pressure and diluted with water (100 ml), and the aqueous layer was extracted with ethyl acetate (100 ml x 2). The combined organic layer was dried over sodium sulfate, filtered and dried by spin drying, and the residue was purified by column chromatography to give Example 2A compound (2.8 g, yield 92.0%). 1 H NMR(400MHz,CHLOROFORM-d)δ8.16(s,1H),8.05(s,1H),5.20(br.s.,1H),4.77-4.65(m,1H),2.45-2.34(m,1H) ,2.31-2.21(m,1H),2.01-1.58(m,11H),1.55-1.30(m,8H),1.22-1.05(m,6H),0.97-0.88(m,9H),0.66(s,3H).

[0244] Example 2B

[0245]

[0246] To a dichloromethane solution (5.0 ml) of the compound of Example 2A (100 mg, 0.2 mmol) and methylsulfonamide (18.0 mg) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.2 mmol) and N,N-dimethylaminopyridine (3.8 mg, 0.03 mmol) under nitrogen protection, and the mixture was reacted at 25 degrees Celsius for 4 hours. Dichloromethane (120 ml) was added to dilute, washed with water, the organic phase was dried over anhydrous sodium sulfate, and the solution was removed by vacuum drying, and the residue was purified by column chromatography to obtain the compound of Example 2B (60.0 mg, yield 54.0%). 1H NMR(400MHz,CHLOROFORM-d)δ8.52(s,1H),8.05-8.01(m,1H),4.75-4.62(m,1H),3.72(br.s.,1H),3.31(s,3H),2.43-2. 34(m,1H),2.29-2.20(m,1H),1.99-1.62(m,10H),1.54-1.32(m,10H),1.23-1.03(m,5H),0.97-0.88(m,9H),0.66(s,3H).

[0247] Example 2

[0248]

[0249] A solution of the compound of Example 2B (60.0 mg, 0.1 mmol) and sodium methoxide (6.0 mg, 0.1 mmol) in methanol (3 ml) was stirred at 25 °C for 1 hour, the pH was adjusted to 1 with dilute acid, the aqueous phase was extracted with ethyl acetate (20 ml x 3), the organic phase was dried over anhydrous sodium sulfate, the solvent was removed in vacuo, and the residue was purified by preparative TLC plate to give the compound of Example 2 (20.0 mg, yield 38.0%). 1 H NMR(400MHz,CHLOROFORM-d)δ8.85(s,1H),3.71(br.s.,1H),3.47-3.39(m,1 H),3.33-3.28(m,3H),2.43-2.33(m,1H),2.24(ddd,J=6.3,9.7,15.7Hz,1H) ,1.96(d,J=11.8Hz,1H),1.88-1.76(m,5H),1.72-1.57(m,5H),1.53-1.32(m ,12H),1.22-1.13(m,3H),1.06-0.98(m,1H),0.97-0.88(m,9H),0.66(s,3H).

[0250] The preparation of Examples 3 to 26 was prepared by referring to the operation of Example 2 and route 2. The results obtained are as follows:

[0251]

[0252]

[0253]

[0254]

[0255]

[0256] Route 3

[0257]

[0258] Embodiment 27

[0259]

[0260] Example 3A

[0261]

[0262] The compound of Reference Example 1F (10.0 g, 23.9 mmol) was dissolved in tetrahydrofuran (60.0 ml), and perchloric acid (240.0 mg, 2.4 mmol, 144.6 μl) (about 10 drops) was added. Formic acid (40.3 g, 874.7 mmol, 33.0 ml) was added dropwise at 30 degrees Celsius over half an hour, and the reaction solution was stirred at 50 degrees Celsius for 11.5 hours. The solvent was removed by concentration, and water (35.0 ml) was added to the reaction solution, and ethyl acetate was extracted (30.0 ml×3). The organic layer was washed with water (10.0 ml×2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was separated by column chromatography to obtain the compound of Example 3A (7.0 g, 15.7 mmol, 65.6% yield). 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.01 (s, 1H), 4.86-4.73 (m, 1H), 2.82-2.67 (m, 1H), 2.47 -2.35(m,2H),2.33-2.16(m,2H),2.05-1.93(m,2H),1.89(d,J=13.1Hz,2H),1.82(dd,J= 5.5,16.8Hz,2H),1.75(dd,J=6.5,14.1Hz,3H),1.71(br.s.,1H),1.58-1.30(m,7H),1. 26(s,3H),1.23-1.02(m,4H),0.95(d,J=6.5Hz,3H),0.83(t,J=7.4Hz,3H),0.68(s,3H).

[0263] Example 3B

[0264]

[0265] The compound of Example 3A (5.8 g, 13.0 mmol) was dissolved in trifluoroacetic acid (40.0 ml) and trifluoroacetic anhydride (20.5 g, 97.4 mmol) at 0 degrees Celsius. After the solid was dissolved, sodium nitrite (2.7 g, 39.0 mmol) was added in batches. Stirring was continued at 0 degrees Celsius for one hour, and the temperature was raised to 40 degrees Celsius and stirring was continued for one hour. The reaction solution was cooled to 30 degrees Celsius and neutralized with 0.5 molar sodium hydroxide aqueous solution at 0 degrees Celsius (pH = 7-8). The reaction solution was extracted with ethyl acetate (40 ml × 3), and the organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated by chromatographic column (silica gel) to obtain the compound of Example 3B (3.5 g, 8.5 mmol, 93.0% yield). 1 H NMR (400MHz, CHLOROFORM-d) δ = 3.59-3.47 (m, 1H), 2.69 (q, J = 6.2Hz, 1H), 2.42-2.31 (m, 2H), 2.29-2.15 (m, 2H), 2.01-1.88 (m, 2H), 1.86 -1.68(m,7H),1.61-1.45(m,6H),1.26(t,J=7.2Hz,5H),1.19-1.12(m,5H),1.02-0.91(m,1H),0.80(t,J=7.4Hz,3H),0.71-0.64(m,3H).

[0266] Example 3C

[0267]

[0268] The compound of Example 3B (3.5 g, 8.5 mmol) was dissolved in methanol (100.0 ml), and potassium hydroxide aqueous solution (70.0 g, 1.3 mol, dissolved in 100.0 ml of water) was added, and the reaction solution was stirred at 100 degrees Celsius for twelve hours. The solvent was removed by concentration, and extracted with dichloromethane (30 ml x 3). The aqueous phase was acidified with monomolar hydrochloric acid (pH = 3-4), extracted with ethyl acetate (30 ml x 3), and the organic layer was washed with water (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The compound of Example 3C (3.2 g, 7.9 mmol, 93.5% yield) was obtained without purification. 1H NMR(400MHz, CHLOROFORM-d)δ=3.65-3.50(m,1H),2.71(d,J=5.8Hz,1H),2.48(dd,J=2.6,14.9Hz,1H),2.43-2.31(m,2H),2.22-2.15(m,1H),2.07-1 .98(m,2H),1.95-1.86(m,3H),1.82-1.70(m,6H),1.53-1.46(m,3H),1.19 -1.10(m,6H),1.02(d,J=6.3Hz,3H),0.86(d,J=10.3Hz,5H),0.69(s,3H).

[0269] Example 3D

[0270]

[0271] To an aqueous sodium hydroxide solution (949.2 mg, 23.7 mmol, dissolved in 10.00 ml of water) was added the compound of Example 3C (3.2 g, 7.9 mmol), the reaction solution was heated to 80 degrees Celsius, sodium borohydride (1.8 g, 47.5 mmol) was added in portions, and the reaction solution was stirred at 100 degrees Celsius for 12 hours. Methanol (6 ml) was added dropwise, and part of the solvent was removed by concentration. The reaction solution was acidified with monomolar hydrochloric acid (pH=5-6), extracted with ethyl acetate (40 ml×3), the organic layer was washed with water (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was obtained without isolation to obtain Example 3D (3.1 g, 7.6 mmol, 96.4% yield). 1 HNMR(400MHz,CHLOROFORM-d)δ=3.70(br.s.,1H),3.46-3.36(m,1H),2.52-2.39(m,1H),2.02-1.88(m,3H),1.85-1.77(m,4H),1.71-1.59(m, 3H),1.53-1.44(m,4H),1.41-1.37(m,1H),1.36-1.27(m,4H),1.24-1. 13(m,4H),1.04(d,J=6.5Hz,3H),0.92-0.88(m,6H),0.73-0.69(m,3H).

[0272] Embodiment 27

[0273]

[0274] The compound of Example 3D (1.3 g, 3.2 mmol) was added to dichloromethane (30.0 ml), and N,N-dimethyl-4-aminopyridine (78.2 mg, 640.00 μmol) and EDCI (736.1 mg, 3.8 mmol) were added, and the reaction solution was stirred at 30 degrees Celsius for 12 hours. Dichloromethane (50 ml) was added to the reaction solution, and the organic layer was washed with water (10 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated by column chromatography to obtain the compound of Example 27 (660.0 mg, 1.4 mmol, 42.6% yield). 1 H NMR(400MHz, CHLOROFORM-d)δ=8.81(br.s.,1H),3.71(br.s.,1H),3.48-3.38(m,1H),3.31(s,3H),2.48(d,J=12.3Hz,1H),2.06-1.94(m,3H) ),1.88-1.75(m,5H),1.70-1.58(m,5H),1.53-1.40(m,5H),1.35-1.17(m,7H),1.03(d,J=6.0Hz,3H),0.92-0.89(m,5H),0.74-0.67(m,3H).

[0275] The preparation of Examples 28 to 36 was carried out by referring to the operation of Example 27 and prepared by Route 3. The results obtained are as follows:

[0276]

[0277]

[0278] Route 4

[0279]

[0280] The preparation of Examples 37 to 39 was carried out by referring to the procedure of Example 27, using the compound of Example 3D as the raw material and undergoing acylation reaction via Route 4. The results obtained are as follows:

[0281]

[0282] Route 5

[0283]

[0284] The operation was the same as that of Example 27, with Example 3D as the raw material, and an acylation reaction was performed, and Example 40 was obtained after purification as follows:

[0285]

[0286] Route 6

[0287]

[0288] Embodiment 50

[0289]

[0290] Example 6A

[0291]

[0292] To a toluene solution (5.0 ml) of the compound of Example 2A (300.0 mg, 629.0 μmol) was added thionyl chloride (1.3 g, 11.0 mmol) and reacted at 100 degrees Celsius for 2 hours. The solution was then rotary evaporated to dryness and dissolved in 10 ml of tetrahydrofuran and then dried again. The resulting product was dissolved in 10 ml of tetrahydrofuran, and an aqueous solution (5.0 ml) of sodium azide (122.8 mg, 1.9 mmol) was added thereto at 0-10 degrees Celsius. After reacting at 10 degrees Celsius for 2 hours, the reaction was quenched with ice water (20 ml), and the aqueous layer was extracted with ethyl acetate (30 ml). The combined organic layer was dried over sodium sulfate, filtered and dried to obtain a red oily product of about 300 mg, which was dissolved in 2 ml of anhydrous toluene, and half of the solution was added to (S)-3-hydroxytetrahydrofuran (500.0 mg, 5.7 mmol) and reacted at 100 degrees Celsius for 10 hours. After the reaction, the solvent was evaporated, the reaction was quenched with water (20 ml), and the aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layer was dried over sodium sulfate, filtered and spin-dried. The crude product was separated by preparative thin layer chromatography (petroleum ether: ethyl acetate = 3:1) to obtain Example 6A (150.0 mg, 240.3 μmol, yield 80.1%, purity 90%). 1 H NMR(400MHz,CHLOROFORM-d)δ8.17(s,1H),8.06(s,1H),5.33-5.17(m,2H),4.79-4.54(m,2H),4.02-3.77(m,5H),2.25-2. 12(m,1H),2.08-1.71(m,10H),1.68-1.61(m,1H),1.55-1.41(m,6H),1.37-1.07(m,12H),0.99-0.90(m,10H),0.68(s,3H).

[0293] Embodiment 50

[0294]

[0295] To a solution of Example 6A compound (150.0 mg, 267 μmol) in tetrahydrofuran / water (5 ml / 3 ml) was added lithium hydroxide monohydrate (11.2 mg, 267 μmol) and reacted at 40 degrees Celsius for 5 hours. After the reaction was completed, ethyl acetate (15 ml) was used for extraction, and the combined organic layer was dried over sodium sulfate, filtered and spin-dried, and the obtained crude product was separated by preparative thin layer chromatography (dichloromethane: ethyl acetate = 1: 1) to obtain Example 50 compound (49.0 mg, yield 34.2%, purity 95%). 1 H NMR(400MHz,CHLOROFORM-d)δ5.27(br.s.,1H),4.64(br.s.,1H),3.99-3.80(m,6H),3.75-3.65(m,1H),3.47-3.37(m,1H),3.33-3.02(m,2H),2.24 -2.12(m,1H),2.08-1.65(m,10H),1.55-1.38(m,7H),1.37-1.13(m,10H), 1.09-1.01(m,1H),0.98(d,J=6.3Hz,3H),0.95-0.87(m,6H),0.68(s,3H).

[0296] The preparation of Examples 41 to 49 was carried out by referring to the operation of Example 50 and prepared by Route 6. The results obtained are as follows:

[0297]

[0298]

[0299]

[0300] Route 7

[0301]

[0302] Embodiment 53

[0303]

[0304] Example 7A

[0305]

[0306] To a toluene solution (5.0 ml) of Example 2A compound (300.0 mg, 629.4 μmol) was added thionyl chloride (1.3 g, 11.0 mmol) and reacted at 100 degrees Celsius for 2 hours. The solution was then spin-dried and dissolved in 10 ml of tetrahydrofuran and spin-dried again. The resulting product was dissolved in 10 ml of tetrahydrofuran, and an aqueous solution (5.0 ml) of sodium azide (122.8 mg, 1.9 mmol) was added thereto at 0-10 degrees Celsius. After reacting for 2 hours at 10 degrees Celsius, the reaction was quenched with ice water (20 ml), and the aqueous layer was extracted with ethyl acetate (30 ml). The combined organic layer was dried over sodium sulfate, filtered and evaporated to obtain about 300 mg of a red oily product, which was dissolved in 2 ml of anhydrous toluene, half of the solution was heated at 100 degrees Celsius for 1 hour, and then the solvent was dried by spin drying. The product was dissolved in a mixed solution of dichloromethane / tetrahydrofuran (1 ml / 1 ml), (3S)-3-hydroxypyrrole (500.0 mg, 4.1 mmol, hydrochloride) and triethylamine (453.9 mg, 4.5 mmol) were added respectively, and the mixture was reacted at 10 degrees Celsius for 10 hours. After the reaction was completed, water (30 ml) was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 ml). The combined organic layer was dried over sodium sulfate, filtered and dried, and the obtained crude product was separated by column chromatography (dichloromethane: methanol = 20: 1) to obtain Example 7A compound (160.0 mg, yield 86.2%, purity 90%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.16 (s, 1H), 8.05 (s, 1H), 5.20 (br.s., 1H), 4.78-4.67 (m, 1H), 4.48 (br.s., 1H), 4.16 (br.s., 1H), 3.54-3.26 (m ,5H),3.18-3.06(m,1H),2.70(br.s.,1H),2.04-1.39(m,19H),1.24-1. 04(m,7H),1.01-0.95(m,6H),0.91(t,J=7.4Hz,3H),0.70-0.62(m,3H).

[0307] Embodiment 53

[0308]

[0309] To a solution of Example 7A compound (150.0 mg, 267.5 μmol) in tetrahydrofuran / water (5 ml / 3 ml) was added lithium hydroxide monohydrate (33.7 mg, 802.5 μmol) and reacted at 40 degrees Celsius for 5 hours. After the reaction was completed, it was extracted with ethyl acetate (20 ml), the combined organic layer was dried over sodium sulfate, filtered and spin-dried, and the obtained crude product was separated by preparative thin layer chromatography (dichloromethane:methane=20:1) to obtain Example 53 compound (90.0 mg, yield 34%, purity 95%). 1 H NMR(400MHz,CHLOROFORM-d)δ5.47(s,1H),4.37(br.s.,1H),3.63(br.s.,1H),3.47- 3.34(m,3H),3.28-2.98(m,3H),2.08-1.01(m,29H),1.00-0.83(m,10H),0.68(s,3H).

[0310] The preparation of Examples 51 to 58 was carried out according to the procedure of Example 53, and the preparation was carried out through Route 7. The results obtained are as follows:

[0311]

[0312]

[0313] Route 8

[0314]

[0315] Embodiment 59

[0316]

[0317] Example 8A

[0318]

[0319] After a mixture of reference example 1 compound (100.0 mg, 0.2 mmol), triethylamine (48.0 mg, 0.5 mmol) and O, N-dimethylhydroxylamine hydrochloride (23.0 mg, 0.2 mmol) in acetonitrile (2 ml) was stirred at 25 degrees Celsius for 0.5 hours, O-benzotriazole-N, N, N', N'-tetramethyluronium tetrafluoroboric acid (95.0 mg, 0.3 mmol) was added. The resulting mixture was stirred at 25 degrees Celsius for 12 hours. After the solvent was removed by vacuum rotary evaporation, the residue was purified by column chromatography to obtain Example 8A compound (90.2 mg, yield 82.1%). 1H NMR(400MHz, CHLOROFORM-d)δ=3.73-3.67(m,4H),3.45-3.36(m,1H),3.18(s,3H),2.51-2.40(m,1H),2.38-2.27(m,1H),2.00-1.89(m,2H),1.87- 1.74(m,5H),1.71-1.56(m,5H),1.53-1.31(m,11H),1.23-1.14(m,3H),1 .06-0.99(m,1H),0.96(d,J=6.3Hz,3H),0.93-0.88(m,6H),0.67(s,3H).

[0320] Embodiment 59

[0321]

[0322] To a solution of Example 8A compound (100.0 mg, 0.2 mmol) in tetrahydrofuran (5 ml) was added methylmagnesium bromide (0.4 ml, 1.1 mmol, 3N) in ether at 0°C, and stirring was continued at 0°C for 30 minutes, then warmed to room temperature and stirred for 12 hours. Ice water was added to quench the reaction, and then extracted with ethyl acetate (60 ml×2). After washing with water, the organic phase was dried over anhydrous sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was purified by preparative TLC to give Example 59 compound (6.0 mg, yield 66.0%). 1 H NMR (400MHz, CHLOROFORM-d) δ = 3.71 (br.s., 1H), 3.48-3.35 (m, 1H), 2.51-2.41 (m, 1H), 2.39-2.29 (m, 1H), 2.14 (s, 3H), 1.99-1.7 9(m,5H),1.76-1.56(m,5H),1.51-1.30(m,10H),1.22-1.11(m,3H),1.00(dt,J=3.3,14.2Hz,1H),0.94-0.87(m,9H),0.66(s,3H).

[0323] Route 9

[0324]

[0325] Embodiment 60

[0326]

[0327] Example 9A

[0328]

[0329] A solution (20 ml) of monomethyl malonate potassium salt (2.4 g, 15.1 mmol) and magnesium chloride (479.4 mg, 5.0 mmol) in tetrahydrofuran was stirred at 60 °C for 3 hours and cooled to 20 °C. A solution (8 ml) of carbonyldiimidazole (816.5 mg, 5.0 mmol) in tetrahydrofuran was added to a solution (8 ml) of Example 2A compound (2.4 g, 5.0 mmol) in tetrahydrofuran and stirred at 25 °C for 2 hours. This solution was then added to the previous reaction mixture and stirred at 35 °C for 10 hours. After the reaction, tetrahydrofuran was dried under reduced pressure and extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed twice with saturated brine (10 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=20:1) to give Example 9A (2.2 g, 4.1 mmol, 81.9% yield). 1H NMR(400MHz,CHLOROFORM-d)δ=8.15(s,1H),8.04(s,1H),5.19(br.s.,1H),4.76-4.66(m,1H),3.76-3.72(m,3H),3.45(s,2H),2 .61-2.40(m,2H),2.01-1.57(m,11H),1.53-1.36(m,6H),1.34-1.03(m,12H),0.99-0.94(m,3H),0.93-0.87(m,6H),0.65(s,3H).

[0330] Embodiment 60

[0331]

[0332] A solution of hydrogen chloride (200.0 mg, 375.4 μmol) in methanol (0.7 ml) was added to a mixed solvent of sodium hydroxide (25.0 mg) in methanol and water (5 ml / 0.3 ml) at -30 degrees Celsius. After stirring for 30 minutes, the mixed solution was added to a mixed solution of hydroxylamine hydrochloride (52.2 mg, 750.9 μmol) and sodium hydroxide (45 mg) in methanol and water (0.6 ml / 0.6 ml) at -30 degrees Celsius, and the stirring was continued for 1 hour. 36.5% hydrochloric acid (0.6 ml) was added and the temperature was raised to 80 degrees Celsius and stirred for 10 hours. The reaction solution was concentrated and extracted with dichloromethane (10 ml x 3). The combined organic layers were washed twice with saturated brine (10 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by preparative plate (dichloromethane: methanol = 10:1) to give Example 60 (20.00 mg, 43.5 μmol, 11.6% yield). 1H NMR(400MHz,CHLOROFORM-d)δppm 5.64(s,1H),3.71(br.s.,1H),3.47-3.36(m,1H),2.75-2.47(m,2H),2.01-1.57(m,11H),1 .49-1.28(m,1H),1.54-1.27(m,12H),1.25-1.09(m,4H),1.05-0.80(m,11H),0.66(s,3H).

[0333] Embodiment 61

[0334]

[0335] Under nitrogen protection at 20°C, to a solution of Example 62 compound (23.0 mg, 50.0 μmol) and potassium carbonate (13.8 mg, 100.1 μmol) in dimethylformamide (2.0 ml) was added iodomethane (8.5 mg, 60.0 μmol, 3.7 μL). After stirring at 20°C for 3 hours, 5 ml of water was added and the mixture was extracted with ethyl acetate (10 ml×3). The combined organic layers were washed twice with saturated brine (10 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated, and the residue was purified by preparation plate (ethyl acetate: petroleum ether = 10:1) to give Example 61 compound (9.0 mg, 34.2% yield). 1 HNMR(400MHz,CHLOROFORM-d)δppm 0.66(s,3H)0.89-1.00(m,13H)1.17-1.54(m,28H)1.55-1.93(m,18H)2.47-2.75(m,2H)3.71(br.s.,1H)3.95(s,3H)5.59(s,1H).

[0336] Route 10

[0337]

[0338] Embodiment 62

[0339]

[0340] Example 10A

[0341]

[0342] The compound of Example 9A (200.0 mg, 365.8 μmol) was dissolved in ethanol (3 ml), and hydrazine monohydrate (23.8 mg, 475.6 μmol, dissolved in ethanol 2 ml) was added dropwise at 0 degrees Celsius within one minute. After the addition was completed, the ice bath was removed and the reaction solution was stirred at 25 degrees Celsius for four hours. The solvent was removed by concentration, and the residue was separated by thin layer chromatography to obtain the compound of Example 10A (90.0 mg, 184.9 μmol, 50.6% yield). 1 H NMR (400MHz, CHLOROFORM-d) δ = 8.17 (d, J = 4.8Hz, 2H), 5.21 (br.s., 1H), 3.49 (d, J=5.5Hz,1H),3.44-3.35(m,1H),3.33-3.22(m,1H),2.00(d,J=12.3Hz,1H),1.91 -1.79(m,4H),1.77-1.69(m,4H),1.65-1.57(m,11H),1.55-1.48(m,3H),1.45(s, 3H),1.29(br.s.,18H),1.20-1.12(m,6H),1.06-0.96(m,9H),0.71-0.63(m,3H).

[0343] Embodiment 62

[0344]

[0345] The compound of Example 10A (90.0 mg, 184.9 μmol) was dissolved in tetrahydrofuran (1.0 ml), methanol (1.0 ml) and water (1.0 ml), and lithium hydroxide monohydrate (77.6 mg, 1.9 mmol) was added. The reaction solution was stirred at 25 degrees Celsius for twelve hours. The reaction solution was neutralized with 1 molar hydrochloric acid to pH = 5-6, and the solution was extracted with ethyl acetate (10 ml x 3). The obtained organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate and concentrated. The residue was separated by thin layer chromatography to obtain the compound of Example 62 (68.0 mg, 148.3 μmol, 80.2% yield). 1H NMR(400MHz, METHANOL-d4)=5.50(s,1H),3.67(br.s.,1H),3.33(br.s.,1H),2.68-2.56(m,1H),2.50-2.39(m,1H),2.03(s,2H),1.95-1.72(m, 8H),1.68-1.49(m,8H),1.47(s,2H),1.37-1.33(m,4H),1.27-1.19(m,5 H),1.05-1.00(m,4H),0.93(br.s.,5H),0.90(br.s.,5H),0.70(s,3H).

[0346] Route 11

[0347]

[0348] Embodiment 63

[0349]

[0350] Example 11A

[0351]

[0352] A mixture of the compound of Reference Example 1 (35.0 g, 83.2 mmol) and p-toluenesulfonic acid (1.4 g, 8.3 mmol) in methanol (350 ml) was stirred at 80 degrees Celsius for 2 hours. After cooling and filtration, the solvent was dried and the residue was purified by silica gel chromatography to obtain compound 11A (30 g, yield 82%). 1 H NMR(400MHz,CHLOROFORM-d)δ3.70(br.s.,1H),3.66(s,3H),3.46-3.34(m,1H),2.41-2.29(m,1H) ,2.27-2.14(m,1H),1.99-1.29(m,24H),1.21-1.09(m,3H),1.05-0.85(m,10H),0.72-0.60(m,3H).

[0353] Example 11B

[0354]

[0355] To a solution of Example 11A compound (200.0 mg, 460.0 μmol) in methanol (10 ml) was added hydrazine hydrate (515.0 mg, 10.3 mmol), and the reaction system was reacted at 25° C. for 12 h. The solvent was dried by spin drying, and the residue was washed with ethyl acetate solution (5 ml) to give Example 11B compound (120.0 mg, 60.2% yield).1 H NMR(400MHz,CHLOROFORM-d)δ6.75(br.s.,1H),3.71(br.s.,1H),3.45-3.36(m,1H),2. 26-2.17(m,1H),2.09-2.02(m,1H),1.59-1.10(m,25H),0.94-0.89(m,9H),0.66(s,3H).

[0356] Embodiment 63

[0357]

[0358] Under nitrogen protection at 20°C, to a solution of compound 11B (180.0 mg, 414.1 μmol) and carbonyldiimidazole (100.7 mg, 621.2 μmol) in dimethylformamide (2.00 ml) and tetrahydrofuran (2 ml) was added triethylamine (83.8 mg, 828.2 μmol, 114.8 μl). After stirring at 70°C for 12 hours, the mixture was cooled to 20°C, 20 ml of water was added, ethyl acetate (20 ml) was added, and the mixture was extracted with ethyl acetate (10 ml×3). The combined organic layers were washed once with saturated brine (10 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography (dichloromethane:methanol=50:1) to obtain Example 63 (72.0 mg, 35.9% yield). 1 HNMR(400MHz,CHLOROFORM-d)δppm 0.67(s,3H)0.79-1.11(m,11H)1.11-1.24(m,4H)1.28-1.99(m,26H)2.40-2.51(m,1H)2.55-2.66(m,1H)3.34-3.48(m,1H)3.72(br.s.,1H).

[0359] Route 12

[0360]

[0361] Embodiment 64

[0362]

[0363] Example 12A

[0364]

[0365] The compound of Example 11A (1.1 g, 2.5 mmol) was dissolved in ammonia methanol solution (14 ml) and stirred at 60-70 degrees Celsius for 18 hours. The crude product was spin-dried and purified by column chromatography to give the compound of Example 12A (200.0 mg, yield 19.0%). 1 HNMR(400MHz,CHLOROFORM-d)δ=5.50(s,2H)3.72(br.s.,1H)3.36-3.50(m,1H)2.24-2.37(m,1H)2.09-2.19(m,1H)1.95-2.01(m,1H)1. 56-1.95(m,9H)1.43-1.54(m,5H)1.30-1.42(m,5H)1.25-1.27(m,1H)1.13-1.24(m,3H)0.98-1.07(m,1H)0.89-0.98(m,9H)0.68(s,3H).

[0366] Example 12B

[0367]

[0368] At 0 degrees Celsius, Burgess reagent (85.0 mg, 357.5 μmol) was added to a solution of compound 12A (150.0 mg, 357.4 μmol) in tetrahydrofuran (3 ml). The reaction solution was stirred at 10-15 degrees Celsius for 3 hours, washed with saturated brine (15 ml x 2), and extracted with ethyl acetate (10 ml x 2). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was dried in vacuo. The crude product was separated by thin layer chromatography preparative plate to obtain Example 12B (30.0 mg, yield 21.0%). 1 H NMR(400MHz,CHLOROFORM-d)δ3.64-3.76(m,1H)3.34-3.50(m,1H)2.34-2.46(m,1H )2.22-2.34(m,1H)1.94-2.02(m,1H)1.85-1.91(m,2H)1.81(br.s.,4H)1.66-1.71( m,2H)1.56-1.63(m,2H)1.41-1.54(m,5H)1.31-1.41(m,4H)1.28-1.31(m,1H)1.14- 1.24(m,3H)0.99-1.07(m,1H)0.97(d,J=6.53Hz,3H)0.84-0.95(m,6H)0.69(s,3H).

[0369] Embodiment 64

[0370]

[0371] Dibutyltin oxide (40.0 mg, 74.7 μmol) and trimethylsilyl azide (52.0 mg, 451.4 μmol) were added to a toluene (2 ml) solution of Example 12B compound (30.0 mg, 74.7 μmol) and stirred at 100-110 degrees Celsius for 18 hours. After the reaction was completed, the reaction solution was cooled to 25-30 degrees Celsius, washed with saturated brine (15 ml x 2), and extracted with ethyl acetate (8 ml x 2). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was vacuum dried. The crude product was separated by thin layer chromatography preparation plate to obtain Example 64 compound (7.0 mg, yield 21.0%). 1H NMR(400MHz,CHLOROFORM-d)δ3.65-3.81(m,1H)3.33-3.39(m,1H)2.96-3.07(m,1H)2.83-2.95(m,1H)2.03-2.08(m,1 H)1.72-2.02(m,6H)1.29-1.70(m,15H)1.12-1.21(m,2H)1.05-1.10(m,3H)0.97-1.04(m,1H)0.94(s,6H)0.70(s,3H).

[0372] Route 13

[0373]

[0374] Embodiment 65

[0375]

[0376] Example 13A

[0377]

[0378] A mixture of 3,4-dihydropyran (1.6 g, 18.4 mmol), Example 12A compound (1.0 g, 2.3 mmol) and p-toluenesulfonic acid (35.9 mg, 0.2 mmol) in 1,4-dioxane (20 ml) was stirred at 25 degrees Celsius for 0.5 hours. After cooling and drying, the residue was extracted with ethyl acetate, washed with water and saturated brine in sequence, and the organic phase was dried and purified by silica gel chromatography to give Example 13A compound (1.3 g, yield 94%). 1H NMR(400MHz,CHLOROFORM-d)δ4.72(br.s.,1H),3.92(dd,J=6.3,10.8Hz,1H),3.79-3.58(m,4H),3.53-3.36(m,2 H),2.40-2.30(m,1H),2.21(ddd,J=6.5,9.2,15.4Hz,1H),1.98-1.08(m,34H),1.06-0.75(m,13H),0.64(s,3H).

[0379] Example 13B

[0380]

[0381] To a solution of the compound of Example 13A (500 mg, 0.8 mmol) in tetrahydrofuran (5 ml) was added lithium aluminum tetrahydride (94.4 mg, 2.5 mmol) at 0°C. The mixture was stirred at 0°C for 1 hour, then 94.4 ml of water was added and filtered. The filtrate was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution. The organic phase was dried to give the compound of Example 13B (400 mg, yield 84%), which was used directly in the next reaction. 1 H NMR(400MHz,CHLOROFORM-d)δ4.74(d,J=3.01Hz,1H),3.84-3.97(m,1H),3.56-3.73(m,4H), 3.37-3.54(m,3H),1.29-2.02(m,34H),1.06-1.20(m,5H),0.83-0.98(m,10H),0.66(s,3H).

[0382] Example 13C

[0383]

[0384] To a solution of Example 13B compound (230.0 mg, 400.1 μmol) in dichloromethane (10 ml) was added pyridine chromate (215.0 mg, 997.4 μmol) in one portion, and the mixture was reacted at 18 degrees Celsius for 2 hours. The reaction solution was filtered and dried by spin drying, and the residue was purified by preparative plate to give Example 13C compound (60.0 mg, 26.0% yield). 1HNMR(400MHz,CHLOROFORM-d)δ9.76(br.s.,1H),4.66-4.77(m,1H),3.64-3.98(m,3H),3 .32-3.58(m,3H),2.26-2.52(m,3H),1.06-2.00(m,37H),0.76-1.02(m,9H),0.64(s,3H).

[0385] Example 13D

[0386]

[0387] To an ethanol solution (500 ml) of the compound of Example 13C (150.0 mg, 233.3 μmol) was added sodium cyanide (11.4 mg, 233.3 mmol), ammonium chloride (12.5 mg, 233.3 mmol), ammonium carbonate (22.4 mg, 233.3 mmol) and aqueous ammonia (4.6 ml). The mixture was stirred at 60 degrees Celsius for 6 hours, and the reaction solution was poured into ice water (50 ml), and the aqueous layer was extracted with ethyl acetate (50 ml x 3). The combined organic layer was washed with saturated brine (50 ml x 2), and the organic layer was dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative plate to give the compound of Example 13D (80.0 mg, yield 72.1%). 1 H NMR(400MHz,CHLOROFORM-d)δ8.50(br.s.,1H),6.15-6.36(m,1H),4.74(d,J=3.01Hz,1H),4.08(t,J=5.52Hz,1H),3. 93(d,J=4.52Hz,1H),3.65-3.74(m,1H),3.39-3.55(m,6H),1.00-2.01(m,38H),0.82-0.98(m,9H),0.60-0.69(m,3H).

[0388] Embodiment 65

[0389]

[0390] To a solution of acetyl chloride (320.5 mg, 4.1 mmol) in methanol (2 ml) was added dropwise a solution of Example 13D (75.0 mg, 116.7 μmol) in methanol (1 ml) at 0°C. The mixture was stirred at 0°C for 4 hours, the reaction solution was spin-dried, and the residue was purified by preparative plate to give Example 65 (55.0 mg, yield 99.0%). 1H NMR(400MHz,METHANOL-d4)δ4.03-4.11(m,1H),3.65(br.s.,1H),3.35(s,1H),1.96-2.04(m,1H),1.67-1.95(m, 7H),1.42-1.66(m,9H),1.24-1.41(m,5H),1.00-1.24(m,5H),0.94-1.00(m,3H),0.84-0.94(m,6H),0.70(s,3H).

[0391] Route 14

[0392]

[0393] Examples 66A and 66B

[0394]

[0395] Example 14A

[0396]

[0397] To a solution of the compound of Example 13C (160.0 mg, 0.3 mmol) in tetrahydrofuran (6 ml) were added trimethyltrifluoromethylsilyl ether (59.6 mg, 0.4 ml) and tetrabutylammonium fluoride (10.9 mg, 0.04 mmol), and the mixture was stirred at 0°C for 1 hour. After the solvent was removed in vacuo, the residue was purified by silica gel column chromatography to give the compound of Example 14A (60.0 mg, yield 33.1%). 1 H NMR(400MHz,CHLOROFORM-d)δ4.73(d,J=3.8Hz,1H),4.03-3.78(m,2H),3.70(br.s.,1H),3.5 8-3.35(m,2H),2.00-1.28(m,28H),1.22-1.01(m,5H),0.98-0.84(m,9H),0.71-0.60(m,3H).

[0398] Examples 66A and 66B

[0399]

[0400] The procedure was the same as in Example 65, using the title compound 14A as the starting material, and purification was performed to give Example 66A and Example 66B (27.0 mg, yield 61.0%). 1H NMR (400 MHz, CHLOROFORM-d) δ 3.92 (dd, J = 4.0, 9.0 Hz, 1H), 3.71 (br. s., 1H), 3.46-3.35 (m, 1H), 2.86-2.65 (m, 1H), 2.14 (dt, J = 3.8, 12.8 Hz, 1H), 1.98 (d, J = 11.8 Hz, 1H), 1.81-1.63 (m, 6H), 1.54-1.08 (m, 18H), 1.05-0.87 (m, 10H), 0.67 (s, 3H). and 68B (10.0 mg, yield 23.0%). 1 H NMR(400MHz,CHLOROFORM-d)δ4.00-3.80(m,1H),3.70(br.s.,1H),3.48-3.34(m,1H),2.72(b r.s.,1H),2.04-1.29(m,26H),1.23-1.07(m,4H),1.05-0.86(m,10H),0.67(d,J=4.5Hz,3H).

[0401] Route 15

[0402]

[0403] Embodiment 67

[0404]

[0405] Example 15A

[0406]

[0407] Elemental iodine (106 mg, 0.4 mmol) was added to a solution of Example 2A compound (100.0 mg, 0.2 mmol) and lead acetate (186.0 mg, 0.4 mmol) in carbon tetrachloride (2 ml), and the reaction system was reacted under light for 12 hours. Sodium thiosulfate solution (1 ml) was added to quench the reaction, and the aqueous layer was extracted with dichloromethane (10 ml×3), dried over sodium sulfate, filtered and dried by spin drying, and the residue was purified by preparative thin layer plate (petroleum ether: ethyl acetate = 5:1) to give Example 15A compound (50.0 mg, yield 38.0%). 1H-NMR(CDCl3,400MHz)δ8.14(s,1H),8.03(s,1H),5.19(br.s.,1H),4.62-4 .77(m,1H),3.23-3.32(m,1H),3.00-3.12(m,1H),1.96-2.02(m,2H),1.85-1 .92(m,2H),1.70-1.82(m,7H),1.66-1.72(m,2H),1.39-1.45(m,2H),1.23-1 .32(m,5H),1.09-1.19(m,6H),0.96(s,3H),0.90-0.93(m,6H),0.67(s,3H).

[0408] Example 15B

[0409]

[0410] A mixture of the compound of Example 15A (100.0 mg, 179 μmol) and triethylphosphite (149.0 mg, 895 μmol) was stirred at 160°C for 6 hours. After dilution with water (5 ml), the mixture was extracted with ethyl acetate (10 ml x 3), the combined organic layers were dried over sodium sulfate, filtered and spin-dried, and the residue was purified by preparative thin layer plate (petroleum ether: ethyl acetate = 1: 1) to give the compound of Example 15B (90.0 mg, yield 84.1%). 1 H-NMR(CDCl3,400MHz)δ8.12(s,1H),8.01(s,1H),5.16(br.s.,1H),4.62-4.73(m,1H),4.03-4.08(m,4H),1.82-1.97(m,3H),1.67-1.81( m,7H),1.55-1.65(m,2H),1.38-1.53(m,6H),1.29(t,J=7.0Hz,9H),1.19-1.26(m,3H),1.01-1.18(m,6H),0.86-0.91(m,6H),0.63(s,3H).

[0411] Embodiment 67

[0412]

[0413] Referring to Example 53, compound 15B (40.0 mg, 70.3 μmol) was used as starting material to obtain the compound of Example 67 (30.0 mg, yield 79.0%). 1H-NMR(CDCl3,400MHz)δ4.06-4.14(m,4H),3.71(br.s.,1H),3.42(d,J=8.0Hz,1H),1.88-2.01(m,2H),1.74-1.87(m,6H),1.62-1.73(m,3H),1 .37-1.55(m,8H),1.33(s,6H),1.22-1.31(m,3H),1.12-1.21(m,4H),0. 97-1.06(m,1H),0.94(d,J=6.8Hz,3H),0.87-0.92(m,6H),0.67(s,3H).

[0414] Route 16

[0415]

[0416] Embodiment 68

[0417]

[0418] Example 16A

[0419]

[0420] To a solution of N-tert-butyloxycarbonyl-1,2,5-thiadiazoline 1,1-dioxide (20.0 mg, 89.5 μmol) in N,N-dimethylformamide (1 ml) was added sodium hydrogen (7.0 mg, 179 μmol) at zero degrees. Half an hour later, a solution of Example 15A (50.0 mg, 89.5 μmol) in N,N-dimethylformamide (1 ml) was added dropwise. After the addition was complete, the reaction system was slowly warmed to room temperature and then reacted for another hour. The reaction was quenched with water (5 ml), the aqueous layer was extracted with ethyl acetate (10 ml x 3), the organic layers were combined, dried over sodium sulfate, filtered and dried by spin drying, and the residue was purified by preparative thin layer plate (petroleum ether: ethyl acetate = 1:1) to obtain compound 16A (30.0 mg, yield 57.5%). 1 H-NMR (CDCl3, 400MHz) δ8.15 (s, 1H), 5.30 (s, 1H), 5.18 (br.s., 1H), 3.90 (t, J = 6.5Hz, 2H), 3.78 (s, 2H), 3.02-3.07 (m, 2H), 1.97 (d, J = 12. 0Hz,2H),1.79-1.88(m,5H),1.64(br.s.,5H),1.30(d,J=7.0Hz,6H),1.03-1.15(m,7H),0.94(s,3H),0.89(d,J=8.0Hz,6H),0.65(s,3H).

[0421] Embodiment 68

[0422]

[0423] Referring to Example 53, Example 16A was used as the starting material (30.0 mg, 57 μmol) to obtain Example 68 (20.0 mg, 67.1% yield). 1 H-NMR (CDCl 3, 400MHz) δ4.22(br.s.,1H),3.71(br.s.,1H),3.52(q,J=6.5Hz,2H),3.39- 3.47(m,2H),3.31-3.38(m,1H),2.97-3.10(m,2H),1.87-2.01(m,2H),1.8 0(d,J=8.8Hz,4H),1.67(br.s.,3H),1.40-1.52(m,5H),1.25-1.39(m,7H) ,1.12-1.24(m,4H),0.99(d,J=6.5Hz,3H),0.88-0.93(m,6H),0.68(s,3H).

[0424] The preparation of Example 69 and Example 70 was prepared by referring to the operation of Example 68 and prepared by Route 16. The results obtained are as follows:

[0425]

[0426]

[0427] Route 17

[0428]

[0429] Embodiment 71

[0430]

[0431] Example 17A

[0432]

[0433] At 25 degrees Celsius, silver carbonate (197.5 mg, 716.2 μmol) was added to a mixture of Example 15A compound (200.0 mg, 200.0 μmol) in acetone (2.8 ml) and water (150.0 μl). Stir for 30 minutes at 25 degrees, then raise the temperature to 80 degrees and continue stirring for 12 hours. Thin layer chromatography (petroleum ether: ethyl acetate = 2: 1) detected the formation of a new compound with increased polarity. The reaction suspension was filtered, and the filtrate was decompressed to remove the solvent to obtain a residue. The residue was purified by thin layer preparation plate (petroleum ether: ethyl acetate = 2: 1) to obtain Example 17A compound (46.0 mg, 27.2% yield, 95% purity). 1 H NMR(400MHz,CHLOROFORM-d)δ8.15(s,1H),8.04(s,1H),5.20(br.s.,1H),4.80-4.62(m,1H),3.77-3.58(m,1H) ,2.07-1.95(m,1H),1.94-1.67(m,8H),1.53-1.40(m,5H),1.38-1.02(m,13H),0.99-0.87(m,9H),0.67(s,3H).

[0434] Example 17B

[0435]

[0436] To a toluene (3 ml) solution of Example 17A compound (40.0 mg, 89.2 μmol) was added ethyl isocyanate (13.0 mg, 178.4 μmol), and the reaction system was stirred at 110° C. for 12 hours. The solvent was spin-dried, and the residue was purified by preparative thin layer plate (petroleum ether: ethyl acetate = 2: 1) to give Example 17B compound (5 mg, 9.7% yield). 1 H-NMR(CDCl3,400MHz)δ8.15(s,1H),8.03-8.07(m,1H),5.19(br.s.,1H),4 .64-4.77(m,1H),3.96(q,J=7.1Hz,2H),3.13-3.25(m,2H),1.89-2.02(m,2 H),1.70-1.89(m,8H),1.56-1.66(m,4H),1.35-1.55(m,7H),1.27-1.33(m, 4H),1.11-1.14(m,3H),0.94-0.97(m,6H),0.88-0.92(m,3H),0.66(s,3H).

[0437] Embodiment 71

[0438]

[0439] Referring to Example 53, the compound of Example 17B was used as the starting material and purified to give the compound of Example 71 (5.0 mg, yield 53.0%). 1 H-NMR (CDCl3, 400MHz) δ = 4.60 (br.s., 1H), 4.00-4.15 (m, 2H), 3.71 (d, J = 1.8Hz, 1H), 3.36-3.45 (m, 1H), 3.16-3.27 (m, 2H), 1.89-2.00 (m, 2H), 1 .74-1.85(m,5H),1.56-1.67(m,5H),1.40-1.51(m,6H),1.26-1.36(m,7 H),1.14(s,3H),0.97(d,J=6.3Hz,3H),0.89-0.93(m,6H),0.67(s,3H).

[0440] Route 18

[0441]

[0442] Embodiment 72

[0443]

[0444] Example 18A

[0445]

[0446] At 0 degrees Celsius, formic acid (8.2 mg, 8.2 micromol) was dropped into a round-bottom flask containing chlorosulfonic acid isocyanate (24.1 mg, 24.1 micromol), stirred at 0 degrees for 5 minutes, and a white solid was produced. Dichloromethane (3.0 ml) was added to the reaction system, and stirring continued at 0 degrees Celsius for 1 hour, then the temperature was raised to 25 degrees and stirring continued for 4 hours. The reaction solution was cooled to 0 degrees, and a mixture of Example 17A compound (50.0 mg, 111.5 micromol) and pyridine (13.5 mg, 13.5 micromol) was added to the reaction system. The reaction mixture was heated to 25 degrees and continued to stir for 12 hours. The solvent was evaporated under reduced pressure, and the residue was purified by thin layer preparation plate (petroleum ether: ethyl acetate = 2: 1) to obtain Example 18A compound (18.0 mg, yield 29.0%, purity 95%). 1H NMR (400MHz, CHLOROFORM-d) δ = 8.15 (s, 1H), 8.04 (s, 1H), 5.20 (br.s., 1H), 4.79-4.65 (m, 3H), 4.34-4.15 ( m,2H),2.07-1.69(m,11H),1.68-1.37(m,12H),1.35-1.04(m,13H),1.02-0.81(m,12H),0.73-0.61(m,4H).

[0447] Embodiment 72

[0448]

[0449] The same method as in Example 53 was used to purify the compound of Example 72 (10.0 mg, yield 56.0%, purity 90%) using the compound of Example 18A as the starting material. 1 H NMR(400MHz,CHLOROFORM-d)δ=4.82(br.s.,2H),4.33-4.15(m,2H),3.71(br.s.,1H),3.49-3.33(m,1H),2.00-1.87(m,4H), 1.84-1.73(m,5H),1.71-1.56(m,12H),1.53-1.38(m,11H),0.99(d,J=7.0Hz,5H),0.85(d,J=7.5Hz,10H),0.69-0.66(m,1H).

[0450] Route 19

[0451]

[0452] Embodiment 73

[0453]

[0454] Example 19A

[0455]

[0456] The compound of Example 15A (1.5 g, 2.7 mmol) was dissolved in N-methylpyrrolidone (8.0 ml), and sodium azide (1.5 g, 23.1 mmol) and acetic acid (1.9 g, 32.3 mmol) were added in sequence. The reaction solution was stirred at 20 degrees Celsius for 20 hours. Saturated sodium bicarbonate aqueous solution (5 ml) was added to quench the reaction, and extracted with ethyl acetate (20 ml x 3). The organic layer was washed with water (10 ml x 4), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (silica gel) to give the compound of Example 19A (1.2 g, yield 89.0%).1 H NMR(400MHz,CHLOROFORM-d)δ8.15(s,1H),8.04(s,1H),5.19(br.s.,1H),4.77-4.65(m,1H),3.35(ddd,J=4.8,8.2 ,12.4Hz,1H),3.20(td,J=7.9,12.2Hz,1H),1.99-1.70(m,10H),1.51-1.42(m,3H),1.18-1.08(m,5H),0.67(s,3H).

[0457] Example 19B

[0458]

[0459] The compound of Example 19A (1.0 g, 2.1 mmol) was dissolved in tetrahydrofuran (20.0 ml), and triphenylphosphine (1.7 g, 6.3 mmol) and water (1.0 ml) were added in sequence under nitrogen protection. The reaction solution was stirred at 20 degrees for 12 hours. The solvent was removed by concentration, and the resulting residue was subjected to thin layer chromatography to give the compound of Example 19B (500.0 mg, yield 50.3%). 1 HNMR(400MHz,CHLOROFORM-d)δ8.15(s,1H),8.04(s,1H),5.20(br.s.,1H),4.77-4.65(m,1H),3.02(br.s.,1H),2.89(b r.s.,1H),2.01-1.70(m,14H),1.60-1.47(m,13H),1.21-1.13(m,18H),0.96(s,8H),0.79(d,J=2.5Hz,7H),0.68(s,3H).

[0460] Example 19C

[0461]

[0462] The compound of Example 19B (50.0 mg, 111.7 μmol) was dissolved in N,N-dimethylformamide (1.0 ml) and dichloromethane (2.0 ml). At 0°C, an aqueous solution (1.0 ml) of sodium bicarbonate (28.2 mg, 335.1 μmol) and thiophosgene (15.4 mg, 134.0 μmol) were added in sequence. The reaction mixture was reacted at 20°C for 30 minutes, water (10 ml) was added, and extraction was performed with dichloromethane (10 ml x 3). The organic layer was washed with water (10 ml) and saturated brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (4.0 ml). (3R)-3-hydroxypyrrole hydrochloride (11.7 mg, 94.5 μmol) and triethylamine (13.6 mg, 134.0 μmol) were added at 20 degrees Celsius. The reaction solution was stirred at 80 degrees Celsius for 4 hours. The solvent was removed by concentration, water (5 ml) was added to the residue, and extracted with ethyl acetate (10 ml x 3). The organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by thin layer chromatography to obtain Example 19C (40.0 mg, yield 62.0%). 1 H NMR(400MHz,METHANOL-d4)δ8.22(s,1H),8.08(s,1H),5.21(br.s.,1H),4.73-4.60(m,1H),4.44(br.s.,1H),3.77-3.57(m,3H),3.53-3.42( m,1H),2.11-1.85(m,7H),1.75(d,J=11.0Hz,3H),1.62-1.45(m,7H),1 .26-1.10(m,10H),1.08-1.02(m,5H),0.88-0.81(m,6H),0.74(s,3H).

[0463] Embodiment 73

[0464]

[0465] Referring to Example 53, Example 19C compound was used as the starting material and purified to give Example 73 compound (27.0 mg, yield 71%). 1H NMR(400MHz,CHLOROFORM-d)δ5.27(t,J=4.5Hz,1H),4.52(br.s.,1H),3.69(br.s.,5H),3.60-3.48(m,1H),3.45-3.33(m,1H),2.13-2.05(m, 2H),2.01-1.89(m,2H),1.86-1.57(m,9H),1.52-1.28(m,12H),1.20-1 .15(m,2H),1.00(d,J=6.3Hz,4H),0.89-0.85(m,5H),0.60(br.s.,3H).

[0466] Route 20

[0467]

[0468] Embodiment 74

[0469]

[0470] Example 20A

[0471]

[0472] The compound of Example 19B (80.0 mg, 178.7 μmol) was dissolved in dichloromethane (4.0 ml), and then diisopropylethylamine (34.6 mg, 268.1 μmol) and 2-isopropyl isocyanate (27.1 mg, 268.1 μmol) were added in sequence, and the reaction solution was stirred at 20 degrees for 12 hours. The solvent was removed by concentration, and the resulting residue was separated by thin layer chromatography to give the compound of Example 20A (60.0 mg, yield 58.0%). 1 H NMR(400MHz,CHLOROFORM-d)δ8.15(s,1H),8.04(s,1H),5.19(br.s.,1H),4.78-4 .63(m,1H),3.53-3.19(m,2H),1.98(d,J=12.3Hz,1H),1.92-1.84(m,2H),1.82-1 .60(m,8H),1.53-1.40(m,6H),1.24(d,J=6.5Hz,7H),1.21-1.08(m,7H),0.98(d, J=6.5Hz,3H),0.95(s,3H),0.87(d,J=4.0Hz,4H),0.80-0.76(m,1H),0.65(s,3H).

[0473] Embodiment 74

[0474]

[0475] Referring to Example 53, Example 74 (48.0 mg, 85.0% yield) was obtained using Example 20A as starting material. 1 H NMR(400MHz,METHANOL-d4)δ3.67(br.s.,1H),3.56(br.s.,1H),3.36(br.s.,1H),2.03(d,J=12.0Hz,1H),2.00-1.82(m,4H),1.81 -1.72(m,3H),1.65-1.48(m,7H),1.44-1.28(m,8H),1.19(d,J=6.5Hz,6H),1.03(d,J=6.3Hz,3H),0.93-0.86(m,5H),0.73(s,3H).

[0476] Route 21

[0477]

[0478] Embodiment 75

[0479]

[0480] Example 21A

[0481]

[0482] The compound of Example 12A (5.0 g, 11.5 mmol) was dissolved in anhydrous toluene (80.0 ml), and then silver carbonate / diatomaceous earth (12.6 g, 46.0 mmol) was added. The reaction solution was stirred at 130 degrees Celsius for twelve hours. After cooling to room temperature, the solvent was removed by concentration. The residue was subjected to column chromatography (silica gel) to give the compound of Example 21A (3.6 g, yield 69.0%). 1 H NMR(400MHz,CHLOROFORM-d)δ3.78(br.s.,1H),3.67(s,3H),3.07(t,J=14.6Hz,1H),2.47-2.31(m,2H), 2.28-2.09(m,3H),2.06-1.87(m,4H),1.75-1.17(m,21H),1.00(s,3H),0.95-0.83(m,10H),0.70(s,3H).

[0483] Example 21B

[0484]

[0485] Under nitrogen protection, a toluene solution (3 ml) of the compound of Example 21A (601.4 mg, 1.4 mmol) was added dropwise to a suspension (20 ml) of sodium hydride (40.0 mg, 1.7 mmol) in anhydrous toluene. Then, a toluene solution (2 ml) of ethyl formate (308.9 mg, 4.2 mmol) was added dropwise. The mixture was stirred at 20 degrees Celsius for 1 hour. Anhydrous ethanol (76.8 mg, 1.7 mmol) was then added and stirring was continued for 11 hours. The reaction solution was poured into ice water and extracted with ethyl acetate (20 ml x 3). The combined organic phase was washed with saturated brine (10 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the compound of Example 21B (500.0 mg, 72.0% yield). 1 H NMR(400MHz,CHLOROFORM-d)δ14.29(br.s.,1H),8.20(s,1H),4.14(q,J=7.0Hz,3H),3.79(br.s.,1H),3.68(s,1H),3.41-3.29(m ,1H),2.27-2.16(m,2H),1.88-1.76(m,2H),1.56-1.30(m,15H),1.20-1.11(m,4H),1.05(s,3H),0.99-0.90(m,9H),0.69(s,3H).

[0486] Example 21C

[0487]

[0488] Example 21B compound (100.0 mg, 210.7 μmol) was dissolved in ethanol (3.00 ml), hydrazine hydrate (21.1 mg, 421.4 μmol) was added to the resulting solution, and the reaction solution was stirred at 80 degrees Celsius for 1 hour. The solvent was removed by concentration, and the resulting residue was separated by thin layer chromatography to give the title compound 21C (65.0 mg, yield 62.0%, white solid). 1H NMR(400MHz,CHLOROFORM-d)δ7.32(br.s.,1H),4.11(q,J=7.1Hz,3H),3.81(br.s. ,1H),3.55-3.44(m,1H),2.78(d,J=15.8Hz,1H),2.62(dd,J=6.9,17.7Hz,1H),2.4 3-2.26(m,1H),2.23-2.09(m,3H),1.96-1.73(m,7H),1.67-1.52(m,4H),1.46-1.3 5(m,3H),1.30-1.20(m,7H),1.10-1.03(m,5H),0.89(d,J=6.3Hz,4H),0.66(s,3H).

[0489] Embodiment 75

[0490]

[0491] The compound of Example 21C (65.0 mg, 138.1 μmol) was dissolved in tetrahydrofuran (4.0 ml), and then an aqueous solution (2.0 ml) of sodium hydroxide (55.2 mg, 1.4 mmol) was added, and the reaction solution was stirred at 30 degrees Celsius for 12 hours. It was acidified to pH 2-3 with 1N dilute hydrochloric acid, extracted with ethyl acetate (10 ml×3), and the organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by thin layer chromatography to give the compound of Example 75 (14.0 mg, yield 22.0%). 1 H NMR(400MHz,METHANOL-d4)δ7.22(s,1H),3.77(br.s.,1H),3.62(dd,J=10.8, 17.6Hz,1H),2.82(d,J=15.8Hz,1H),2.58(dd,J=7.4,17.7Hz,1H),2.40-2.26 (m,1H),2.23-2.08(m,2H),1.99-1.73(m,6H),1.69-1.47(m,4H),1.46-1.24( m,8H),1.12(s,4H),1.00(t,J=7.3Hz,3H),0.94(d,J=6.5Hz,3H),0.72(s,3H).

[0492] Route 22

[0493]

[0494] Embodiment 76

[0495]

[0496] Example 22A

[0497]

[0498] The compound of Example 21C (90.0 mg, 191.2 μmol) was dissolved in N,N-dimethylformamide (4.0 ml), and then dimethyl sulfate (440.0 mg, 3.5 mmol) and potassium carbonate (79.3 mg, 573.6 μmol) were added, and the reaction solution was stirred at 30 degrees Celsius for 12 hours. The solvent was removed by concentration, and the resulting residue was separated by thin layer chromatography to give the mixture of Example 22A (20.0 mg, 19.0% yield, white solid). 1 H NMR (400MHz, METHANOL-d4) δ7.15 (s, 1H), 4.18-4.06 (m, 2H), 3.78 (s, 3H), 3.56 (dt, J = 10.7, 17.0Hz, 1H), 2.78 (dd, J = 6.7, 15.9Hz, 1H), 2 .52(td,J=6.3,17.7Hz,1H),2.41-2.27(m,1H),2.18(s,1H),1.98-1.52(m,11H),1.43-1.32(m,5H),1.25(t,J=7.0Hz,4H),0.71(s,3H).

[0499] Embodiment 76

[0500]

[0501] Referring to the operating method of Example 53, the compound of Example 22A (20.0 mg, 37.1 μmol) was used as the starting material, the ethoxy group was removed with LiOH, and then separated by thin layer chromatography to obtain the compound of Example 76 (10.0 mg, yield 50%). 1 HNMR(400MHz,CHLOROFORM-d)δ7.17(s,1H),6.96(s,1H),3.81(s,3H),3.70(s,1H),2.74(d,J=15.8Hz,1H),2.67-2.58(m,1H),2.5 8-2.20(m,3H),2.13(d,J=15.8Hz,1H),1.94-1.69(m,5H),1.65-1.48(m,4H),1.48-1.22(m,10H),1.15-0.79(m,15H),0.67(s,3H).

[0502] Route 23

[0503]

[0504] Embodiment 77

[0505]

[0506] Example 23A

[0507]

[0508] After dissolving the compound of Example 21B (400.0 mg, 895.6 μmol) in methanol (10.0 ml), sodium borohydride (203.3 mg, 5.4 mmol) was added, and the reaction solution was stirred at 0 degrees Celsius for 1 hour. Saturated ammonium chloride solution (5 ml) was added to quench the reaction, and the solvent was concentrated to remove it. Water (5 ml) was added to the residue, and it was extracted with ethyl acetate (10 ml x 3). The organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to thin layer chromatography to obtain the compound of Example 23A (120.0 mg, yield 28.0%, colorless oil). 1 H NMR(400MHz,CHLOROFORM-d)δ4.10(q,J=7.1Hz,2H),3.68(br.s.,1H),3.64(s,1H),3.38(tt,J=5.1,10.0Hz,1H),2.39-2.27(m,1H),2.23-2 .13(m,1H),1.98-1.84(m,3H),1.65-1.54(m,3H),1.45-1.36(m,5H), 1.31-1.24(m,6H),1.17-1.10(m,3H),0.90(s,3H),0.67-0.61(m,3H).

[0509] Embodiment 77

[0510]

[0511] Using the compound of Example 23A as the starting material (100.0 mg, 208.9 μmol), referring to the preparation method of Example 65, the compound of Example 77 (20.0 mg, yield 20.0%) was obtained by TLC separation. 1H NMR(400MHz,CHLOROFORM-d)δ3.71(br.s.,1H),3.62(t,J=5.6Hz,2H),3.47-3.36(m,1H),1.98(d,J=12.0Hz,1H),1.92-1.75(m,5H ),1.69-1.56(m,8H),1.51-1.39(m,9H),1.19-1.06(m,7H),0.95-0.92(m,4H),0.89-0.85(m,8H),0.82-0.76(m,2H),0.67(s,3H).

[0512] Route 24

[0513]

[0514] Embodiment 78

[0515]

[0516] Example 24A

[0517]

[0518] The compound of Example 21A (10.0 g, 23.1 mmol) was dissolved in pyridine (100 ml), and acetic anhydride (28.3 g, 277.4 mmol) and 4-N,N-dimethylaminopyridine (282.4 mg, 2.3 mmol) were added. The mixture was refluxed at 110°C for 6 hours. The reaction was completed by TLC detection. The solvent was removed by concentration and the residue was separated by TLC chromatography to give the compound of Example 24A (9.2 g, yield 84.0%). 1 H NMR(400MHz,CHLOROFORM-d)δ5.19(br.s.,1H),3.68(s,3H),2.81(t,J=14.3Hz,1H),2.49-2.39(m,1H),2.35- 1.99(m,9H),1.94-1.73(m,5H),1.71-1.08(m,15H),1.09-1.00(m,3H),0.99-0.84(m,6H),0.75-0.63(m,3H).

[0519] Example 24B

[0520]

[0521] Diethylaminosulfur trifluoride (132.4 mg, 821.6 μmol) was added dropwise to a solution of Example 24A compound (130.0 mg, 273.9 μmol) in dichloromethane (3.0 ml), and stirred at 25-30 degrees Celsius for 18 hours. After the reaction was completed, the reaction solution was quenched with ice water, extracted with ethyl acetate (10 ml x 2), the organic phase was washed with saturated brine (15 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin layer chromatography preparation plate (petroleum ether / ethyl acetate = 10 / 1) to obtain Example 24B compound (75.0 mg, yield 50.1%, purity 90%). 1 H NMR(400MHz,CHLOROFORM-d)δ0.67(s,3H)0.88-0.97(m,6H)0.97-1.04(m,3H)1.05-1.23(m,5H)1.32-1.41(m,3H)1.43-1.54(m,3H)1.5 7-1.69(m,6H)1.78-1.90(m,6H)1.96-2.04(m,1H)2.07-2.12(m,3H)2.12-2.31(m,2H)2.32-2.43(m,1H)3.68(s,3H)5.09-5.19(m,1H).

[0522] Embodiment 78

[0523]

[0524] The same operation as the title compound 53 was carried out, using compound 24B as the starting material (75.0 mg, 151.0 μmol), and the title compound 78 (55.0 mg, yield 74.0%, purity 90%) was obtained after reaction treatment and purification. 1 H NMR(400MHz,CHLOROFORM-d)δ0.69(s,3H)0.90-0.99(m,9H)1.13-1.25(m,3H)1.31-1.54(m,10H)1.55 -1.79(m,5H)1.80-1.87(m,3H)1.87-1.97(m,2H)1.97-2.03(m,1H)2.20-2.53(m,3H)3.75(br.s.,1H).

[0525] Route 25

[0526]

[0527] Examples 79A and 79B

[0528]

[0529] Example 25A

[0530]

[0531] Lithium hydroxide monohydrate (35.3 mg, 1.5 mmol) was added to a mixed solution of methanol (2 ml) and water (0.5 ml) of the compound of Example 24A (100.0 mg, 0.2 mmol) and stirred at 20-25 degrees Celsius for 18 hours. After the reaction was completed, the reaction solution was acidified with 2M dilute hydrochloric acid, washed with saturated brine (15 ml × 2), extracted with ethyl acetate (10 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried under reduced pressure. The crude product was separated by thin layer chromatography preparation plate (dichloromethane / methanol = 20 / 1) to obtain the compound of Example 25A (60.0 mg, yield 88.0%). 1 H NMR(400MHz,CHLOROFORM-d)δ=5.17(br.s.,1H)2.70-2.89(m,1H)2.34-2.49(m,2H)2.23(d,J=3.51Hz,3H)2.06(s,3H)1.98-2.05(m ,2H)1.74-1.90(m,5H)1.60-1.70(m,1H)1.29-1.58(m,8H)1.08-1.24(m,5H)1.01-1.06(m,3H)0.86-0.97(m,6H)0.63-0.72(m,3H).

[0532] Example 25B

[0533]

[0534] Under nitrogen protection at 0 degrees Celsius, a solution of methylmagnesium bromide (0.4 ml, 651.2 μmol, 3N) in diethyl ether was added dropwise to a solution of Example 25A compound (60.0 mg, 130.2 μmol) in tetrahydrofuran (4 ml) and stirred for 2 hours. After the reaction was completed, it was quenched with a saturated ammonium chloride solution and extracted with ethyl acetate (10 ml x 2). The organic phase was washed with saturated brine (15 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by thin layer chromatography preparation plate (dichloromethane / methanol = 20 / 1) to obtain Example 25B compound.

[0535] Example 25B1 compound (35.0 mg, yield 56.0%). 1H NMR(400MHz,CHLOROFORM-d)δ5.03-5.14(m,1H)2.31-2.43(m,1H)2.18-2.30(m,1H)2.04(s,3H)1.90-2.00(m,1H)1.72-1.86(m ,4H)1.53-1.69(m,4H)1.26-1.51(m,11H)1.19-1.23(m,3H)1.01-1.17(m,5H)0.94-0.99(m,3H)0.85-0.94(m,6H)0.64(s,3H).

[0536] Example 25B2 compound (15.0 mg, yield 24.0%). 1 H NMR(400MHz,CHLOROFORM-d)δ5.04-5.13(m,1H)2.33-2.42(m,1H)2.19-2.30(m,1H)2.05-2.09(m,3H)1.86-2.03(m,3H)1 .73-1.84(m,5H)1.29-1.61(m,12H)1.21(s,3H)1.06-1.15(m,5H)0.90-0.95(m,6H)0.84-0.90(m,3H)0.59-0.67(m,3H).

[0537] Examples 79A and 79B

[0538]

[0539] Sodium hydroxide (1.5 g, 37.5 mmol) was added to a solution of Example 25B1 compound (35.0 mg, 73.4 μmol) in methanol (2.0 ml) and stirred at 70-80 degrees Celsius for 55 hours. After the reaction was completed, it was acidified with 2N dilute hydrochloric acid to a pH value of about 5, extracted with ethyl acetate (8 ml x 2), and the organic phase was washed with saturated brine (10 ml x 2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified by thin layer chromatography (dichloromethane / methanol = 15 / 1) to give Example 79A compound (20.0 mg, yield 63.0%). 1 H NMR(400MHz,CHLOROFORM-d)δ3.66-3.77(m,1H)2.33-2.44(m,1H)2.19-2.30(m,1H)1.76-1.99(m,4H)1 .53-1.73(m,5H)1.29-1.51(m,12H)1.25-1.27(m,1H)1.10-1.23(m,6H)0.79-1.01(m,9H)0.66(s,3H).

[0540] The same operation as Example 79A was performed using Example 25B2 (15.0 mg, 31.5 μmol) as starting material. The crude product was purified by thin layer chromatography (dichloromethane / methanol = 15 / 1) to give Example 79B (6.0 mg, 44.0% yield). 1 HNMR(400MHz,CHLOROFORM-d)δ3.62-3.72(m,1H),2.33-2.46(m,1H),2.19-2.30(m,1H),1.87-2.08(m,3H),1.72-1 .86(m,3H),1.52-1.69(m,3H),1.27-1.52(m,13H),1.19(s,3H),1.02-1.15(m,3H),0.87-0.95(m,9H),0.65(s,3H).

[0541] Route 26

[0542]

[0543] Embodiment 80

[0544]

[0545] Example 26A

[0546]

[0547] Under nitrogen protection at 0 degrees Celsius, Tebbe reagent (0.5M toluene solution, 0.1 mmol) was added to a tetrahydrofuran (2.0 ml) solution of the compound of Example 24A (60.0 mg, 0.1 μmol). After stirring at 0 degrees Celsius for 4 hours, the temperature was raised to 25-30 degrees Celsius and stirred for 16 hours. 2 ml of 2M sodium hydroxide aqueous solution was added to the reaction solution and filtered, and the filtrate was extracted with ethyl acetate (10 ml x 2), and the organic phase was washed with saturated brine (15 ml x 2), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was purified by thin layer chromatography (petroleum ether / ethyl acetate = 5 / 1) to obtain the compound of Example 26A (33.0 mg, yield 55.0%). 1H NMR(400MHz,CHLOROFORM-d)δ5.02-5.19(m,1H)4.56(br.s.,2H)3.67(s,3H)2.42-2.56(m,1H)2.31-2.42(m,1H)2.20-2.29(m,1H)2.10-2.2 0(m,1H)2.07(s,3H)1.72-2.04(m,8H)1.58-1.71(m,2H)1.47-1.57(m, 2H)1.30-1.47(m,5H)1.02-1.24(m,6H)0.83-0.99(m,9H)0.67(s,3H).

[0548] Example 26B

[0549]

[0550] Under nitrogen protection, diethylzinc (22.9 mg, 185.8 μmol) and diiodomethane (79.6 mg, 297.2 μmol) were added to a toluene (2.0 ml) solution of Example 26A compound (40.0 mg, 92.9 μmol) in sequence. Stir at 25-30 degrees Celsius for 0.5 hours, during which the reaction solution gradually turned into a white suspension. Then, nitrogen was replaced with oxygen, during which the suspension changed from white to pink. Then, the reaction solution was stirred at 65-75 degrees Celsius for 3.5 hours, during which the suspension changed from pink to light yellow. After the reaction was completed, the reaction solution was cooled to room temperature, quenched with saturated ammonium chloride solution (10 ml), extracted with ethyl acetate (10 ml × 3), and the organic phase was washed with saturated brine (15 ml × 2), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was purified by thin layer chromatography (petroleum ether / ethyl acetate=10 / 1) to give Example 26B (30.0 mg, yield 69%). 1 H NMR(400MHz,CHLOROFORM-d)δ0.03-0.17(m,2H)0.20-0.30(m,2H)0.44-0.64(m,2H)0.68(s,3H)0.88(t,J=7.40Hz,3H)0.92-0.97(m,6H)1.15-1.24 (m,4H)1.28-1.55(m,11H)1.62-1.69(m,2H)1.71-1.87(m,4H)1.89-2.00 (m,2H)2.22-2.29(m,1H)2.32-2.39(m,1H)3.68(s,3H)3.69-3.73(m,1H).

[0551] Embodiment 80

[0552]

[0553] The operation was the same as that in Example 53. The starting material was compound 26B (30.0 mg, 67.5 μmol). The title compound 80 (20.0 mg, yield 65%) was obtained by purification by thin layer chromatography (petroleum ether / ethyl acetate=3 / 1). 1 H NMR(400MHz,CHLOROFORM-d)δ0.03-0.16(m,2H)0.18-0.28(m,2H)0.43-0.62(m,2H)0.67(s ,3H)0.84-0.89(m,3H)0.92-0.96(m,6H)1.12-1.23(m,4H)1.26-1.28(m,1H)1.28-1.38(m,4 H)1.38-1.45(m,3H)1.45-1.54(m,3H)1.60-1.68(m,2H)1.72-1.77(m,1H)1.79-1.85(m,2H )1.87-1.93(m,1H)1.93-1.99(m,1H)2.20-2.33(m,2H)2.36-2.45(m,1H)3.65-3.73(m,1H).

[0554] Route 27

[0555]

[0556] Embodiment 81

[0557]

[0558] Example 27A

[0559]

[0560] Under nitrogen protection, dry palladium / carbon (5.0 mg) was added to a methanol (4 ml) solution of compound 26A (33.0 mg, 69.8 μmol), and the atmosphere was replaced three times with a hydrogen balloon. The reaction solution was stirred at 20-28 degrees Celsius for 18 hours under 1 atmosphere of hydrogen. The reaction solution was then filtered and the solvent was evaporated under reduced pressure to give Example 27A (25.0 mg, yield 75%). 1HNMR(400MHz,CHLOROFORM-d)δ5.01-5.16(m,1H)3.68(s,3H)2.30-2.44(m,1H)2.17-2.29(m,1H)2.07(s,3H)1.92-2.05(m,2 H)1.68-1.89(m,5H)1.41-1.62(m,5H)1.30-1.41(m,5H)1.09-1.23(m,6H)0.97-1.05(m,2H)0.83-0.95(m,13H)0.66(s,3H).

[0561] Embodiment 81

[0562]

[0563] The operation was the same as that in Example 53, using compound 27A (50.0 mg, 105.3 μmol) as starting material. The crude product was purified by thin layer chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound 81 (30.0 mg, yield 68%). 1 H NMR(400MHz,CHLOROFORM-d)δ3.66-3.78(m,1H)2.36-2.47(m,1H)2.22-2.33(m,1H)1.91-2.00(m,2H)1.78-1.88(m,2H) 1.61-1.71(m,2H)1.43-1.55(m,6H)1.21-1.43(m,9H)1.20(br.s.,3H)0.98-1.07(m,2H)0.88-0.97(m,12H)0.68(s,3H).

[0564] Route 28

[0565]

[0566] Examples 82A and 82B

[0567]

[0568] Example 28A

[0569]

[0570] Borane tetrahydrofuran solution (1M, 58.0 micromol) was added to a tetrahydrofuran (1.5 ml) solution of Example 26A compound (25.0 mg, 58.0 micromol) and stirred at 25-30 degrees Celsius for 4 hours. After the reaction was completed, the reaction solution was cooled to 0 degrees Celsius, and water (0.1 ml), 5 molar sodium hydroxide aqueous solution (0.2 ml) and hydrogen peroxide (30% aqueous solution, 6.9 mmol) were added in sequence. Stir for 3 hours at 25-30 degrees Celsius. After the reaction was completed, the reaction solution was quenched with saturated sodium sulfite solution (2 ml), extracted with ethyl acetate (8 ml × 2), and the organic phase was washed with saturated brine (10 ml × 2), dried over anhydrous sodium sulfate, filtered, and dried under reduced pressure. The crude product was purified by thin layer chromatography (petroleum ether / ethyl acetate = 3 / 1) to give Example 28A1 compound (6.0 mg, yield 14%, purity 60%). 1 H NMR (400 MHz, CHLOROFORM-d) δ 3.70-3.75 (m, 1H), 3.68 (s, 3H), 3.57-3.67 (m, 2H), 2.32-2.42 (m, 1H), 2.19-2.29 (m, 1H), 1.76-2.03 (m, 6H), 1.54-1.69 (m, 6H), 1.33-1.50 (m, 10H), 1.13-1.23 (m, 4H), 0.88-0.97 (m, 9H), 0.68 (s, 3H). and Example 28A1 compound (9.0 mg, yield 28%, purity 80%). 1 H NMR(400MHz,CHLOROFORM-d)δ3.69-3.74(m,1H),3.66(s,3H),3.41-3.51(m,2H),2.29-2.40(m,1H),2.16-2.27(m,1H),1.84-1.97(m ,3H),1.67-1.82(m,3H),1.56-1.66(m,6H),1.39-1.51(m,8H),1.30(d,J=3.01Hz,2H),1.06-1.22(m,4H),0.91(s,9H),0.66(s,3H).

[0571] Examples 82A and 82B

[0572]

[0573] The operation was the same as that of Example 53. Compounds 28A1 (35.0 mg, 78.0 μmol) and 28A2 (25.0 mg, 55.7 μmol) were used as starting materials. The crude product was purified by thin layer chromatography (petroleum ether / ethyl acetate / acetic acid = 20 ml / 20 ml / 1 drop) to give Example 82A and Example 82B.

[0574] Example 82A compound (15.0 mg, yield 44%) 1 H NMR(400MHz,CHLOROFORM-d)δ3.68-3.74(m,1H),3.54-3.68(m,2H),2.30-2.44(m,1H),2.17-2.30 (m,1H),1.74-2.03(m,6H),1.28-1.70(m,15H),1.06-1.24(m,5H),0.81-0.98(m,9H),0.65(s,3H).

[0575] Example 82B compound (10.0 mg, 39% yield, 95% purity). 1 H NMR(400MHz,CHLOROFORM-d)δ3.66-3.77(m,1H),3.41-3.48(m,2H),2.33-2.44(m,1H),2.19-2.30(m,1H),1.80-1.94(m,3H),1.58-1.71 (m,3H),1.42-1.54(m,7H),1.29-1.41(m,5H),1.23-1.25(m,3H),1.12-1.21(m,3H),0.98-1.09(m,2H),0.87-0.94(m,9H),0.65(s,3H).

[0576] Route 29

[0577]

[0578] Embodiment 83

[0579]

[0580] At 0 degrees Celsius, sodium hydroxide (13.2 mg, 552.2 μmol) was added to a mixed solution of compound 11A (40.0 mg, 92.0 μmol) in N,N-dimethylformamide (1 ml) and tetrahydrofuran (2 ml) and stirred for 5 minutes. Then, iodomethane (270.0 mg, 1.9 mmol) was added to the reaction solution and stirred at 25-30 degrees Celsius for 18 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (10 ml × 2), the organic phase was washed with saturated brine (15 ml × 2), dried over anhydrous sodium sulfate, and filtered. The crude product of the filtrate was concentrated under reduced pressure and purified by thin layer chromatography (petroleum ether / ethyl acetate = 7 / 3) to obtain Example 83 (20 mg, yield 48%, purity 95%). 1H NMR(400MHz,CHLOROFORM-d)δ0.68(s,3H)0.89-1.00(m,10H)1.11-1.21(m,3H)1.31-1.70(m,12H)1. 71-2.02(m,9H)2.22-2.32(m,1H)2.37-2.48(m,1H)2.93-3.06(m,1H)3.36(s,3H)3.68-3.75(m,1H).

[0581] Route 30

[0582]

[0583] Embodiment 84

[0584]

[0585] Example 30A

[0586]

[0587] At -60 degrees Celsius and under nitrogen protection, n-butyl lithium (0.1 ml, 2.5 mol / L n-hexane solution) was added to a solution of methoxymethyl triphenylphosphonium chloride (151.7 mg, 442.4 micromol) in ether (5.0 ml), and the reaction solution was stirred at 25-30 degrees Celsius for half an hour, during which blood-red phosphine ylide was generated. Then, under ice bath, a solution of Example 24A compound (70.0 mg, 147.5 micromol) in tetrahydrofuran (2.0 ml) was added dropwise to the reaction solution, and stirred at 25-30 degrees Celsius for 3 hours. The reaction solution was quenched with saturated ammonium chloride solution and then extracted with ethyl acetate (10 ml x 2). The organic phase was washed with saturated brine (15 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by TLC preparative plate to give Example 30A (30.0 mg, yield 38%, purity 95%). 1 H NMR(400MHz,CHLOROFORM-d)δ0.55-0.72(m,3H)0.82-0.94(m,10H)1.03-1.20( m,5H)1.23-1.34(m,7H)1.44-1.54(m,2H)1.57-1.63(m,1H)1.69-1.88(m,7H)1. 90-1.99(m,2H)2.05(d,J=3.51Hz,3H)2.17-2.27(m,1H)2.31-2.38(m,1H)2.42 -2.59(m,1H)3.44-3.58(m,3H)3.58-3.75(m,3H)4.96-5.15(m,1H)5.74(s,1H).

[0588] Example 30B

[0589]

[0590] Concentrated hydrochloric acid (12M, 200.0 μL) was added dropwise to a solution of Example 30A compound (30.0 mg, 59.7 μmol) in dioxane (2.0 mL), and stirred at 25-30 degrees Celsius for 2 hours. After the reaction was completed, the reaction solution was extracted with ethyl acetate (10 mL × 2), the organic phase was washed with saturated brine (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin layer chromatography preparation plate (petroleum ether / ethyl acetate = 8 / 1) to obtain Example 30B compound (15.0 mg, 42% yield, purity 85%). 1 H NMR(400MHz,CHLOROFORM-d)δ0.64(s,3H)0.82-0.94(m,7H)0.94-1.03(m,3H)1. 04-1.17(m,5H)1.31-1.39(m,3H)1.40-1.52(m,3H)1.55-1.62(m,1H)1.68(br.s .,6H)1.74-1.89(m,4H)1.92-1.99(m,2H)2.04(s,6H)2.15-2.25(m,1H)2.28-2. 38(m,1H)3.66(d,J=2.01Hz,1H)3.70(s,1H)5.04-5.13(m,1H)9.62-9.65(m,1H).

[0591] Example 30C

[0592]

[0593] Diethylaminosulfur trifluoride (82.5 mg, 511.6 μmol) was added dropwise to a solution of Example 30B compound (50.0 mg, 102.3 μmol) in dichloromethane (2.0 ml), and stirred at 25-30 degrees Celsius for 36 hours. After the reaction was completed, the reaction solution was quenched with ice water, extracted with ethyl acetate (10 ml × 3), and the organic phase was washed with saturated brine (15 ml × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by thin layer chromatography preparation plate (petroleum ether / ethyl acetate = 8 / 1) to obtain Example 30C compound (40.0 mg, yield 69%, purity 90%). 1H NMR(400MHz,CHLOROFORM-d)δ0.66(s,3H)0.87-1.00(m,9H)1.02-1.21(m,6H)1.28(br.s.,6H)1.42-1.55(m,4H)1.55-1.72(m,5H)1.7 5-1.87(m,3H)1.91-2.02(m,2H)2.04-2.09(m,3H)2.17-2.29(m,1H)2.31-2.42(m,1H)3.68(s,3H)5.06-5.17(m,1H)5.40-5.75(m,1H).

[0594] Embodiment 84

[0595]

[0596] Using compound 30C (40.0 mg, 78.33 μmol) as starting material, the operation was the same as that of Example 53. The crude product obtained after the reaction was separated and purified by TLC preparation plate (petroleum ether / ethyl acetate = 3 / 1) to obtain Example 84 (25.0 mg, yield 67%, purity 95%) as a white solid. 1 H NMR(400MHz,CHLOROFORM-d)δ0.66(s,3H)0.85-0.95(m,9H)0.95-1.04(m,1H)1.07-1.22(m,4H)1.24-1.25(m,1 H)1.27-1.54(m,10H)1.54-2.00(m,10H)2.18-2.31(m,1H)2.33-2.45(m,1H)3.71(br.s.,1H)5.32-6.09(m,1H).

[0597] Route 31

[0598]

[0599] Embodiment 85

[0600]

[0601] Example 31A

[0602]

[0603] Compound 19B (20.0 mg, 44.7 mmol) was dissolved in dichloromethane (3.0 ml), and N,N-dimethyl-4-aminopyridine (1.1 mg, 9.0 mmol) and a dichloromethane solution (1 ml) of phenylsulfonyl chloride (11.8 mg, 67.0 mmol) were added in sequence, and stirred at 20 degrees Celsius for 12 hours. The solvent was removed by concentration, and the resulting residue was separated by thin layer chromatography to give Example 31A (12.0 mg, yield 48%, nearly colorless liquid). 1 H NMR(400MHz,CHLOROFORM-d)δ8.13(s,1H),7.87(d,J=7.5Hz,2H),7.62-7.48(m,3H),5.17(br.s.,1H),3.52-3.47(m,2H),3.0 8-2.99(m,1H),2.97-2.88(m,1H),1.94-1.67(m,8H),1.51-1.24(m,10H),1.20-0.99(m,9H),0.93-0.81(m,9H),0.60(s,3H).

[0604] Embodiment 85

[0605]

[0606] By referring to the same operating procedures as Example 53, compound 31A was used as the starting material (42.0 mg, 75.0 mmol) and purified to give Example 85 (15.0 mg, yield 37.59%). 1 H NMR(400MHz,CHLOROFORM-d)δ7.87(d,J=7.3Hz,2H),7.62-7.56(m,1H),7.56 -7.50(m,2H),4.31(t,J=5.9Hz,1H),3.48-3.32(m,1H),3.10-2.86(m,2H),1. 92(d,J=12.0Hz,1H),1.86-1.71(m,5H),1.69-1.52(m,7H),1.50-1.25(m,11 H),1.20-1.06(m,5H),0.89(s,4H),0.85(d,J=6.5Hz,3H),0.66-0.55(m,3H).

[0607] The preparation of Example 86 and Example 87 was carried out by referring to the procedure of Example 85 and prepared by route 31. The results obtained are as follows:

[0608]

[0609] Route 32

[0610]

[0611] Embodiment 88

[0612]

[0613] Potassium carbonate (27.8 mg, 27.8 μmol) and dimethyl sulfate (25.3 mg, 25.3 μmol) were added to a solution of Example 2 compound (40.0 mg, 80.4 μmol) in acetone (1.0 ml) at 20 degrees Celsius. The mixture was stirred for 12 hours. The reaction was complete as determined by thin layer chromatography (petroleum ether / ethyl acetate = 1 / 2). The solvent was evaporated under reduced pressure, and the compound of Example 88 (23.0 mg, yield 13%, white solid) was separated and purified using a thin layer preparation plate (petroleum ether / ethyl acetate = 1 / 2). 1 HNMR(400MHz,METHANOL-d4)δ3.68(br.s.,1H),3.29(s,6H),2.81-2.53(m, 2H),2.02-1.29(m,20H),1.23-0.98(m,7H),0.96-0.87(m,6H),0.73(s,3H).

[0614] Route 33

[0615]

[0616] Embodiment 89

[0617]

[0618] Example 33A

[0619]

[0620] To a pyridine solution (20 ml) of the compound of Example 11A (5.0 g, 11.5 mmol) were added acetic anhydride (7.1 g, 69.1 mmol) and N,N-dimethylaminopyridine (140.5 mg, 1.2 mmol), and the reaction mixture was stirred at 80 degrees Celsius for 12 hours. The solvent was dried, the system was washed with saturated sodium bicarbonate aqueous solution (10 ml), the reaction system was extracted with ethyl acetate (15 ml x 3), the combined organic layer was dried over sodium sulfate, filtered and evaporated to give the compound of Example 33A (5.0 g, 84% yield). 1H-NMR(CDCl3,400MHz)δ5.10(br.s.,1H),4.43(d,J=5.0Hz,1H),3.67(s,3H),2.40-2.18(m,2H),2.08(s,3H),2.05( s,3H),1.90-1.67(m,9H),1.52-1.29(m,10H),1.17-0.99(m,6H),0.94-0.91(m,6H),0.91-0.87(m,3H),0.65(s,3H).

[0621] Example 33B

[0622]

[0623] To a methanol solution of the compound of Example 33A (100.0 mg, 193.0 μmol) was added hydrochloric acid (12 M, 0.2 ml) and the mixture was stirred at 20 degrees Celsius for 12 hours. The solvent was dried, the system was washed with saturated aqueous sodium bicarbonate solution (10 ml), the reaction system was extracted with ethyl acetate (15 ml x 3), the combined organic layer was dried over sodium sulfate, filtered and evaporated to give the compound of Example 33B (90.0 mg, 98% yield). 1 H-NMR(CDCl3,400MHz)δ5.10(br.s.,1H),3.67(s,3H),3.47(d,J=5.0Hz,1H),2.40-2.18(m,2H),2.08(s,3H), 1.90-1.67(m,9H),1.52-1.29(m,10H),1.17-0.99(m,6H),0.94-0.91(m,6H),0.91-0.87(m,3H),0.65(s,3H).

[0624] Example 33C

[0625]

[0626] To a toluene (8 ml) and acetonitrile solution (2 ml) of the compound of Example 33B (100.0 mg, 209.0 μmol), triphenylphosphine (304.0 mg, 1.2 μmol) and imidazole (83.0 mg, 1.2 μmol) was added iodine (266.0 mg, 1.1 mmol). The mixture was reacted at 20 degrees Celsius for 1 hour, saturated sodium sulfite solution (10 ml) was added to the reaction system, the aqueous layer was extracted with ethyl acetate (10 ml x 3), the organic layers were combined, dried over sodium sulfate, filtered and evaporated, and the residue was purified by preparative thin layer plate (petroleum ether / ethyl acetate = 10 / 1) to give the compound of Example 33C (100.0 mg, 81%). 1H-NMR(CDCl3,400MHz)δ5.07(br.s.,1H),5.01(br.s.,1H),3.71-3.60(m, 3H),2.39-2.29(m,1H),2.27-2.15(m,1H),2.04(s,3H),2.00-1.93(m,1H) ,1.88-1.74(m,6H),1.73-1.58(m,5H),1.55-1.38(m,4H),1.36-1.20(m,5 H),1.17-1.06(m,4H),1.03(s,3H),0.93-0.87(m,6H),0.68-0.61(m,3H).

[0627] Example 33D

[0628]

[0629] Potassium carbonate (1.0 g, 7.8 mmol) was added to Example 33C compound (2.3 g, 3.9 mmol) and pyrazole (534.0 mg, 7.8 mmol) in DMF (30 ml). The mixture was reacted at 60 degrees Celsius for 12 hours, water (50 ml) was added to the reaction system, the aqueous layer was extracted with ethyl acetate (30 ml x 3), the organic layers were combined, dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 20 / 1) to give Example 33D compound (1.4 g, 78%). 1 H NMR(CDCl3,400MHz)δ5.70-5.44(m,2H),5.13(br.s.,1H),3.66(s,3H),2.57-2.47(m,1H),2.41-2.30(m,1H),2.25-2.16( m,2H),2.06(s,3H),1.96-1.64(m,9H),1.52-1.30(m,6H),1.25-1.05(m,6H),0.99(s,3H),0.93-0.88(m,6H),0.65(s,3H).

[0630] Example 33E

[0631]

[0632] Under nitrogen protection, diethylzinc (1M, 3.3 ml) was added dropwise to a dichloromethane solution of diiodomethane (438.0 mg, 1.6 mmol) at zero degrees. After 30 minutes, a dichloromethane (2 ml) solution of Example 33D compound (150.0 mg, 327.0 μmol) was added dropwise at zero degrees, and the mixture was reacted at 20 degrees Celsius for 12 hours. Water (5 ml) was added to the reaction system, and the system was adjusted to Ph=6 with hydrochloric acid solution (1 M). The aqueous layer was extracted with dichloromethane (10 ml×3), and the organic layers were combined, dried over sodium sulfate, filtered and evaporated to give Example 33E compound (110.0 mg, 71%). 1 H NMR(CDCl3,400MHz)δ5.15-5.09(m,1H),3.68(s,3H),2.41-2.20(m,4H),2.13-2.08(m,3H),1.99(d,J=12.0Hz,1H),1.90-1.70(m,5H), 1.44-1.02(m,15H),0.95-0.87(m,6H),0.84(s,3H),0.82(d,J=5.0Hz,1H),0.79-0.68(m,2H),0.67(s,3H),0.63(dd,J=4.0,8.8Hz,1H).

[0633] Embodiment 89

[0634]

[0635] To an ethanol solution (1 ml) of the compound of Example 33E (40.0 mg, 84.3 μmol) was added a 10% aqueous solution of potassium hydroxide (1 ml), and the mixture was reacted at 70 degrees Celsius for 12 hours. The system was adjusted to Ph = 2 with a hydrochloric acid solution (1 M), the aqueous layer was extracted with ethyl acetate (10 ml x 3), the organic layers were combined, dried over sodium sulfate, filtered and evaporated. The residue was purified by preparative thin layer plate (petroleum ether / ethyl acetate = 2 / 1) to give the compound of Example 89 (10.0 mg, 28.36%). 1 H NMR (CDCl3, 400MHz) δ3.81-3.70 (m, 1H), 2.58-2.43 (m, 1H), 2.39 (dd, J = 5.1 ,10.2Hz,1H),2.31-2.19(m,2H),1.98-1.76(m,5H),1.72-1.55(m,6H),1.46 (dd,J=5.5,10.5Hz,4H),1.23-1.02(m,6H),0.95-0.88(m,6H),0.82-0.78( m,3H),0.76-0.68(m,2H),0.68(s,3H),0.64(br.s.,1H),0.63-0.52(m,1H).

[0636] Route 34

[0637]

[0638] Example 34A

[0639]

[0640] To a dry 25 ml round-bottom flask, dry palladium carbon (50 mg, water <1%) and Example 33D compound (600.0 mg, 720.1 μmol) were added, followed by anhydrous methanol (5.0 ml) and tetrahydrofuran (5.0 ml). The reaction system was purged with nitrogen three times, and then purged with hydrogen three times. The reaction solution was stirred at 25 degrees Celsius in a hydrogen atmosphere (15 psi) for 48 hours. The reaction solution was filtered through diatomaceous earth, washed with dichloromethane / methanol (10 / 1, 20 ml), and the filtrate was concentrated to give Example 34A compound (550.0 mg, 91% yield). 1 H NMR(400MHz,CHLOROFORM-d)δ5.13(br.s.,1H),3.68(s,3H),2.43-2.18(m,3H),2.06(s,3H),2.01-1.63( m,14H),1.55-1.15(m,25H),0.95(d,J=6.5Hz,6H),0.91(s,6H),0.88(d,J=2.3Hz,2H),0.70-0.66(m,3H).

[0641] Example 34B

[0642]

[0643] Using Example 35A (550.0 mg, 1.3 mmol) as starting material, the synthetic operation was the same as Example 53 to obtain Example 34B (400.0 mg, 75.3% yield). 1H NMR(400MHz,CHLOROFORM-d)δ3.72(br.s.,1H),2.48-2.35(m,1H),2.28(ddd, J=6.4,9.5,15.7Hz,1H),2.02-1.87(m,3H),1.81(d,J=13.3Hz,3H),1.77-1.6 0(m,5H),1.55-1.41(m,7H),1.39-1.26(m,7H),1.20-1.13(m,3H),1.08-1.02 (m,1H),0.98-0.95(m,4H),0.92(s,3H),0.90-0.85(m,2H),0.70-0.67(m,3H).

[0644] Embodiment 90

[0645]

[0646] The same operation as in Example 2A was performed with Example 34B (100.0 mg, 247.2 μmol) as the starting material for acylation reaction and purification to obtain Example 90 (20.0 mg, 16.8% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ 3.72 (br.s., 1H), 3.32 (s, 3H), 2.46-2.34 (m, 1H), 2.30-2.18 (m, 1H), 1.99-1.86 (m, 3H), 1.85-1.77 (m, 3H), 1.74-1.62 (m, 4H), 1.56-1. 40(m,8H),1.38-1.26(m,7H),1.22-1.16(m,3H),1.10-1.02(m,1H),0.97-0.93(m, 4H),0.91(s,3H),0.90(d,J=2.0Hz,1H),0.88(d,J=3.0Hz,1H),0.71-0.66(m,3H).

[0647] Route 35

[0648]

[0649] Embodiment 91

[0650]

[0651] Example 35A

[0652]

[0653] Sodium hydroxide (79.6 mg, 2.0 mmol) was added to a solution of Example 13A compound (1.2 g, 2.0 mmol) in methanol (15.0 ml) and water (1.5 ml), and stirred at 25-30 degrees Celsius for 18 hours. After the reaction was completed, the solvent was concentrated to 5 ml, diluted with ethyl acetate to 12 ml, and acidified to pH = 5-6 with 2M dilute hydrochloric acid and citric acid. After separation, the organic phase was washed with saturated brine (25 ml × 3), extracted with ethyl acetate (20 ml × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to give Example 35A compound (1.1 g, purity 90%). 1H NMR(400MHz,CHLOROFORM-d)δ0.63(s,3H)0.81-0.97(m,10H)0.98-1.23(m,4H)1.28-1.49(m,9H)1.57-1.76(m,6H)1.76-1.98(m,9H)2.04(s, 2H)2.09(s,2H)2.17-2.31(m,1H)2.34-2.47(m,1H)3.34-3.52(m,3H)3 .54-3.64(m,1H)3.87-4.05(m,2H)4.44-4.58(m,1H)4.66-4.79(m,1H)

[0654] Example 35B

[0655]

[0656] Dicyclohexylcarbodiimide (1.3 g, 6.4 mmol) was added to a solution of Example 35A compound (1.4 g, 2.1 mmol) and N-hydroxysuccinimide (734.0 mg, 6.4 mmol) in tetrahydrofuran (15.0 ml) and acetonitrile (1.5 ml) and stirred at 20-28 degrees Celsius for 18 hours. After the reaction was completed, the mixture was filtered and the filtrate was vacuum dried. The resulting crude product was dissolved in 12 ml of N, N-dimethylformamide, and ammonia (910.0 mg, 7.3 mmol) was added thereto. The reaction solution was stirred at 50-60 degrees Celsius for 20 minutes. After the reaction was completed, the reaction solution was cooled to room temperature and washed with saturated brine (35 ml × 2), extracted with ethyl acetate (20 ml × 2), and the organic phase was dried over anhydrous sodium sulfate. After filtration, low pressure was dried to obtain Example 35B compound (1.8 g, yield 94.8%, purity 67%). 1 H NMR(400MHz,CHLOROFORM-d)δ4.74(dd,J=3.8,7.8Hz,1H),4.52(dd,J=3.6,7.9Hz,1H),4.04-3.86(m,2H),3.70-3.58(m,1H),3. 54-3.37(m,3H),3.26-3.16(m,2H),2.36-2.08(m,3H),2.02-1.73(m,19H),1.70-1.03(m,42H),0.99-0.80(m,10H),0.65(s,3H)

[0657] Example 35C

[0658]

[0659] The compound of Example 35B (2.0 g, 3.4 mmol) was dissolved in tetrahydrofuran (20.0 ml). At 0 degrees Celsius, lithium aluminum tetrahydride (1.0 g, 27.2 mmol) was added in portions. The reaction solution was stirred at 70 degrees Celsius for 12 hours. After cooling to 0 degrees Celsius, water (2 ml) was added dropwise to the reaction solution, and the mixture was extracted with dichloromethane / methanol (10 / 1, 30 ml×3). The organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on a silica gel column (pre-washed with triethylamine (1 ml) in petroleum ether / ethyl acetate (10:1, 10 ml)) to give the compound of Example 35C (1.3 g, 69.1% yield). 1 HNMR(400MHz,CHLOROFORM-d)δ4.76-4.68(m,1H),4.52(td,J=4.3,8.0Hz,1H),4.00-3. 87(m,2H),3.60(d,J=10.3Hz,1H),3.51-3.36(m,3H),2.73-2.56(m,2H),1.99-1.91(m,2 H),1.83(d,J=10.5Hz,4H),1.71-1.67(m,4H),1.52(d,J=3.5Hz,6H),1.39-1.29(m,5H) ,1.14-1.00(m,4H),0.93-0.91(m,2H),0.89(s,3H),0.86(d,J=5.8Hz,2H),0.63(s,3H).

[0660] Example 35D

[0661]

[0662] The compound of Example 35C (200.0 mg, 348.5 μmol) was dissolved in dichloromethane (4.0 ml), triethylamine (70.5 mg, 697.0 μmol) and phenylsulfonyl chloride (123.1 mg, 697.0 μmol) were added in sequence, and the reaction solution was stirred at 20 degrees Celsius for 12 hours. The solvent was removed by concentration, and the residue was separated by thin layer chromatography to obtain the compound of Example 35D (180.0 mg, 72.3% yield). 1H NMR(400MHz,CHLOROFORM-d)δ7.89(d,J=7.3Hz,2H),7.62-7.52(m,3H),4.75(d,J=3.3 Hz,1H),4.53(d,J=3.5Hz,1H),4.34(d,J=4.3Hz,1H),3.95(br.s.,2H),3.66-3.58(m,1 H),3.48(br.s.,3H),3.06-2.88(m,2H),1.91-1.84(m,3H),1.73(br.s.,3H),1.55(br. s.,7H),1.41-1.24(m,8H),1.17-0.98(m,6H),0.91(br.s.,3H),0.61(d,J=2.3Hz,3H).

[0663] Embodiment 91

[0664]

[0665] The compound of Example 35D (140.0 mg, 196.06 μmol) was dissolved in methanol (5.0 ml), and p-toluenesulfonic acid monohydrate (37.3 mg, 196.0 μmol) was added. The reaction solution was stirred at 20 degrees Celsius for 12 hours. The solvent was removed by concentration, and the residue was separated by thin layer chromatography to give the compound of Example 91 (92.0 mg, 85.9% yield). H NMR (400 MHz, CHLOROFORM-d) δ7.89 (d, J = 7.3 Hz, 2H), 7.62-7.56 (m, 1H), 7.56-7.49 (m, 2H), 4.95 (d, J = 5.5 Hz, 1H), 3.70 (br. s., 1H), 3.47-3.34 (m, 1H), 3.01-2.81 (m, 2H), 1.93 (d, J = 12.0Hz,1H),1.84-1.74(m,4H),1.68-1.57(m,3H),1.52-1.28(m,14H),1.20-1.06(m,5H), 1.04-0.96(m,2H),0.92(br.s.,2H),0.89(br.s.,3H),0.85(d,J=6.5Hz,4H),0.62(s,3H).

[0666] The preparation of Example 92 and Example 93 was prepared by referring to the operation of Example 91 and prepared by Route 35. The results obtained are as follows:

[0667]

[0668] Route 36

[0669]

[0670] Embodiment 94

[0671]

[0672] Example 36A

[0673]

[0674] Trimethylsilyl isocyanate (361.3 mg, 3.1 mmol, 415.35 μL) was added to a solution of Example 35C (1.5 g, 2.61 mmol) in dichloromethane (10.0 mL). The reaction solution was stirred at 25 degrees Celsius for 12 hours. TLC (dichloromethane / methanol = 10 / 1) showed that the reaction was complete. 5 mL of water was added to the reaction solution, and extracted with dichloromethane (5 mL × 3), and the combined organic layers were washed with 10 mL of brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated to give Example 36A (1.4 g, yield 86.9%). 1 H NMR (400MHz, CHLOROFORM-d) δ4.77-4.69(m,1H),4.60-4.47(m,2H),4.39(br.s.,2H),4.00-3.87(m,2H),3.60(d,J=10. 3Hz,1H),3.52-3.38(m,3H),3.20-3.01(m,2H),2.10-1.75(m,9H),1.63-0.98(m,29H),0.96-0.82(m,11H),0.62(s,3H)

[0675] Embodiment 94

[0676]

[0677] Referring to the operating procedures of Example 65, Example 94 (692.0 mg, yield 67.8%) was obtained by purification using Example 36A as the starting material. 1 H NMR(400MHz,CHLOROFORM-d)δ4.66(br.s.,1H),4.44(br.s.,1H),3.72(br.s.,1H),3.49-3.36(m,1H),3 .14(dt,J=6.3,13.2Hz,2H),1.99(d,J=12.0Hz,1H),1.94-0.98(m,33H),0.97-0.87(m,9H),0.67(s,3H)

[0678] Route 37

[0679]

[0680] Embodiment 95

[0681]

[0682] Example 37A

[0683]

[0684] The compound of Example 35C (200.0 mg, 357.2 μmol) was dissolved in dichloromethane (2 ml), and triethylamine (72.3 mg, 714.5 μmol, 99.0 μl) was added. At 0 degrees Celsius, ethyl monochlorooxalyl (97.6 mg, 714.5 μmol, 79.9 μl) was added and dissolved in dichloromethane (1 ml). The reaction solution was stirred at 30 degrees Celsius for twelve hours. The solvent was concentrated to remove the solvent, and water (5 ml) was added to the residue, and extracted with ethyl acetate (10 ml x 3). The organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by thin layer chromatography to obtain the compound of Example 37A (130.0 mg, 54.0% yield). 1 H NMR(400MHz,CHLOROFORM-d)δ7.11(d,J=4.8Hz,1H),4.77-4.64(m,1H),4.53-4.41(m,1H),4.37-4.2 5(m,4H),3.99-3.87(m,1H),3.63-3.54(m,1H),3.44(dd,J=5.5,10.8Hz,1H),3.36-3.20(m,2H),2.33 -2.19(m,1H),1.98-1.90(m,2H),1.86-1.73(m,5H),1.60(d,J=8.0Hz,3H),1.51(d,J=3.0Hz,3H),1. 38(s,4H),1.25(d,J=7.0Hz,3H),1.13-1.05(m,3H),0.92(s,3H),0.86(d,J=5.3Hz,2H),0.62(s,3H).

[0685] Embodiment 95

[0686]

[0687] The operation was the same as that of Example 53 and Example 65 compounds. Example 37A (150.0 mg, 222.6 μmol) was used for two-step synthesis and purification to obtain Example 95 compound (6.0 mg, 9.1% yield). 1H NMR(400MHz,METHANOL-d4)δ3.67(br.s.,1H),3.34-3.34(m,1H),2.95-2.87(m,2H),2.03(d,J=12.0Hz,1H),1.93-1.73(m ,6H),1.63-1.48(m,9H),1.39(br.s.,4H),1.26-1.14(m,4H),1.02(d,J=6.3Hz,3H),0.95-0.89(m,8H),0.74-0.68(m,3H).

[0688] Route 38

[0689]

[0690] Example 38A

[0691]

[0692] Add dichloromethane (10 ml), sodium bicarbonate aqueous solution (292.8 mg, 3.5 mmol), dissolved in water (5.0 ml) and Example 35C compound (100.0 mg, 174.2 μmol) to a 100 ml three-necked flask, add triphosgene (103.4 mg, 348.5 μmol) at 0 degrees Celsius in one portion, and stir the reaction solution at 0 degrees Celsius for one hour. Pour the reaction solution into a separatory funnel, separate the organic layer, and extract the aqueous phase with dichloromethane (20 ml x 2). Wash the organic layer with water (10 ml), dry it over anhydrous sodium sulfate, filter and concentrate to obtain Intermediate A. At 0°C, (3S)-hydroxypyrrole (43.1 mg, 348.5 μmol) and triethylamine (35.2 mg, 348.5 μmol) were added to a dichloromethane solution (5 ml) of Intermediate A. After two hours, the ice bath was removed and the reaction solution was stirred at 30°C for two hours. The solvent was removed by concentration and the residue was separated by thin layer chromatography to give Example 38A (76.0 mg, 63.5% yield). 1H NMR(400MHz,CHLOROFORM-d)δ4.76-4.68(m,1H),4.54-4.46(m,2H),4.24-4.12(m,1H),4.00-3 .87(m,2H),3.62-3.56(m,1H),3.52-3.37(m,7H),3.23(br.s.,1H),3.15(br.s.,1H),2.06-1.9 3(m,4H),1.83(d,J=11.0Hz,4H),1.73-1.66(m,4H),1.48(br.s.,2H),1.44-1.36(m,5H),1.29- 1.23(m,3H),1.13-1.03(m,3H),0.92(br.s.,2H),0.89(s,3H),0.88-0.85(m,3H),0.62(s,3H).

[0693] Embodiment 96

[0694]

[0695] Using Example 38A (76.0 mg, 110.6 μmol) as starting material and referring to the operating steps of Example 65, Example 96 (40.0 mg, 69.7% yield) was obtained by TLC separation. 1 H NMR(400MHz,METHANOL-d4)δ4.43-4.38(m,1H),3.67(br.s.,1H),3.49-3.41(m,3H),3.34-3.33(m,1H),3.30 (br.s.,1H),3.20-3.06(m,2H),2.02(qd,J=4.3,13.1Hz,2H),1.95-1.90(m,2H),1.86(br.s.,1H),1.80-1.7 2(m,3H),1.69-1.63(m,2H),1.59-1.53(m,4H),1.46-1.41(m,3H),1.37(d,J=2.0Hz,2H),1.31-1.31(m,3H), 1.21-1.17(m,3H),1.11-1.07(m,2H),0.99(s,3H),0.92(s,3H),0.90(br.s.,3H),0.88(s,3H),0.71(s,3H).

[0696] Route 39

[0697]

[0698] Embodiment 97

[0699]

[0700] Example 39A

[0701]

[0702] Example 35C (1.3 g, 2.3 mmol) was dissolved in tetrahydrofuran (12 ml), triethylamine (458.4 mg, 4.5 mmol) was added, and chloroethyl isocyanate (478.1 mg, 4.5 mmol) was added dropwise, dissolved in tetrahydrofuran (3 ml), and the reaction solution was stirred at 30 degrees Celsius for 12 hours. Water (5 ml) was added, and ethyl acetate was extracted (10 ml x 3). The organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated by thin layer chromatography to obtain Example 39A (1.2 g, 77.8% yield). 1 H NMR(400MHz,CHLOROFORM-d)δ5.03(br.s.,1H),4.79(br.s.,1H),4.72(d,J=4.3Hz,1H),4.51( dd,J=3.8,13.3Hz,1H),4.42(br.s.,1H),3.93(d,J=5.8Hz,2H),3.63(s,2H),3.58-3.53(m,4H) ,3.47(d,J=3.0Hz,2H),3.19-3.03(m,2H),1.83(d,J=10.3Hz,4H),1.52(br.s.,7H),1.44-1.36 (m,5H),1.30-1.23(m,5H),1.10-1.03(m,2H),0.92(d,J=4.0Hz,2H),0.89(s,3H),0.71(s,3H).

[0703] Example 39B

[0704]

[0705] Sodium hydroxide (63.6 mg, 2.6 mmol) (65% in mineral oil) was suspended in tetrahydrofuran (25 ml), and Example 39A (600.0 mg, 883.1 μmol) dissolved in tetrahydrofuran (5 ml) was added dropwise at 0°C under nitrogen protection. The ice bath was removed after one hour, and stirring was continued at 30°C for eleven hours. Water (5 ml) was added, acidified with monomolar hydrochloric acid (pH=5-6), and extracted with ethyl acetate (20 ml×3). The organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was separated by thin layer chromatography to give Example 39B (360.0 mg, 63.4% yield). 1HNMR(400MHz,CHLOROFORM-d)δ8.95(s,1H),4.72(d,J=4.3Hz,1H),4.51(dd,J=3.8,7.8Hz,1 H),3.99-3.89(m,2H),3.83-3.77(m,1H),3.67-3.56(m,2H),3.53-3.39(m,4H),3.28(t,J=7. 0Hz,1H),1.83(d,J=11.5Hz,4H),1.69(d,J=10.5Hz,5H),1.52(br.s.,6H),1.52-1.51(m,2H) ,1.42-1.36(m,4H),1.14-1.03(m,5H),0.89(br.s.,3H),0.87(d,J=3.3Hz,4H),0.63(s,3H).

[0706] Embodiment 97

[0707]

[0708] Using the compound of Example 39B (360.0 mg, 559.9 μmol) as the starting material, the synthetic operation was the same as that of Example 65, and the compound of Example 97 (200.0 mg, 75.2% yield) was obtained by purification. 1 H NMR(400MHz,METHANOL-d4)δ4.62(br.s.,1H),3.67(br.s.,1H),3.51-3.44(m,2 H),3.43-3.37(m,2H),3.32-3.29(m,1H),3.13(t,J=7.0Hz,2H),2.03(d,J=12.3H z,1H),1.97-1.72(m,6H),1.68-1.42(m,11H),1.32(d,J=12.3Hz,6H),1.23-1.0 7(m,4H),0.99(d,J=6.5Hz,3H),0.93(s,3H),0.90(d,J=3.3Hz,2H),0.72(s,3H).

[0709] Route 40

[0710]

[0711] Embodiment 98

[0712]

[0713] Example 40A

[0714]

[0715] The compound of Example 19B (100.0 mg, 223.4 μmol) was dissolved in dichloromethane (2.0 ml), and triethylamine (33.9 mg, 335.1 μmol) was added at 0°C, followed by ethyl chlorooxalate (61.0 mg, 446.7 μmol), and the reaction solution was stirred at 20°C for 16 hours. The solvent was removed by concentration, and the residue was separated by thin layer chromatography to give the compound of Example 40A (50.0 mg, 91.29 μmol, 40.7% yield). 1 H NMR(400MHz,CHLOROFORM-d)δ8.17(s,1H),8.09-8.04(m,1H),7.04(br.s.,1H),5.21(br.s.,1H) ,4.78-4.65(m,1H),4.37(q,J=7.2Hz,2H),3.52-3.36(m,1H),3.35-3.23(m,1H),2.05-1.87(m,3 H),1.83-1.71(m,4H),1.59(s,3H),1.54-1.47(m,3H),1.41(t,J=7.2Hz,4H),1.34-1.27(m,4H), 1.23-1.12(m,5H),1.00(d,J=6.5Hz,3H),0.98(s,3H),0.92(t,J=7.3Hz,3H),0.71-0.64(m,3H).

[0716] Embodiment 98

[0717]

[0718] The compound of Example 40A (50.0 mg, 91.2 μmol) was dissolved in tetrahydrofuran (1.0 ml), methanol (1.0 ml) and water (1.0 ml), and lithium hydroxide monohydrate (76.6 mg, 1.8 mmol) was added, and the reaction solution was stirred at 25 degrees Celsius for twelve hours. The reaction solution was extracted with dichloromethane / methanol (10 / 1, 10 ml×3), and the organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate and concentrated to give the compound of Example 98 (38.0 mg, 89.7% yield). 1H NMR(400MHz,CHLOROFORM-d)δ7.32(br.s.,1H),3.71(br.s.,1H),3.42(d,J=3 .8Hz,2H),3.37-3.23(m,1H),1.96(d,J=11.8Hz,1H),1.92-1.76(m,5H),1.73 -1.56(m,5H),1.54-1.38(m,6H),1.37-1.25(m,7H),1.24-1.12(m,4H),0.99( d,J=6.5Hz,4H),0.92(br.s.,1H),0.90(s,3H),0.88(br.s.,1H),0.66(s,3H).

[0719] The preparation of Example 99 was prepared by referring to the procedure of Example 98 via route 40. The results obtained are as follows:

[0720]

[0721] Route 41

[0722]

[0723] Embodiment 100

[0724]

[0725] Example 41A

[0726]

[0727] To a solution of Example 2A compound (500.0 mg, 1 mmol) in tetrahydrofuran (5 ml) were added triethylamine (153.0 mg, 1.5 mmol) and ethyl chloroformate (167.0 mg, 1.5 mmol), and the reaction system was reacted at 25 degrees Celsius for 2 hours. The system was cooled to degrees Celsius, and a solution of sodium borohydride (210.0 mg, 5.5 mmol) in methanol (5 ml) was slowly added to the reaction system, and the reaction was carried out at 0 degrees Celsius for 15 minutes and at 25 degrees Celsius for 15 minutes. The reaction was quenched with 0.2M dilute hydrochloric acid, and the aqueous layer was extracted with ethyl acetate (10 ml×3). The organic layers were combined, dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate=4 / 1, dichloromethane / ethyl acetate=1 / 1) to give Example 41A compound (600.0 mg, crude product). 1 H NMR(400MHz,CHLOROFORM-d)δ8.15(s,1H),8.04(s,1H),5.19(br.s.,1H),4.77-4.66(m,1H) ,3.66-3.57(m,2H),2.06-1.77(m,7H),1.45-1.06(m,21H),0.97-0.88(m,9H),0.66(s,3H).

[0728] Example 41B

[0729]

[0730] To a solution of Example 41A compound (280.0 mg, 605.0 μmol), triphenylphosphine (476.0 mg, 1.8 mmol) and imidazole (124.0 mg, 1.8 mmol) in toluene (4 ml) and acetonitrile (1 ml) was added iodine (461.0 mg, 1.8 mmol) at zero degree, and the reaction system was reacted at 25° C. for 3 hours. Saturated sodium sulfite solution (10 ml) was added to the reaction system, the aqueous layer was extracted with ethyl acetate (10 ml×3), the organic layers were combined, dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate=20 / 1) to give the title compound 41B compound (250.0 mg, 70%). 1 H-NMR(CDCl3,400MHz)δ8.16(s,1H),8.07-8.02(m,1H),5.20(br.s.,1H),4.76-4.66(m,1H) ,3.24-3.08(m,2H),2.01-1.72(m,10H),1.46-1.06(m,17H),0.97-0.89(m,9H),0.66(s,3H).

[0731] Example 41C

[0732]

[0733] Sodium cyanide (171.0 mg, 3.5 mmol) was added to a solution of Example 41B compound (400.0 mg, 699 μmol) in N,N-dimethylformamide (5 ml), and the reaction system was reacted at 100 degrees Celsius for 2 hours. Water (10 ml) was added to the reaction system, and the aqueous layer was extracted with ethyl acetate (10 ml x 3), and the organic layers were combined, dried over sodium sulfate, filtered and evaporated to give the title compound 41C compound (225.0 mg, 68%). 1 H NMR (400 MHz, CHLOROFORM-d) δ8.15 (d, J = 3.0 Hz, 1H), 8.04 (s, 1H), 5.19 (br. s., 1H), 4.77-4.66 (m, 1H), 3.46 (d, J = 4.5 Hz, 1H), 2.37-2.25 (m, 2H), 2.01-1.66 (m, 10H), 1.39-1.03 (m, 12H), 0.98-0.87 (m, 9H), 0.66 (d, J = 1.5 Hz, 3H) and the product of deformylation at the 3-position (75 mg, 24%), 1 H NMR(400MHz,CHLOROFORM-d)δ=8.14(s,1H),5.19(br.s.,1H),3.46(br.s.,1H),2.30(dt,J =3.8,6.9Hz,2H),2.02-1.66(m,11H),1.43-1.03(m,17H),0.94-0.86(m,9H),0.66(s,3H).

[0734] Example 41D

[0735]

[0736] Example 41C compound (100.0 mg, 212 μmol) in 30% potassium hydroxide in methanol: water (volume ratio 1:1) (10 ml) solution was reacted at 90 degrees Celsius for 16 hours. Water (10 ml) and ethyl acetate (10 ml) were added to the reaction system, the organic layer was washed with saturated potassium hydroxide solution (20 ml), the aqueous layer was combined, the aqueous layer was adjusted to Ph = 4 with 4M hydrochloric acid, the aqueous layer was extracted with ethyl acetate (20 ml x 3), the organic layers were combined, dried over sodium sulfate, filtered and evaporated to give the title compound 41D compound (85.0 mg, 92%), 1H NMR(400MHz,CHLOROFORM-d)δ3.71(br.s.,1H),3.52-3.32(m,1H),2.33(qt,J=7.9, 16.0Hz,2H),2.00-1.33(m,22H),1.22-1.00(m,5H),0.96-0.83(m,8H),0.66(s,3H).

[0737] Embodiment 100

[0738]

[0739] Cyclohexylcarboxylic diimide (36.0 mg, 172 μmol), N,N-dimethylpyridine (14.0 mg, 115 μmol) and methanesulfonamide (16.0 mg, 172 μmol) were added to a solution of Example 41D compound (50.0 mg, 115.0 μmol) in dichloromethane (1 ml) at 25 degrees Celsius, and the reaction system was reacted at 25 degrees Celsius for 12 hours. Water (5 ml) was added to the reaction system, and the system was adjusted to Ph = 2 with hydrochloric acid (1M), extracted with ethyl acetate (10 ml x 3), and the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative thin layer plate (dichloromethane / methanol = 20 / 1) to obtain Example 100 compound (15.0 mg, 25% yield). 1 H NMR(400MHz,CHLOROFORM-d)δ3.70(br.s.,1H),3.47-3.36(m,1H),3.28(s,3H),2.36 -2.23(m,2H),1.95-1.40(m,20H),1.26-1.05(m,7H),0.95-0.88(m,9H),0.65(s,3H).

[0740] Route 42

[0741]

[0742] Embodiment 101

[0743]

[0744] Example 42A

[0745]

[0746] Under nitrogen protection, to the dioxane (550 ml) solution of the compound of reference example 1A (35.0 g, 89.6 mmol) was added p-toluenesulfonic acid (1.5 g, 8.9 mmol) and dihydropyran (11.3 g, 134.4 mmol). The reaction was completed by TLC detection, and hydrogenated at 50 degrees Celsius for 2 hours (50 psi). The solvent was partially evaporated, water (50 ml) was added, and extracted with ethyl acetate (50 ml × 3). The combined organic layer was washed with brine (50 ml), dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography to obtain the title compound 42A compound (33.0 g, 77.5% yield). 1 H NMR(400MHz,CHLOROFORM-d)δ4.67-4.76(m,1H),3.81-3.94(m,1H),3.39-3.65(m,2H),2.76-2.90(m,1H),2.18 -2.43(m,4H),1.62-2.01(m,12H),1.29-1.59(m,12H),1.07-1.14(m,2H),0.92(d,J=6.27Hz,3H),0.64(s,3H).

[0747] Example 42B

[0748]

[0749] Under nitrogen protection at -78 degrees Celsius, lithium diisopropylamide (2 mol / L, 6.74 ml) was added dropwise to tetrahydrofuran (100.0 ml), and hexamethylphosphoric triamide (2.4 g, 13.4 mmol, 2.4 ml) was added dropwise to the above solution. After the addition, the solution was stirred at -78 degrees Celsius for 30 minutes. Then, a tetrahydrofuran solution of compound 42A (2.0 g, 4.2 mmol) was added dropwise to the above solution and stirred at -78 degrees Celsius for 30 minutes. Finally, a tetrahydrofuran (8 ml) solution of iodomethane (4.9 g, 34.5 mmol) was slowly added to the reactor, and then the temperature was raised to room temperature and stirred overnight. Add saturated ammonium chloride (10 ml), quench with 10% citric acid, adjust pH to 4, add water (20 ml), extract with ethyl acetate (200 ml x 3), wash the combined organic layers once with saturated brine (100 ml), dry the organic phase over anhydrous sodium sulfate, filter and evaporate to give the title compound 42B (2.1 g, crude product), which is used directly in the next reaction.

[0750] Example 42C

[0751]

[0752] To the methanol solution of Example 42B compound (2.1 g, 4.2 mmol) was added p-toluenesulfonic acid (73.1 mg, 424.0 μmol). The reaction was heated to 80 degrees Celsius and stirred for 2 hours. The main solvent was evaporated (50 degrees Celsius) and 2 ml of water was added. It was extracted with ethyl acetate (5 ml x 3). The combined organic layer was washed with saturated sodium bicarbonate (2 ml) and saturated brine (5 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by column (petroleum ether / ethyl acetate = 10 / 1 to 3 / 1) to give the title compound 42C compound (350.0 mg, 17.7% yield). 1HNMR(400MHz,CHLOROFORM-d)δ0.61-0.73(m,3H)0.93(d,J=6.53Hz,3H)1.01(dd,J=12.05,6.53Hz,1H)1.09-1.24(m,7H)1.26-1.38(m,6H)1.40-1.52 (m,5H)1.62-1.87(m,6H)1.89-2.04(m,2H)2.06-2.15(m,1H)2.16-2.27(m, 2H)2.31-2.40(m,1H)2.57(t,J=11.29Hz,1H)3.59(br.s.,1H)3.67(s,3H).

[0753] Example 42D

[0754]

[0755] To the compound of Example 42C (340.0 mg, 812.21 μmol) was added a solution of sodium hydroxide (105.5 mg, 2.6 mmol) in water (60.0 ml), heated to 80°C, sodium borohydride (184.3 mg, 4.8 mmol) was added portionwise, the reaction was heated to 100°C and stirred for 8 hours, cooled to 15°C, quenched by the addition of saturated ammonium chloride (100 ml), the pH was adjusted to 2-3 with 1 mol dilute hydrochloric acid, extracted with ethyl acetate (100 ml×3), the combined organic layers were washed with saturated brine (100 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate=2 / 1→1 / 2, with a small amount of acetic acid) to give the title compound 42D (230.0 mg, 62.6% yield). 1HNMR(400MHz,CHLOROFORM-d)δppm 0.66(s,3H)0.86-1.05(m,11H)1.08-1.29(m,6H)1.30-1.54(m,7H)1.59-2.00(m,11H)2. 26(ddd,J=15.94,9.41,6.27Hz,1H)2.35-2.47(m,1H)3.36-3.47(m,1H)3.60(br.s.,1H)

[0756] Embodiment 101

[0757]

[0758] Under nitrogen protection at 20°C, a mixture of methanesulfonamide (16.4 mg, 172.1 μmol), Example 42D compound (70.0 mg, 172.1 μmol), dicyclohexylcarbodiimide (71.0 mg, 344.3 μmol) and diisopropylethylamine (22.2 mg, 172.1 μmol) was stirred in dichloromethane (2 ml) for 10 hours, 10 ml of water was added, and the mixture was extracted with ethyl acetate (15 ml×3). The combined organic layers were washed once with saturated brine (10 ml), and the organic phase was concentrated to obtain Example 101 compound (15.0 mg, 16.2% yield). 1 HNMR(400MHz,CHLOROFORM-d)δppm 0.66(s,3H)0.88-1.03(m,10H)1.07-1.19(m,7H)1.29-1.42(m,7H)1.45-1.74(m,11H)1.77-2.03(m,14H)2.25(ddd,J=1 5.75,9.72,6.15Hz,1H)2.34-2.47(m,1H)3.29(s,3H)3.43(dd,J=10.04,5.02Hz,2H)3.59(br.s.,1H)4.40(br.s.,1H).

[0759] Route 43

[0760]

[0761] Embodiment 102

[0762]

[0763] Example 43A

[0764]

[0765] Tetrachlorophosphate (200 mg, 803.6 μmol) was added to a solution of Example 17A (240.0 mg, 534.9 μmol) in anhydrous tetrahydrofuran (15 ml) under nitrogen protection at -30 degrees Celsius, and stirred for 2.5 hours. The solvent was dried by vortexing, and water (10 ml) was added, filtered, and the filter cake was dissolved in methanol and dried by vortexing under reduced pressure to give a crude product of Example 43A (240.0 mg, 80.6% yield). 1 H NMR(400MHz,METHANOL-d4)δ8.21(s,1H),5.18(br.s.,1H),4.03(td,J=7.7,14.8Hz,2H),3.46(br.s.,2H),2.05(d,J=12.5Hz,1H),1.93-1 .80(m,6H),1.75-1.60(m,7H),1.54(br.s.,3H),1.43-1.06(m,15H),1.01(d,J=6.5Hz,3H),0.99(s,3H),0.93(t,J=7.3Hz,3H),0.73(s,3H)

[0766] Embodiment 102

[0767]

[0768] Referring to the operating procedures of Example 2, Example 43A compound was used as the starting material (240.0 mg, 479.4 μmol) and purified to give Example 102 compound (200.0 mg, 79.4% yield). 1 H NMR(400MHz,METHANOL-d4)δ4.03(td,J=7.7,15.8Hz,2H),3.68(br.s.,1H),3.47(br.s.,1H),2.04(d,J=11.8Hz,1H),1.98-1.71(m, 8H),1.67-1.48(m,9H),1.34(br.s.,7H),1.26-1.09(m,4H),1.02(d,J=6.5Hz,3H),0.99(br.s.,1H),0.96-0.90(m,6H),0.73(s,3H).

[0769] Route 44

[0770]

[0771] Embodiment 103

[0772]

[0773] Example 44A

[0774]

[0775] The compound of Example 21A (2.0 g, 4.6 mmol) was dissolved in formic acid (24.4 g, 530.1 mmol), and perchloric acid (4.6 mg, 46.2 μmol) was added. The reaction solution was stirred at 25°C for twelve hours. The solvent was removed by concentration, and the residue was purified by column chromatography on silica gel to give the compound of Example 44A (700.0 mg, 32.9% yield). 1 H NMR(400MHz,CHLOROFORM-d)δ8.15(s,1H),5.32-5.21(m,1H),3.68(s,3H),2.87-2.74(m,1H),2.47-2.34(m,2H),2.29-2.19(m,3H),2.11- 2.01(m,3H),1.94-1.76(m,6H),1.72-1.66(m,1H),1.58-1.40(m,6H) ,1.36-1.12(m,9H),1.07(s,3H),0.98-0.89(m,7H),0.72(br.s.,3H).

[0776] Example 44B

[0777]

[0778] The compound of Example 44A (80.0 mg, 173.6 μmol) was dissolved in dichloromethane (3.0 ml), and pyridinium tribromide (55.5 mg, 173.6 μmol) was added at 25 degrees Celsius under nitrogen protection, and the reaction solution was stirred at 40 degrees Celsius for four hours. Dichloromethane (25 ml) was added to the reaction solution, and the organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate and concentrated. The residue was separated by thin layer chromatography to obtain the compound of Example 44B (40.0 mg, 42.69% yield). 1 H NMR(400MHz,CHLOROFORM-d)δ8.13(s,1H),5.34-5.21(m,1H),4.79(dd,J=5.1,14.2 Hz,1H),3.71-3.59(m,3H),3.05-2.93(m,1H),2.69(dd,J=5.3,13.8Hz,1H),2.53(dd ,J=4.5,14.8Hz,1H),2.43-2.14(m,3H),2.00-1.79(m,5H),1.71-1.62(m,2H),1.53 -1.21(m,9H),1.17-1.13(m,2H),1.08(s,2H),0.95-0.80(m,7H),0.74-0.66(m,3H).

[0779] Example 44C

[0780]

[0781] The compound of Example 44B (100.0 mg, 185.3 μmol) and thiourea (28.2 mg, 370.6 μmol) were dissolved in pyridine (2.0 ml), and the reaction solution was stirred at 90 degrees Celsius for twelve hours. The solvent was removed, and water (5 ml) was added to the residue, and extracted with ethyl acetate (10 ml x 3). The obtained organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate and concentrated. The residue was separated by thin layer chromatography to obtain the compound of Example 44C (45.0 mg, 47.0% yield). 1 H NMR(400MHz,CHLOROFORM-d)δ8.15(br.s.,1H),6.95(br.s.,1H),5.35-5.20(m,1H),3.67(s,3H),3.10(br.s.,1H),2.92-2.73( m,1H),2.54-2.16(m,4H),2.05-1.61(m,9H),1.47-1.27(m,9H),1.08(d,J=9.8Hz,4H),0.91(d,J=6.5Hz,4H),0.69-0.62(m,3H).

[0782] Embodiment 103

[0783]

[0784] Referring to the operating procedures of Example 2, Example 44C compound was used as the starting material (45.0 mg, 87.1 μmol) and purified to give Example 103 compound (19.0 mg, 45.9% yield, yellow solid). 1 H NMR(400MHz,METHANOL-d4)δ3.76(br.s.,1H),3.48(dd,J=10.9,15.2Hz,1H),2.77( d,J=16.6Hz,1H),2.44-2.30(m,2H),2.25-2.18(m,2H),2.01-1.96(m,1H),1.95-1.8 8(m,1H),1.84-1.74(m,3H),1.67-1.61(m,2H),1.55-1.47(m,3H),1.40-1.29(m,5H) ,1.20-1.15(m,3H),1.12(s,3H),1.01-0.95(m,6H),0.94-0.86(m,5H),0.73(s,3H).

[0785] Experimental Example 1: In vitro study

[0786] FXR biochemical assay Experimental purpose:

[0787] The activation of FXR binding by the compounds was detected by homogeneous luminescence proximity amplification assay (alphascreen).

[0788] Experimental Materials:

[0789] 1. Protein: Glutathione-S-transferase labeled FXR human protein (Invitrogen)

[0790] 2. Coactivator: Biotinylated steroid receptor coactivator (Anaspec)

[0791] 3. Detection reagent: Alphascreen detection kit (PerkinElmer)

[0792] Experimental methods:

[0793] 1. Compound dilution: Prepare the test compound as 40 μL DMSO solution, then dilute the compound 3-fold to 10 concentration points. Prepare the reference compound as 400 μM DMSO solution, then dilute it 1.5-fold to 10 concentration points. Add the diluted DMSO solution to the microwells of a 384-well plate at a volume of 150 nL per well.

[0794] 2. Prepare a mixed solution of FXR human protein labeled with glutathione-S-transferase and steroid receptor coactivator labeled with biotin at concentrations of 0.4 nM and 30 nM, respectively. Add 15 μL per well to the microwells of a 384-well plate. Incubate at room temperature for 1 hour.

[0795] 4. Dilute the receptor bead mixture in the homogeneous proximity luminescence amplification test (alphascreen) kit by 125 times and add 7.5ul per well to the microwells of the 384-well plate. Protect the experiment from light and incubate at room temperature for 1 hour.

[0796] 5. Dilute the donor bead mixture in the homogeneous proximity luminescence amplification test (alphascreen) kit by 125 times and add 7.5ul per well to the microwells of the 384-well plate. Protect the experiment from light and incubate at room temperature for 1 hour.

[0797] 6. EC50 test: Use Envision to excite at 680nm wavelength and read the absorption signal at 520-620nm.

[0798] 7. Data analysis: Prism 5.0 was used to analyze the data and calculate the EC50 value of the compound's activation effect. The maximum signal value of the compound was then compared with the maximum signal value of the reference compound to obtain the compound's activation efficacy percentage (Efficacy).

[0799] FXR cell experiments

[0800] Purpose:

[0801] The effects of compounds on cell function activity were detected by β-lactamase reporter gene technology.

[0802] Experimental Materials:

[0803] 1. Cell line: FXR HEK 293T DA

[0804] 2. Cell culture medium: DMEM medium supplemented with 10% serum and Penicillin / Streptomycin (1×)

[0805] 3. Detection reagents: Reporter gene assay kit (Invitrogen)

[0806] Experimental methods:

[0807] 1. Compound dilution: Prepare the test compound as a 100 μM DMSO solution, then dilute the compound 3-fold to 10 concentration points. Prepare the reference compound as a 100 μM DMSO solution, then dilute it 1.3-fold to 10 concentration points. Add the diluted DMSO solution to the microwells of a 384-well plate at a volume of 200 μL per well.

[0808] 2. Cell inoculation: Resuscitate FXR HEK 293T DA cells, resuspend in culture medium, and dilute to a density of 5×10 5 / mL, and added into the microwells of a 384-well plate at a volume of 40 μL per well.

[0809] 3. Incubate the 384-well plate at 37°C, 5% CO2 for 16 hours.

[0810] 4. Add 6 μL of 1 mM LiveBLAzer TM -FRET B / G (CCF4-AM) substrate was mixed with 60 μL of solution B and 934 μL of solution C and added to the microwells of a 384-well plate at a volume of 8 μL per well.

[0811] 5. Incubate the 384-well microplate at room temperature in the dark for 2 hours.

[0812] 6. EC50 test: Use Envision to excite at 409nm wavelength and read the absorption signal at 460 and 530nm.

[0813] 7. Data analysis: Prism 5.0 was used to analyze the data and calculate the EC50 value of the compound's activation effect. The maximum signal value of the test compound was then compared with the maximum signal value of the reference compound (chenodeoxycholic acid) to obtain the compound's activation efficacy percentage (Efficacy).

[0814] Table 1 Biochemical test results and cell test results EC 50 :

[0815]

[0816]

[0817]

[0818] Experimental Example 2: In vivo study

[0819] Pharmacokinetics of single-dose mice:

[0820] Twelve C57BL / 6J male mice were randomly divided into two groups, 6 in each group. The first group was the intravenous group, which was injected with 2 mg / kg by tail vein (the solvent was 10% HPbCD aqueous solution. When the drug solubility was not ideal, a cosolvent was added); the second group was the oral group, which was gavage-administered 10 mg / kg, 10 mL / kg (the solvent was 0.5% HPMC aqueous solution). Plasma samples (K2-EDTA was used as anticoagulant) were collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration in the intravenous group; plasma samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after administration in the oral group. There were 6 animals in each group, and blood samples from 3 animals were collected at one time point. The first batch of 3 animals and the second batch of 3 animals were staggered. Plasma samples were analyzed using LC-MS / MS. Plasma concentrations and time were obtained, and PK parameters were calculated using Phoenix WinNonlin 6.3.

[0821] Table 2

[0822]

[0823] a h, L / kg, mL / min / kg, nM.h; b nM,h,nM.h,%

[0824] Cassette-type drug administration mouse liver-blood ratio experiment:

[0825] Six C57BL / 6J male mice were grouped as an oral group. The formulation contained five developed drugs and was administered orally at 2 mg / kg / compound (solvent was 0.5% HPMC aqueous solution). The five compounds were first dissolved in the solvent, and then 1 mg / mL solutions (clear solutions or suspensions) were formed by ultrasound or mediation. Then, the five compound solutions were mixed in equal volumes (1:1:1:1:1, v:v:v:v:v) in a glass bottle. After oral administration by gavage, plasma and liver tissue samples were collected from three animals at 0.5 hours after administration; the corresponding samples were collected from the other three animals at 3 hours after administration. After liver tissue was collected, it was homogenized using ice-cold homogenization buffer (methanol: 15mM PBS buffer (pH 7.4) = 1:2, v:v) according to liver weight: homogenization buffer volume = 1:3. Plasma and liver tissue samples were analyzed using a five-in-one LC-MS / MS analysis method developed in advance. Plasma concentrations and liver homogenate concentrations were obtained, and the liver tissue to plasma concentration ratio was calculated using Excel.

[0826] Table 3

[0827]

[0828]

[0829] Conclusion: As shown in Table 3, after oral administration of the compounds of the present invention in the same dosage list, the concentrations of the drugs in the liver at 0.5 hours and 3 hours were higher than those of the control compounds, and the liver / blood concentration ratio was also higher than that of the control compounds, showing a significant effect.

Claims

1. A compound represented by formula V, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof: in, R4 is selected from H, or C optionally substituted with 1, 2, 3, 4 or 5 R 1-3 Alkyl, C 3-10 Cycloalkyl or 5- to 6-membered aryl; R5 is selected from H, halogen or C 1-3 alkyl; R6 is selected from H or OH; n is selected from 0, 1 or 2; L is selected from: -NHC(=O)N(R L )(CH2) 0-2 -, -NHC(=S)NH-, -P(=O)(OEt)O-, -NHS(=O)2-, -NHC(=O)C(=O)O- or -OP(=O)(OR L )O-; The above R L Select from H or C 1-3 alkyl; The above R are independently selected from halogen, CN, OH, NH2, SH, or optionally substituted by 1, 2, 3, 4 or 5 R': 1-3 Alkyl or C 1-3 Alkoxy, and / or Optionally, any one R L and R4 are connected together to form a 4-6 membered heterocycloalkyl group optionally substituted by 1, 2, 3, 4, or 5 R; the above R' is selected from halogen, CN, OH, NH2 or SH, provided that when R4 is selected from C 1-3 When it is an alkyl group, R is not selected from OH and NH2.

2. The compound according to claim 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: The stereoisomers of the compound represented by formula V are represented by the following formula V':

3. The compound according to claim 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R is selected from halogen, CN, OH, NH2, SH, or C optionally substituted with 1, 2 or 3 R' 1-3 Alkyl or C 1-3 Alkoxy.

4. The compound according to claim 3, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R is selected from F, Cl, Br, I, OH, CN, NH2, SH, Me, Et, or CF3.

5. The compound according to claim 4, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R is selected from F, Cl, OH, NH2, SH, Me, Et, or CF3.

6. The compound according to claim 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R5 is selected from H, F, Cl, Br, I, Me or Et.

7. The compound according to claim 6, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R5 is selected from H, Me or Et.

8. The compound according to claim 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R4 is selected from H, or Me, Et, optionally substituted with 1, 2, 3, 4 or 5 R 9. The compound according to claim 8, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R4 is selected from H, or is selected from Me, Et, 10. The compound according to claim 9, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R4 is selected from H, Me, Et, 11. The compound according to claim 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: L is selected from -NHC(=O)N(R L )(CH2) 0-2 -, -NHC(=S)NH-, -NHS(=O)2- or -NHC(=O)C(=O)O-.

12. The compound according to claim 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: L is selected from -NHC(=O)NH-, -NHC(=O)NHCH2-, -NHC(=O)NH(CH2)2-, -P(=O)(OEt)O-, -NHS(=O)2-, -NHC(=O)C(=O)O- or -OP(=O)(OMe)O-.

13. The compound according to claim 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R L Selected from H.

14. The compound according to claim 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R L When the structural unit -L-R4 is connected together with R4 to form a 4-6 heterocycloalkyl ring optionally substituted by 1, 2, 3, 4 or 5 R, the structural unit -L-R4 is selected from 15. The compound according to claim 14, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: R L When the structural unit -L-R4 is connected together with R4 to form a 4- to 6-membered heterocycloalkyl group optionally substituted by 1, 2, 3, 4 or 5 R, the structural unit -L-R4 is selected from 16. The compound according to claim 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, characterized in that: -L-R4 is selected from:

17. The compound according to claim 1, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, which is selected from:

18. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 17, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.

19. Use of the compound according to any one of claims 1 to 17, its tautomer, its stereoisomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 18 in the preparation of a medicament for preventing or treating a disease that benefits from FXR agonism.

20. The use according to claim 19, characterized in that The disease that benefits from FXR agonism is selected from cardiovascular disease, liver / biliary system disease, obesity, diabetes, lower urinary tract symptoms and benign prostatic hyperplasia or ureteral calculi.

21. The use according to claim 20, characterized in that The cardiovascular disease is selected from cardiovascular diseases associated with hypertriglyceridemia and / or hypercholesterolemia.

22. The use according to claim 20, characterized in that The cardiovascular disease is selected from atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, thrombosis, coronary artery disease, stroke or hypertension.

23. The use according to claim 20, characterized in that The liver / biliary system disease is selected from cholestatic liver disease, and high HDL cholesterol disease, high triglyceride disease or fibrotic disease.

24. The use according to claim 20, characterized in that The liver / biliary system disease is selected from non-alcoholic fatty hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, gallstones, non-alcoholic cirrhosis, biliary atresia, cholestatic liver disease, chronic liver disease, hepatitis infection, alcoholic liver disease, and liver fibrosis.

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