CN107531743B - Chenodeoxycholic acid derivatives - Google Patents

Chenodeoxycholic acid derivatives Download PDF

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CN107531743B
CN107531743B CN201680024495.9A CN201680024495A CN107531743B CN 107531743 B CN107531743 B CN 107531743B CN 201680024495 A CN201680024495 A CN 201680024495A CN 107531743 B CN107531743 B CN 107531743B
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CN107531743A (en
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贺海鹰
李鹏
肖华玲
陈正霞
张杨
陈曙辉
胡国平
黎健
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Chia Tai Tianqing Pharmaceutical Group Co Ltd
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Abstract

The application discloses a compound shown as a formula I, a formula II, a formula III, a formula IV or a formula V, a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and discloses an application of the compound in preparing a medicine for treating FXR related diseases.

Description

Chenodeoxycholic acid derivatives
Technical Field
The present application relates to the field of medicine. Specifically, the application relates to a compound shown as a formula I, a formula II, a formula III, a formula IV or a formula V, a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and relates to application thereof in preparing medicines for treating FXR related diseases.
Background
The nicotinic ester 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)) that 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. Magelsdorf, et al, Cell 83: 841-850 (1995)). Northern and in situ analyses showed that FXR is abundantly expressed in lung, intestine, kidney, and adrenal gland (BM. Formanet al, Cell 81: 687-693(1995) and W. Seolet al, mol. Endocrinol.9: 72-85 (1995)). FXR forms heterodimers with 9-cis retinoic acid receptor (RXR) and binds to DNA. FXR/RXR heterodimers preferentially bind to components consisting of the binuclear receptor half-site of the consensus AG (G/T) TCA, which form inverted repeats and are separated by a single nucleoside (IR-1 motif) (BM. Forman, et al, Cell 81: 687-693 (1995)). However, these compounds fail to activate mouse and human FXR, making the nature of endogenous FXR ligands uncertain. Some naturally occurring bile acids bind and activate FXR at physiological concentrations (pctwoo 00/37077, published 6/29/2000)). As described above, cholic acids as FXR ligands include chenodeoxycholic acid (CDCA), deoxycholic acid (DCA), lithocholic acid (LCA), and taurine and glycine conjugates of these cholic acids.
WO-2005082925 discloses the use of INT747 for the preparation of a medicament for the treatment of FXR-related diseases.
Figure GPA0000233715180000031
Summary of The Invention
One aspect of the present application provides a compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure GPA0000233715180000041
wherein,
R7、R8and R9Each independently selected from H, halogen, OH, NH2SH, CN, or selected from C optionally substituted with 1, 2, 3, 4 or 5R1-3Alkyl or C1-3Alkoxy, optionally, R8And R9Can be linked together to form a 3-6 membered ring; or, R9Selected from H, R7And R8Form with the carbon atom to which they are attached a 5-to 6-membered heteroaromatic ring optionally substituted with 1, 2, 3, 4 or 5R or C3-6A cycloalkyl group;
r is respectively and independently selected from halogen, CN, OH and NH2SH, or C optionally substituted with 1, 2, 3, 4 or 5R1-3Alkyl radical, C1-3A heteroalkyl group;
r' is selected from halogen, CN, OH, NH2SH, Me or trifluoromethyl;
provided that R is7、R8And R9Not simultaneously H, and, when R is8When it is OH, R7And R9Not simultaneously selected from H, and R8Or R9Is not selected from
Figure GPA0000233715180000042
Another aspect of the present application provides a compound of formula II, formula III, or formula IV, a tautomer thereof, or a pharmaceutically acceptable salt thereof:
Figure GPA0000233715180000043
wherein,
R1、R2、R3、R5each independently selected from H, halogen, OH, NH2SH, CN, or selected from C optionally substituted with 1, 2, 3, 4 or 5R1-3Alkyl or C1-3An alkoxy group;
when R is2When it is OH, R1And R3Is not simultaneously selected from H;
optionally, R2、R3Can be linked together to form a 3-6 membered ring;
Figure GPA0000233715180000044
represents a single or double bond;
ring A is selected from a 5-6 membered heteroaromatic ring optionally substituted with 1, 2, 3, 4 or 5R;
l is selected from: a single bond, -C (═ O) S-, -C (═ O) N (R)L)S(＝O)2(C(RL)2)0-2-、-C(＝O)N(C(RL)3)S(＝O)2-、-N(RL)C(＝O)O(C(RL)2)0-2-、-N(RL)C(＝O)N(RL)(C(RL)2)0-2-、-OC(＝O)N(RL)-、-OS(＝O)2N(RL)-、-N(RL)C(＝S)N(RL)-、-N(RL)C(＝S)-、-P(＝O)(ORL)O-、-S(＝O)2N(RL)-；
RLSelected from H, or selected from C optionally substituted with 1, 2, or 3R1-3An alkyl group;
R4selected from H, or selected from optionally substituted with 1, 2, 3, 4, or 5R: c1-3Alkyl radical, C3-10Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;
r is respectively and independently selected from halogen, CN, OH and NH2SH, or optionally substituted with 1, 2, 3, 4, or 5R': c1-3Alkyl radical, C1-3A heteroalkyl group; and/or
Optionally, any one RLCan be reacted with R4Joined together to form a 4-6 membered ring optionally substituted with 1, 2, 3, 4, or 5R;
r' is selected from halogen, CN, OH, NH2SH, Me, trifluoromethyl;
"hetero" represents a heteroatom or heteroatom group selected from-NH-, -O-, -S-, ═ O, ═ S, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O) -and/or-S (═ O)2-；
The number of said "hetero" on each of the above "hetero" containing groups is 1, 2, 3, 4, or 5.
Another aspect of the present application provides a compound of formula V, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure GPA0000233715180000051
wherein,
R4selected from H, or selected from C optionally substituted with 1, 2, 3, 4 or 5R1-3Alkyl radical, C3-10Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;
R5selected from H, halogen, OH, NH2SH, CN, or selected from C optionally substituted with 1, 2, 3, 4 or 5R1-3Alkyl or C1-3An alkoxy group;
R6selected from H or OH;
n is selected from 0, 1 or 2;
l is selected from: single bond, -C (═ O) -, -C (═ O) S-, -C (═ O) N (R)L)S(＝O)2(C(RL)2)0-2-、-C(＝O)N(C(RL)3)S(＝O)2-、-N(RL)C(＝O)O(C(RL)2)0-2-、-N(RL)C(＝O)N(RL)(C(RL)2)0-2-、-OC(＝O)N(RL)-、-OS(＝O)2N(RL)-、-N(RL)C(＝S)N(RL)-、-N(RL)C(＝S)-、-P(＝O)(OEt)O-、-S(＝O)2N(RL)-、-C(＝O)NHS(＝O)2NH-、-C(＝O)NHS(＝O)2NHCH2-、-C(＝O)NHS(＝O)2N(RL)-、-C(＝O)NHS(＝O)2NHC(＝O)-、-NHS(＝O)2-, -NHC (═ O) C (═ O) O-OR-OP (═ O) (OR)L)O-；
R is as defined aboveLSelected from H, or selected from C optionally substituted with 1, 2, or 3R1-3An alkyl group;
r is respectively and independently selected from halogen, CN, OH and NH2SH, or optionally substituted with 1, 2, 3, 4 or 5R': c1-3Alkyl radical, C1-3Heteroalkyl and/or
Optionally, any one RLAnd R4Joined together to form a 4-6 membered ring optionally substituted with 1, 2, 3, 4, or 5R;
r' is selected from halogen, CN, OH, NH2SH, Me or trifluoromethyl;
provided that when R is4Is selected from C1-3When alkyl, R is not selected from OH and NH2。
Another aspect of the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, formula II, formula III, formula IV, or formula V, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
Another aspect of the present application provides the use of a compound of formula I, formula II, formula III, formula IV or formula V, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, for the preparation of a medicament for the prevention or treatment of diseases which benefit from FXR agonism, including cardiovascular diseases, diseases of the liver/biliary system, obesity, diabetes, lower urinary tract symptoms (vicinity) and Benign Prostatic Hyperplasia (BPH) or ureteral calculi.
Another aspect of the present application provides a method for preventing or treating diseases benefiting from FXR agonism, including cardiovascular diseases, diseases of the liver/gallbladder system, obesity, diabetes, lower urinary tract symptoms (vicinity) and Benign Prostatic Hyperplasia (BPH) or ureteral calculus, comprising administering to a patient a therapeutically effective amount of a compound represented by formula I, its tautomer, its stereoisomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof as described above.
Detailed Description
One aspect of the present application provides a compound of formula I, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure GPA0000233715180000061
wherein,
R7、R8and R9Each independently selected from H, halogen, OH, NH2SH, CN, or selected from C optionally substituted with 1, 2, 3, 4 or 5R1-3Alkyl or C1-3Alkoxy, optionally, R8And R9Can be linked together to form a 3-6 membered ring; or, R9Selected from H, R7And R8Form with the carbon atom to which they are attached a 5-to 6-membered heteroaromatic ring optionally substituted with 1, 2, 3, 4 or 5R or C3-6A cycloalkyl group;
r is respectively and independently selected from halogen, CN, OH and NH2SH, or C optionally substituted with 1, 2, 3, 4 or 5R1-3Alkyl radical, C1-3A heteroalkyl group;
r' is selected from halogen, CN, OH, NH2SH, Me or trifluoromethyl;
provided that R is7、R8And R9Not simultaneously H, and, when R is8When it is OH, R7And R9Not simultaneously selected from H, and R8Or R9Is not selected from
Figure GPA0000233715180000071
In one embodiment, in the compounds of formula I, R7Selected from H, F, Cl, Br, I, OH, NH2、SH、CN、Me、Et、
Figure GPA0000233715180000072
Figure GPA0000233715180000073
In one embodiment, in the compounds of formula I, R7Is selected from H or
Figure GPA0000233715180000074
In one embodiment, in the compounds of formula I, R is as defined above8And R9Each independently selected from H, F, Cl, Br, I, OH, NH2、SH、CN、Me、Et、
Figure GPA0000233715180000075
Or, R8And R9Are joined together to form C3-6A cycloalkyl group.
In one embodiment, in the compounds of formula I, R is as defined above8And R9Each independently selected from H, F, OH, Me, Et,
Figure GPA0000233715180000076
Figure GPA0000233715180000077
or, R8And R9Are linked together to form a cyclopropyl group, and R8And R9Not H at the same time.
In one embodiment, in the compounds of formula I, R9Selected from H, R7And R8Form, with the carbon atom to which it is attached, an imidazolyl, pyrazolyl, pyrrolyl, thienyl, oxazolyl, thiazolyl, furyl or cyclopropyl group, optionally substituted by 1 or 2R.
In one embodiment, in the compounds of formula I, R9Selected from H, R7And R8Forming, with the carbon atom to which they are attached, an optionally methyl-or amino-substituted radical
Figure GPA0000233715180000078
In one aspect, in the formulaIn the compounds of formula I, R9Selected from H, R7And R8Form with the carbon atom to which they are attached
Figure GPA0000233715180000079
Figure GPA00002337151800000710
Another aspect of the present application provides a compound of formula II, formula III, or formula IV, a tautomer thereof, or a pharmaceutically acceptable salt thereof:
Figure GPA0000233715180000081
wherein,
R1、R2、R3、R5each independently selected from H, halogen, OH, NH2SH, CN, or selected from C optionally substituted with 1, 2, 3, 4 or 5R1-3Alkyl or C1-3An alkoxy group;
when R is2When it is OH, R1And R3Is not simultaneously selected from H;
optionally, R2、R3Can be linked together to form a 3-6 membered ring;
Figure GPA0000233715180000082
represents a single or double bond;
ring A is selected from a 5-6 membered heteroaromatic ring optionally substituted with 1, 2, 3, 4 or 5R;
l is selected from: a single bond, -C (═ O) S-, -C (═ O) N (R)L)S(＝O)2(C(RL)2)0-2-、-C(＝O)N(C(RL)3)S(＝O)2-、-N(RL)C(＝O)O(C(RL)2)0-2-、-N(RL)C(＝O)N(RL)(C(RL)2)0-2-、-OC(＝O)N(RL)-、-OS(＝O)2N(RL)-、-N(RL)C(＝S)N(RL)-、-N(RL)C(＝S)-、-P(＝O)(ORL)O-、-S(＝O)2N(RL)-；
RLSelected from H, or selected from C optionally substituted with 1, 2, or 3R1-3An alkyl group;
R4selected from H, or selected from optionally substituted with 1, 2, 3, 4, or 5R: c1-3Alkyl radical, C3-10Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;
r is respectively and independently selected from halogen, CN, OH and NH2SH, or optionally substituted with 1, 2, 3, 4, or 5R': c1-3Alkyl radical, C1-3A heteroalkyl group; and/or
Optionally, any one RLCan be reacted with R4Joined together to form a 4-6 membered ring optionally substituted with 1, 2, 3, 4, or 5R;
r' is selected from halogen, CN, OH, NH2SH, Me, trifluoromethyl;
"hetero" represents a heteroatom or heteroatom group selected from-NH-, -O-, -S-, ═ O, ═ S, -C (═ O) O-, -C (═ O) -, -C (═ S) -, -S (═ O) -and/or-S (═ O)2-；
The number of said "hetero" on each of the above "hetero" containing groups is 1, 2, 3, 4, or 5.
In one embodiment of the present invention, R is selected from halogen, CN, OH, NH2SH, or optionally substituted with 1, 2, 3, 4, or 5R': c1-3Alkyl radical, C1-3Alkoxy radical, C1-3An alkylamino group.
In one embodiment of the present invention, R is selected from F, Cl, Br, I, OH, CN, NH2、SH、Me、Et、
Figure GPA0000233715180000083
CF3。
In one embodiment of the present invention, R is1、R2、R3、R5Each independently selected from H, halogen, OH, NH2、SH、CN、Me、Et、
Figure GPA0000233715180000091
In one embodiment of the present invention, R is2、R3Linked together to form a cyclopropyl group.
In one embodiment of the present invention, the ring A is selected from imidazolyl, pyrazolyl, pyrrolyl, thienyl, oxazolyl, thiazolyl, furyl optionally substituted with 1 or 2R.
In one embodiment of the present invention, the above ring A is selected from substituted with methyl
Figure GPA0000233715180000092
In one embodiment of the present invention, the ring A is selected from
Figure GPA0000233715180000093
In one embodiment of the present invention, R is4Selected from H, or Me, Et, optionally substituted by 1, 2, 3, 4, or 5R,
Figure GPA0000233715180000094
Figure GPA0000233715180000095
In one embodiment of the present invention, R is4Selected from H, or from Me, Et, optionally substituted by 1, 2, 3, 4, or 5R,
Figure GPA0000233715180000096
Figure GPA0000233715180000097
In one embodiment of the present invention, R is4Selected from: H. me, Et,
Figure GPA0000233715180000101
Figure GPA0000233715180000102
In one embodiment of the present invention, L is selected from: single bond, -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(RL)(CH2)0-2-、-OC(＝O)NH-、-OS(＝O)2NH-、-NHC(＝S)NH-、-NHC(＝S)-、-P(＝O)(ORL)O-、-S(＝O)2NH-。
In one embodiment of the present invention, L is selected from: single bond, -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-。
In one embodiment of the present invention, R isLAnd R4When taken together to form a 4-to 6-membered ring optionally substituted with 1, 2, 3, 4, or 5R, the structural unit-L-R4Selected from optionally substituted by 1 or 2R
Figure GPA0000233715180000103
In one embodiment of the present invention, R isLAnd R4When taken together to form a 4-to 6-membered ring optionally substituted with 1, 2, 3, 4, or 5R, the structural unit-L-R4Is selected from
Figure GPA0000233715180000104
In one embodiment of the present invention, the above-mentioned structural unit-L-R4Selected from:
Figure GPA0000233715180000105
Figure GPA0000233715180000111
another aspect of the present application provides a compound of formula V, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure GPA0000233715180000112
wherein,
R4selected from H, or selected from C optionally substituted with 1, 2, 3, 4 or 5R1-3Alkyl radical, C3-10Cycloalkyl, 3-6 membered heterocycloalkyl, 5-6 membered aryl or 5-6 membered heteroaryl;
R5selected from H, halogen, OH, NH2SH, CN, or selected from C optionally substituted with 1, 2, 3, 4 or 5R1-3Alkyl or C1-3An alkoxy group;
R6selected from H or OH;
n is selected from 0, 1 or 2;
l is selected from: single bond, -C (═ O) -, -C (═ O) S-, -C (═ O) N (R)L)S(＝O)2(C(RL)2)0-2-、-C(＝O)N(C(RL)3)S(＝O)2-、-N(RL)C(＝O)O(C(RL)2)0-2-、-N(RL)C(＝O)N(RL)(C(RL)2)0-2-、-OC(＝O)N(RL)-、-OS(＝O)2N(RL)-、-N(RL)C(＝S)N(RL)-、-N(RL)C(＝S)-、-P(＝O)(OEt)O-、-S(＝O)2N(RL)-、-C(＝O)NHS(＝O)2NH-、-C(＝O)NHS(＝O)2NHCH2-、-C(＝O)NHS(＝O)2N(RL)-、-C(＝O)NHS(＝O)2NHC(＝O)-、-NHS(＝O)2-, -NHC (═ O) C (═ O) O-OR-OP (═ O) (OR)L)O-；
R is as defined aboveLSelected from H, or selected from C optionally substituted with 1, 2, or 3R1-3Alkyl, preferably RLIs selected from H or C1-3An alkyl group;
r is respectively and independently selected from halogen, CN, OH and NH2SH, or optionally substituted with 1, 2, 3, 4 or 5R': c1-3Alkyl radical, C1-3Heteroalkyl and/or
Optionally, any one RLAnd R4Joined together to form a 4-6 membered ring optionally substituted with 1, 2, 3, 4, or 5R;
r' is selected from halogen, CN, OH, NH2SH, Me or trifluoromethyl;
provided that when R is4Is selected from C1-3When alkyl, R is not selected from OH and NH2。
In one embodiment, the stereoisomer of the compound of formula V is represented by the following formula V':
Figure GPA0000233715180000121
in one embodiment, in the compound of formula V, R is selected from halogen, CN, OH, NH2SH, or C optionally substituted with 1, 2, 3, 4 or 5R1-3Alkyl radical, C1-3Alkoxy or C1-3An alkylamino group.
In one embodiment, in the compound of formula V, R is preferably selected from F, Cl, Br, I, OH, CN, NH2、SH、Me、Et、
Figure GPA0000233715180000122
Or CF3。
In one embodiment, in the compound of formula V, R is preferably selected from F, Cl, OH, NH2、SH、Me、Et、
Figure GPA0000233715180000123
Or CF3。
In one embodiment, in the compound of formula V, R5Selected from H, F, Cl, Br, I, OH、NH2、SH、CN、Me、Et、
Figure GPA0000233715180000124
In one embodiment, in the compound of formula V, R5Selected from H, Me or Et.
In one embodiment, in the compound of formula V, R is as defined above4Selected from H, or Me optionally substituted by 1, 2, 3, 4 or 5R,
Figure GPA0000233715180000125
In one embodiment, in the compound of formula V, R is as defined above4Preferably selected from H, or from Me, Et, optionally substituted by 1, 2, 3, 4 or 5R,
Figure GPA0000233715180000131
Figure GPA0000233715180000132
In one embodiment, in the compound of formula V, R is as defined above4More preferably from H, Me, Et,
Figure GPA0000233715180000133
Figure GPA0000233715180000134
In one embodiment, in the compound of formula V, L is selected from the group consisting of 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(RL)(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(RL)-、-C(＝O)NHS(＝O)2NHC(＝O)-、-NHS(＝O)2-, -NHC (═ O) C (═ O) O-OR-OP (═ O) (OR)L)O-。
In one embodiment, in the compound represented by formula V, L is preferably selected from the group consisting of 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(CH2)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(CH3)-、-C(＝O)NHS(＝O)2NHC(＝O)-、-NHS(＝O)2-, -NHC (═ O) C (═ O) O-or-OP (═ O) (OMe) O-.
In one embodiment, in the compound of formula V, R is as defined aboveLAnd R4When taken together to form a 4-to 6-membered ring optionally substituted with 1, 2, 3, 4 or 5R, structural unit-L-R4 is selected from optionally substituted with 1 or 2R
Figure GPA0000233715180000141
Figure GPA0000233715180000142
In one embodiment, in the compound of formula V, R is as defined aboveLAnd R4When joined together to form a 4-to 6-membered ring optionally substituted with 1, 2, 3, 4 or 5R, structural unit-L-R4 is preferably selected from
Figure GPA0000233715180000143
Figure GPA0000233715180000144
In one embodiment, in the compound of formula V, the above junctionConstitutional unit-L-R4Selected from:
Figure GPA0000233715180000145
Figure GPA0000233715180000151
the compounds are as follows:
Figure GPA0000233715180000152
Figure GPA0000233715180000161
Figure GPA0000233715180000171
Figure GPA0000233715180000181
Figure GPA0000233715180000191
Figure GPA0000233715180000201
Figure GPA0000233715180000211
pharmaceutical composition
Another aspect of the present application provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, formula II, formula III, formula IV, or formula V, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
The compounds of the present application or salts thereof may be administered alone as the active substance, preferably in the form of a pharmaceutical composition thereof.
In another aspect, the present application provides a pharmaceutical composition comprising a compound of 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.
Administration of a compound of the present application or a pharmaceutically acceptable salt thereof may be carried out in pure form or in the form of a suitable pharmaceutical composition by any acceptable means of administration that provides a medicament for similar use. The pharmaceutical compositions of the present application may be prepared by combining a compound of the present application with a suitable pharmaceutically acceptable carrier, diluent, vehicle 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, aerosols, and the like.
Typical routes of administration for the compounds of the present application or pharmaceutically acceptable salts or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration and the like. The preferred route of administration is oral.
The pharmaceutical compositions of the present application can be manufactured by methods known to those of ordinary skill in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, lyophilizing, and the like.
In a preferred embodiment, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions may be formulated by mixing the active compounds with pharmaceutically acceptable carriers well known in the art. These carriers enable the compounds of the present application to be formulated as tablets, pills, dragees, capsules, liquids, gels, slurries, suspensions and the like, for oral administration to a patient.
Solid oral pharmaceutical compositions can be prepared by conventional mixing, filling or tableting methods. For example, it can be obtained by the following method: the active compounds are mixed with solid excipients, the mixture obtained is optionally milled, if desired with further suitable auxiliaries, and the mixture is then processed to granules, to give tablets or dragee cores. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like. Such as microcrystalline cellulose, glucose solutions, gum arabic syrups, gelatin solutions, sucrose and starch pastes; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbitol, or dicalcium phosphate; silicon dioxide; croscarmellose sodium, pregelatinized starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, carboxymethylcellulose, crospovidone, and the like. The dragee cores may optionally be coated, in particular with enteric coatings, according to methods well known in normal pharmaceutical practice.
The pharmaceutical compositions of the present application may also be adapted for parenteral administration, such as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms. Suitable excipients, such as fillers, buffers or surfactants can be used.
The amount of compound or composition administered to a patient is not fixed and depends on the drug administered, the purpose of the administration such as prevention or treatment; the condition of the patient, the mode of administration, etc. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. The effective dosage will depend on the disease state being treated and the judgment of the attending clinician, which will depend on factors such as the severity of the disease, the age, weight and general condition of the patient.
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 may be sterilized by filtration. The aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparation is usually 3 to 11, more preferably 5 to 9, and most preferably 7 to 8. It will be appreciated that the use of certain of the aforementioned excipients, carriers or stabilizers may result in the formation of a pharmaceutical salt.
Therapeutic uses
The compounds of the present application are FXR agonists. The compounds of the present application are useful in a method for preventing or treating dyslipidemia or a disease associated with dyslipidemia, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of the present application.
The compounds of the present application are useful for lowering total cholesterol levels, lowering LDL cholesterol levels, lowering VLDL cholesterol levels, raising HDL cholesterol levels, and/or lowering triglyceride levels. Reducing triglyceride levels as described herein refers to reducing triglyceride levels in a subject in need of treatment to below the initial triglyceride level of the subject prior to administration of a compound of the present application. For example, the compounds of the present application may reduce triglyceride production or reduce triglyceride secretion by the liver by reducing fat absorption. The compounds of the present application may also lower serum triglycerides and hepatic triglycerides.
The compounds of the present application may be used for the prevention or treatment of cardiovascular diseases associated with hypertriglyceridemia and/or hypercholesterolemia, such as, but not limited to, atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, thrombosis, coronary artery disease, stroke, or hypertension in a subject (e.g., a mammal, particularly a human).
The compounds of the present application may be used for the prevention or treatment of diseases of the liver/biliary system, such as, but not limited to, cholestatic liver disease, high HDL cholesterol disease, high triglyceride disease, or fibrotic disease, in a subject (e.g. a mammal, particularly a human), in particular, 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 C), alcoholic liver disease, or hepatic fibrosis.
The compounds of the present application may be used for the prevention or treatment of obesity in a subject (e.g., a mammal, particularly a human).
The compounds of the present application may be used for the prevention or treatment of diabetes, or insulin resistance, glucose intolerance related diseases in a subject (e.g., a mammal, particularly a human).
The compounds of the present application may be used for the prevention or treatment of lower urinary tract symptoms (vicinity) and Benign Prostatic Hyperplasia (BPH) or ureteral calculus in a subject (e.g. a mammal, particularly a human).
Another aspect of the present application provides the use of a compound of formula I, formula II, formula III, formula IV or formula V, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described above, for the preparation of a medicament for the prevention or treatment of diseases which benefit from FXR agonism, including cardiovascular diseases, diseases of the liver/biliary system, obesity, diabetes, lower urinary tract symptoms (vicinity) and Benign Prostatic Hyperplasia (BPH) or ureteral calculi.
Another aspect of the present application provides a method for preventing or treating a disease benefiting from FXR agonism, including cardiovascular diseases, diseases of the liver/biliary system, obesity, diabetes, lower urinary tract symptoms (vicinity) and Benign Prostatic Hyperplasia (BPH) or ureteral calculus, comprising administering to a patient a therapeutically effective amount of a compound represented by formula I, formula II, formula III, formula IV or formula V, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
The cardiovascular disease includes cardiovascular disease associated with hypertriglyceridemia and/or hypercholesterolemia. The cardiovascular disease further comprises atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, thrombosis, coronary artery disease, stroke, or hypertension. The diseases of the liver/gallbladder system include cholestatic liver diseases, high HDL cholesterol diseases, high triglyceride diseases, or fibrotic diseases. The disease of the liver/gallbladder system further comprises nonalcoholic steatohepatitis (NASH), Primary Biliary Cirrhosis (PBC), Primary Sclerosing Cholangitis (PSC), gallstones, nonalcoholic cirrhosis, biliary atresia, cholestatic liver disease, chronic liver disease, hepatitis infection (type B or C), alcoholic liver disease, or hepatic fibrosis.
Definitions and explanations
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commodity or its active ingredient. In the following description, certain specific details are included to provide a thorough understanding of various disclosed embodiments. One skilled in the relevant art will recognize, however, that the embodiments may be practiced without one or more of the specific details, or with other methods, components, materials, and so forth.
Unless otherwise required by the application, in the specification and claims, the word "comprise" and its variants, such as "comprises" and "comprising," are to be construed in an open, inclusive sense, i.e., "including but not limited to.
Reference throughout this specification to "one embodiment" or "an embodiment" or "in another embodiment" or "in certain embodiments" means that a particular reference element, structure or feature described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrase "in one embodiment" or "in an embodiment" or "in another embodiment" or "in certain embodiments" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular elements, structures, or characteristics may be combined in any suitable manner in one or more embodiments.
It should be understood that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a reaction comprising "a catalyst" includes one catalyst, or two or more catalysts. It will also be understood that the term "or" is generally employed in its sense including "and/or" unless the context clearly dictates otherwise.
The terms "optionally" or "optionally" mean that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. For example, ethyl is "optionally" substituted with halo, meaning that ethyl may be unsubstituted (CH)2CH3) Monosubstituted (e.g. CH)2CH2F) Polysubstituted (e.g. CHFCH)2F、CH2CHF2Etc.) or completely substituted (CF)2CF3). It will be appreciated by those skilled in the art that any group containing one or more substituents will not incorporate any substitution or substitution pattern which is sterically impossible and/or cannot be synthesized.
C as used hereinm～nMeaning that the moiety has m to n carbon atoms. For example, "C1-3The alkyl group means that the alkyl group has 1 to 3 carbon atoms.
Numerical ranges herein refer to each integer in the given range. E.g. "C1-3Alkyl means that the group may be selected from C1、C2And C3Alkyl groups of (a); "C3-10Cycloalkyl "means that the group can be selected from C3、C4、C5、C6、C7、C8、C9And C10Cycloalkyl groups of (a); "3-6 membered heterocycloalkyl" means that the group can be selected from 3-, 4-, 5-, and 6-membered heterocycloalkyl.
The term "substituted" or "substituted" means that any one or more hydrogen atoms on a particular atom is replaced with a substituent, including variations of deuterium and hydrogen, so long as the valency 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 substituted. The keto substitution does not occur on the aromatic group. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemical realizability.
When any variable (e.g., R) occurs more than one time in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2R, the group may optionally be substituted with up to two R, and there are separate options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected, such as "A-L-Z" where L represents a single bond, it means that the structure A is directly connected to Z, in fact A-Z.
When a substituent's bond can cross-link two atoms on a ring, such substituent can be bonded to any atom on the ring. When no atom is indicated in the listed substituents for connecting to a compound included in the general chemical structure but not specifically mentioned, such substituent may be bonded through any atom thereof. Combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds. For example, a structural unit
Figure GPA0000233715180000251
Meaning that it may be substituted at any position on the cyclohexyl or cyclyldiene, including
Figure GPA0000233715180000252
Figure GPA0000233715180000253
In some preferred embodiments of the present application, the L group is attached to R at the right end of the group4Are connected. For example, L may be selected from-C (═ O) S-, in some preferred forms of this application, the right end of-C (═ O) S-and R4The connection is carried out in a connecting way,i.e. S atom and R4Connecting; for another example, L may be selected from-OC (═ O) N (R)L) -, -OC (═ O) N (R) in some preferred modes of this applicationL) Right end of-and R4To which, i.e. the N atom is bound to R4Connecting; as another example, L may be selected from-N (R)L)C(＝O)N(RL)(C(RL)2)0-2-N (R) in some preferred forms of this applicationL)C(＝O)N(RL)(C(RL)2)0-2Right end of-and R4Linked, i.e. "C (═ O) N (R)L)(C(RL)2)0-2N atom of moiety and R4Are connected.
Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
The term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, which is attached 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 (CH)3)2、-CH(CH3)(CH2CH3)、-CH(CH2CH3)2、-C(CH3)3、-C(CH2CH3)3、-CH2CH(CH3)2、-CH2CH(CH3)(CH2CH3) And the like. The term "C1～8The alkyl group "means an alkyl group having 1 to 8 carbon atoms. The term "C1～6The alkyl group "means an alkyl group having 1 to 6 carbon atoms. The term "C1～4The alkyl group "means an alkyl group having 1 to 4 carbon atoms. The "alkyl group", "C1～8Alkyl group "," C1～6Alkyl "or" C1～4Alkyl "may be unsubstituted or substituted with one or more substituents selected from hydroxy, halogen or amino.
The term "cycloalkyl" as used herein refers to an all-carbon cyclic saturated hydrocarbon group consisting of only carbon and hydrogen atoms, including monocyclic structures, fused-ring structures, spiroRing or bridge structures, e.g. C3-10Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexyl, cycloheptyl, and the like,
Figure GPA0000233715180000261
Adamantyl, and the like. The "cycloalkyl" may be unsubstituted or independently substituted with one or more substituents including, but not limited to, alkyl, alkoxy, cyano, hydroxy, aryl, heteroaryl, amino, halo, sulfonyl, sulfinyl, phosphoryl, or hydroxy.
The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi-electron system. For example, the aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. "aryl" includes but is not limited to phenyl, naphthyl, anthryl, and the like.
The term "hetero" denotes a heteroatom or a heteroatom group (i.e., a heteroatom-containing radical) including atoms other than carbon (C) and hydrogen (H) and radicals containing these heteroatoms, and includes, for example, 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) -, -C (═ NH) -, -S (═ O)2N (h) -or-S (═ O) n (h) -; the number of said "hetero" on each of the above "hetero" containing groups is optionally 1, 2, 3, 4 or 5.
The term "heteroalkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, some of which are substituted or replaced by the above-mentioned heteroatoms or groups of heteroatoms. In some embodiments, the term "heteroalkyl," by itself or in combination with another term, means a stable straight-chain, branched-chain hydrocarbon radical, or combination thereof, having a number of carbon atoms and at least one heteroatom constituent. In one exemplary embodiment, the heteroatoms are 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 heteroatom group may be located at any internal position of the heteroalkyl group (includingThe position at which the hydrocarbyl 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-OCH3and-CH ═ CH-N (CH)3)-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, e.g. -CH2-NH-OCH3。
The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom structure selected from the above-mentioned heteroatoms or heteroatom groups, the remaining ring atoms being C, and having at least one aromatic ring. Preferably, the heteroaryl group includes at least one ring atom selected from N, O, S. Heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, 1, 2, 4-oxadiazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl, tetrazolyl, triazolyl, triazinyl, benzofuranyl, benzothienyl, indolyl, isoindolyl, and the like. The term "5-or 6-membered heteroaryl" refers to heteroaryl groups having 5 to 6 ring atoms. The "heteroaryl" or "5-or 6-membered heteroaryl" may be unsubstituted or substituted by one or more groups selected from hydroxy, halogen or C1～4Alkyl substituents.
The term "heterocycloalkyl"Refers to a non-aromatic monocyclic, fused polycyclic, bridged or spiro ring system group containing at least one ring atom structure selected from the above-mentioned heteroatoms or heteroatom groups, with the remaining ring atoms being C. Preferably, the "heterocycloalkyl" includes at least one heteroatom selected from N, O, S, S (O) n (where n is 0, 1 or 2) as a ring atom structure, with the remaining ring atoms being C. Such rings may be saturated or unsaturated (e.g. with one or more double bonds), but do not have a fully conjugated pi-electron system. Non-limiting examples of "heterocycloalkyl" include oxiranyl, thietanyl, cycloazethyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuryl, pyrrolidinyl, oxazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, tetrahydropyranyl, dihydrothiopyranyl, azepanyl, oxepanyl, thiepanyl, oxaazabicyclo [2.2.1]Heptyl and azaspiro [3.3 ]]A heptyl radical,
Figure GPA0000233715180000271
Figure GPA0000233715180000272
And the like. The term "5-or 6-membered heterocycloalkyl" refers to heterocycloalkyl groups having 5 to 6 ring atoms.
Unless otherwise specified, "cyclic" means cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. Wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are as previously defined. Wherein, cycloalkenyl or cycloalkynyl means that an alkenyl or alkynyl structure is included in the ring atom structure of the cycloalkyl group. Heterocycloalkenyl or heterocycloalkynyl means a cycloalkenyl or cycloalkynyl group which contains at least one ring atom structure selected from the above-mentioned heteroatoms or heteroatom groups, the remaining ring atoms being C. Cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl are unsaturated (e.g. have one or more double bonds), but do not have a completely conjugated pi-electron system.
The term "pharmaceutically acceptable" as used herein is intended to refer 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 human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present application prepared from the compounds found herein to have particular substituents with relatively nontoxic acids or bases. When compounds of the present application contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of a base in neat solution or in a suitable inert solvent. When compounds of the present application contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of the pharmaceutically acceptable acid addition Salts include inorganic acid Salts, and organic acid Salts, and also include Salts of amino acids (e.g., 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 both basic and acidic functionalities and thus can be converted to any base or acid addition salt.
Preferably, the neutral form of the compound is regenerated by contacting the salt with a base or acid and isolating the parent compound in a conventional manner. The parent form of the compound differs from the various salt forms by certain physical properties, such as solubility in polar solvents.
In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert the compounds of the present application. In addition, prodrugs can be converted to the compounds of the present application in an in vivo environment by chemical or biochemical means.
Certain compounds of the present application may exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present application.
Certain compounds of the present application may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present application.
The illustrations of mesomeric, ambiscientific and scientific, or enantiomerically pure compounds herein are from Maehr, j.chem.ed.1985, 62: 114-120. In 1985, 62: 114-120. Unless otherwise indicated, the absolute configuration of a stereocenter is indicated by wedge bonds and dashed bonds. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include the E, Z geometric isomer unless otherwise specified. Likewise, all tautomeric forms are included within the scope of the present application.
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, as well as racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present application. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present application.
Optically active (R) -and (S) -isomers as well as D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers 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 (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers by fractional crystallization or chromatography, as is well known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamate formation from amines).
The compounds of the present application may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may be labelled with radioactive isotopes, such as tritium (A), (B), (C3H) Iodine-125 (125I) Or C-14(14C) In that respect All isotopic variations of the compounds of the present application, whether radioactive or not, are intended to be encompassed within the scope of the present application.
The term "pharmaceutically acceptable carrier" refers to any formulation or carrier medium capable of delivering an effective amount of an active agent herein, without interfering with the biological activity of the active agent and without toxic side effects to the host or patient, and representative carriers include water, oils, vegetables and minerals, cream bases, lotion bases, ointment bases, and the like. These include suspending agents, viscosity enhancers, skin penetration enhancers, and the like. Their preparation is known to those skilled in the cosmetic or topical pharmaceutical field. For additional information on the carrier, reference may 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.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.
The term "effective amount" or "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. For oral dosage forms herein, an "effective amount" of one active agent in a composition is the amount needed to achieve the desired effect when combined with another active agent in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.
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.
The term "patient" refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably humans.
The phrase "therapeutically effective amount" as used herein refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that a researcher, veterinarian, medical doctor or other clinician is seeking in a tissue, system, animal, individual, or human, which includes one or more of the following:
(1) prevention of diseases: for example, preventing a disease, disorder or condition in an individual who is susceptible to the disease, disorder or condition but has not experienced or developed disease pathology or symptomatology.
(2) Inhibiting the disease: for example, inhibiting the disease, disorder or condition (i.e., arresting the further development of the pathology and/or condition) in an individual who is experiencing or presenting the pathology or condition of the disease, disorder or condition.
(3) And (3) relieving the diseases: for example, relieving the disease, disorder or condition (i.e., reversing the pathology and/or symptomatology) in an individual who is experiencing or presenting with the pathology or symptomatology of the disease, disorder or condition.
Therapeutic dosages of the compounds of the present application may be determined, for example, by: the particular use of the treatment, the mode of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of the compound 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 the route of administration. For example, the compounds of the present application can be provided for parenteral administration by a physiological buffered aqueous solution containing about 0.1-10% w/v of the compound. Some typical dosage ranges are from about 1. mu.g/kg to about 1g/kg body weight/day. In certain embodiments, the dosage range is from about 0.01mg/kg to about 100mg/kg body weight/day. The dosage will likely depend on such variables as the type and extent of progression of the disease or disorder, the general health status of the particular patient, the relative biological efficacy of the selected compound, the excipient formulation and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
The compounds of the present application may 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 combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, the examples of the present application.
The chemical reactions of the embodiments herein are carried out in a suitable solvent that is compatible with the chemical changes of the present application and the reagents and materials required therefor. In order to obtain the compounds of the present application, it is sometimes necessary for a person skilled in the art to modify or select the synthesis steps or reaction schemes based on the existing embodiments.
An important consideration in any synthetic route planning in the art is the selection of suitable protecting groups for reactive functional groups (e.g., amino groups in the present application). Greene and Wuts (protective groups In Organic Synthesis, Wiley and Sons, 1991) are the authorities of this area for trained practitioners. All references cited herein are incorporated in their entirety.
The reactions described herein can be monitored according to any suitable method known in the art. For example, it can be determined by a broad spectrum method such as nuclear magnetic resonance spectroscopy (e.g.1H or13C) Infrared spectroscopy, spectrophotometry (e.g. UV-visible light) or mass spectrometry, or monitoring product formation by chromatography, e.g. High Performance Liquid Chromatography (HPLC) or thin layer chromatography.
The solvents used herein are commercially available. The following abbreviations are used in this application: aq represents water; HATU represents O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate; EDC for N- (3-dimethylaminopropyl) -N' -ethylcarbonA diimine hydrochloride salt; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalent, 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 for ethyl acetate; EtOH stands for ethanol; MeOH represents methanol; CBz represents benzyloxycarbonyl, an amine protecting group; BOC represents tert-butylcarbonyl, an amine protecting group; HOAc represents acetic acid; NaCNBH3Represents sodium cyanoborohydride; r.t. represents room temperature; O/N stands for overnight; THF represents tetrahydrofuran; boc2O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; TFAA represents trifluoroacetic anhydride; DIPEA stands for diisopropylethylamine; SOCl2Represents thionyl chloride; CS2Represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N- (phenylsulfonyl) benzenesulfonamide; NCS represents 1-chloropyrrolidine-2, 5-dione; n-Bu4NF represents tetrabutyl ammonium fluoride; iPrOH represents 2-propanol; mp represents melting point; LDA represents lithium diisopropylamide; PTSA represents p-toluenesulfonic acid; TMSCl represents trimethylchlorosilane; BF (BF) generator3-Et2O represents boron trifluoride diethyl etherate; ac of2O represents acetic anhydride; DMAP for N, N-dimethylaminopyridine; EDCI represents 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride; TEA for triethylamine; TBTU represents O, N-dimethylhydroxylamine hydrochloride; MeMgBr stands for methyl magnesium bromide; burgess reagent stands for Burgis reagent; bu2OSn represents dibutyltin oxide; TMSN3Represents trimethylsilyl azide; DHP represents 3, 4-dihydropyran; PCC stands for pyridinium chromate; AcCl represents acetyl chloride; TMSCF3Represents trimethyltrifluoromethylsilyl ether; TBAF stands for tetrabutylammonium fluoride; pb (OAc)4Represents lead tetraacetate; p (OEt)3Represents triethyl phosphite; pyridine represents Pyridine; PPh3Represents triphenylphosphine; thiophosgene stands for Thiophosgene; DAST represents diethylaminosulfur trifluoride; et (Et)2Zn represents diethyl zinc; ph3PCH2OCH3Cl represents methoxy methyl triphenyl phosphonium chloride; n-BuLi represents n-butyllithium; PhSO2Cl represents phenylsulfonyl chloride; MsCl generationEpethanesulfonyl chloride; TMSNCO stands for trimethylsilyl isocyanate.
The compound is made by hand or
Figure GPA0000233715180000301
The software names, and the commercial compounds are under the supplier catalog name.
Detailed Description
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.
Reference example 1 INT-747 preparation
Figure GPA0000233715180000311
Reference example 1A
Figure GPA0000233715180000313
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, sodium hypochlorite (210 ml, 3.4 mol) was added dropwise over 30 minutes at 0 ℃, after stirring for 16 hours at 28 ℃, saturated sodium bisulfite solution (500 ml) was added to quench, the aqueous layer was extracted with ethyl acetate (1000 ml × 2), the combined organic layers were washed with water (1000 ml × 5), the organic layers were dried over sodium sulfate, filtered and spun dry, and the residue was recrystallized (dichloromethane, 200 ml) to give reference example 1A (yellow solid, 41.0 g, 69.0% yield).1H 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).
Reference example 1B
Figure GPA0000233715180000312
To a solution of the compound (246.0 g, 629.9 mmol) of referential example 1A in methanol (2L) was added p-toluenesulfonic acid (10.9 g, 63.0 mmol) in one portion, and the mixture was reacted at 80 ℃ for 4 hours. After cooling to room temperature, evaporation to dryness, quenching with saturated sodium bicarbonate solution (1500 ml), the aqueous layer was extracted with ethyl acetate (1500 ml × 3), the combined organic layers were washed with brine (1000 ml × 3), dried over sodium sulfate, filtered and spun dry, and the residue was recrystallized (ethyl acetate, 500 ml) to give reference example 1B (white solid, 202 g, 79% yield).1H 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).
Reference example 1C
Figure GPA0000233715180000321
Lithium diisopropylamide (87.4 g, 815.6 mmol) was added dropwise to a tetrahydrofuran (500.0 ml) solution of trimethylchlorosilane (107.5 g, 989.5 mmol) at-78 deg.C under nitrogen, and after stirring for 40 minutes, a tetrahydrofuran (300 ml) solution of the compound of reference example 1B (50 g, 123.6 mmol) was added dropwise. After the addition was complete, stirring was continued for 40 minutes at-78 ℃, triethylamine (182.5 g, 1.8 mol) was added, after 1 hour, the reaction mixture was quenched with saturated sodium bicarbonate (1000 ml), and the aqueous layer was extracted with ethyl acetate (1000 ml × 3). The combined organic layers were washed with water (100 ml × 6) and saturated brine (1000 ml × 2), and the organic layers were dried over sodium sulfate, filtered and spun dry to give reference example 1C (tan oil, 68 g, 100% yield) which was 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).
Reference example 1D
Figure GPA0000233715180000322
To a solution of the compound of reference example 1C (68.0 g, 123.9 mmol) in dichloromethane (500.0 ml) was added anhydrous acetaldehyde (10.1 g, 229.2 mmol). A solution of boron trifluoride-diethyl ether (64.4 g, 453.4 mmol) in dichloromethane (300 ml) was added dropwise at-78 degrees celsius under nitrogen. The dropping rate was such that the internal temperature was kept at-78 ℃, after stirring for 1 hour, the temperature was raised to 30 ℃ and stirring was continued 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 layers were washed with saturated brine (1000 ml × 2), dried over sodium sulfate, filtered and dried by spinning, and the residue was purified by column chromatography to give reference example 1D (yellow solid, 43.0 g, yield 81.0%).1H 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).
Reference example 1E
Figure GPA0000233715180000331
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 stirred at 50 ℃ for 2 hours. After spin-drying of the solvent, water (500.0 ml) was added, extraction was performed with ethyl acetate (500.0 ml × 2), the aqueous phase was adjusted to pH 3 with dilute HCl, extraction was performed with dichloromethane (600.0 ml × 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%).1H 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).
Reference example 1F
Figure GPA0000233715180000332
To an aqueous solution (600.0 ml) of the compound (140.0 g, 336.1 mmol) of referential example 1E in NaOH (0.5 mol) was added 10% Pd-C (19.9 g, 134.4 mmol) in one portion, and hydrogen gas at 15psi was introduced to react at 100 ℃ for 16 hours. Suction filtration, pH adjustment of the filtrate to 3 with dilute hydrochloric acid, extraction of the aqueous layer with dichloromethane (1500.0 ml × 3), washing of the combined organic layers with brine (1000.0 ml × 3), drying over sodium sulfate, filtration and spin drying gave reference example 1F (white solid, 101.0 g, yield 72.0%) which was used directly in the next step without further purification.1H 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).
Reference example 1 INT-747
Figure GPA0000233715180000341
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 stirred at 100 degrees celsius for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride (150.0 ml) was added, the pH was adjusted to 3 with dilute hydrochloric acid, the aqueous layer was extracted with dichloromethane (300.0 ml × 3), the combined organic layers were 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%).1H 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).
Route 1
Figure GPA0000233715180000342
Example 1
Figure GPA0000233715180000343
Example 1A
Figure GPA0000233715180000344
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) was added acetic anhydride (1.0 g, 9.5 mmol) under nitrogen, and after stirring at 40 ℃ for 12 hours, water (100.0 ml) was added to quench, the aqueous layer was extracted with ethyl acetate (100.0 ml × 2), the organic layer was washed successively with 1 mol aqueous hydrochloric acid solution and saturated brine, the combined organic layers were dried over sodium sulfate, filtered and spun dry, and the residue was purified by column chromatography to give the compound of example 1A (1.1 g, 92.0% yield).
Example 1B
Figure GPA0000233715180000351
A mixture of the compound of example 1A (0.1 g, 0.2 mmol) and carbonyldiimidazole (60.0 mg, 0.4 mmol) in acetonitrile (3 ml) was reacted at 25 ℃ for 0.5 h, then sodium hydrosulfide (40.0 mg, 0.8 mmol) was added and the reaction was continued at 25 ℃ for 12 h. Concentrated under reduced pressure, diluted with water (80.0 ml), pH adjusted to 3 with dilute hydrochloric acid, aqueous layer extracted with ethyl acetate (100.0 ml × 2), combined organic layers washed with water (100.0 ml), brine (100.0 ml), dried over sodium sulfate, filtered and spun dry, and the residue purified by preparative TLC plate to give the title compound of example 1B (40.0 mg)Yield 39.0%).1H 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).
Example 1
Figure GPA0000233715180000352
To a mixture of the compound from example 1B (30.0 mg, 0.06 mmol) in water (2.0 ml) and ethanol (2.0 ml) was added potassium hydroxide (0.5 g, 8.9 mmol) under nitrogen. After stirring at 80 ℃ for 24 hours, the mixture was neutralized with 1 mol hydrochloric acid, and the aqueous layer was extracted with ethyl acetate (100 ml. times.4). The combined organic layers were dried over sodium sulfate, filtered and spun-dried, and the residue was purified by preparative TLC plate to give the compound of example 1 (20.0 mg, yield 62.0%).1H 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).
Route 2
Figure GPA0000233715180000361
Example 2
Figure GPA0000233715180000362
Example 2A
Figure GPA0000233715180000363
Perchloric acid (6.0 g, 60.0 mmol) is added to the compound of reference example 1 (2.7 g, 6.4 mmol) and formic acid (0.3 g, 6.4 mmol) in tetrahydrofuran (40 ml) under nitrogen. After stirring at 55 ℃ for 6 hours, the mixture was concentrated under reduced pressure and then concentrated with water (100 mm)L) and the aqueous layer was extracted with ethyl acetate (100 ml × 2). The combined organic layers were dried over sodium sulfate, filtered and spun dry, and the residue was purified by column chromatography to give the compound of example 2A (2.8 g, 92.0% yield).1H 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).
Example 2B
Figure GPA0000233715180000371
To a solution of the compound of example 2A (100 mg, 0.2 mmol) and methylsulfonamide (18.0 mg) in dichloromethane (5.0 ml) was 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 and the mixture was reacted for 4 hours at 25 ℃. After dilution with dichloromethane (120 ml), washing with water, drying of the organic phase over anhydrous sodium sulfate, removal of the solution by vacuum drying and purification of the residue by column chromatography gave 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).
Example 2
Figure GPA0000233715180000372
A solution of the compound from 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 ℃ for 1 hour, the pH was adjusted to 1 with dilute acid, the aqueous phase was extracted with ethyl acetate (20 ml × 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 2Compound (20.0 mg, yield 38.0%).1H NMR(400MHz，CHLOROFORM-d)δ8.85(s，1H)，3.71(br.s.，1H)，3.47-3.39(m，1H)，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).
Preparation of examples 3-to 26 prepared by route 2, according to the procedure of example 2, the results are as follows:
Figure GPA0000233715180000373
Figure GPA0000233715180000381
Figure GPA0000233715180000391
Figure GPA0000233715180000401
Figure GPA0000233715180000411
Figure GPA0000233715180000421
Figure GPA0000233715180000431
route 3
Figure GPA0000233715180000432
Example 27
Figure GPA0000233715180000433
Example 3A
Figure GPA0000233715180000434
The compound of reference example 1F (10.0 g, 23.9 mmol) was dissolved in tetrahydrofuran (60.0 ml), perchloric acid (240.0 mg, 2.4 mmol, 144.6 μ l) (approximately 10 drops) was added, formic acid (40.3 g, 874.7 mmol, 33.0 ml) was added dropwise at thirty degrees celsius over half an hour, and the reaction was stirred at fifty degrees celsius for eleven and one-half hours. The solvent was removed by concentration, and water (35.0 ml) was added to the reaction solution, followed by extraction with ethyl acetate (30.0 ml. times.3). The organic layer was washed with water (10.0 ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was isolated by column chromatography to give the compound of example 3A (7.0 g, 15.7 mmol, 65.6% yield).1H 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).
Example 3B
Figure GPA0000233715180000441
The compound from 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 zero degrees centigrade, after the solids dissolved, sodium nitrite (2.7 g, 39.0 mmol) was added in portions, stirring was continued for an additional hour at zero degrees centigrade and heating to forty degrees centigrade was continued for an additional hour. After the reaction solution was cooled to thirty degrees celsius, it was neutralized with a zero point five mole aqueous sodium hydroxide solution (pH 7-8) at zero degrees celsius. The reaction solution was extracted with ethyl acetate (40 ml. times.3), and the organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated by column chromatography (silica gel) to give the compound of example 3B (3.5 g, 8.5 mmol, 93.0% yield).1H 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).
Example 3C
Figure GPA0000233715180000442
The compound from example 3B (3.5 g, 8.5 mmol) was dissolved in methanol (100.0 ml), aqueous potassium hydroxide (70.0 g, 1.3mol, in water 100.0 ml) was added and the reaction was stirred at one hundred degrees celsius for twelve hours. The solvent was partially removed by concentration and extracted with dichloromethane (30 ml. times.3). The aqueous phase was acidified with one mole of hydrochloric acid (pH 3-4), extracted with ethyl acetate (30 ml × 3), and the organic layer was washed with water (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The compound of example 3C was obtained without purification (3.2 g, 7.9 mmol, 93.5% yield).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)。
Example 3D
Figure GPA0000233715180000451
To an aqueous solution of sodium hydroxide (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 was heated to eighty degrees celsius, sodium borohydride (1.8 g, 47.5 mmol) was added in portions, and the reaction was stirred at one hundred degrees celsiusTwelve hours. Methanol (6 ml) was added dropwise, concentrated to remove part of the solvent, the reaction was acidified with one mole of 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 as example 3D (3.1 g, 7.6 mmol, 96.4% yield).1HNMR(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)。
Example 27
Figure GPA0000233715180000452
The compound of example 3D (1.3 g, 3.2 mmol) was added to dichloromethane (30.0 ml) and the reaction was stirred at thirty degrees celsius for twelve hours with the addition of N, N-dimethyl-4-aminopyridine (78.2 mg, 640.00 μmol) and EDCI (736.1 mg, 3.8 mmol). Dichloromethane (50 ml) was added to the reaction solution, and the organic layer was washed with water (10 ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated by column chromatography to give the compound of example 27 (660.0 mg, 1.4 mmol, 42.6% yield).1H 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).
Preparation of examples 28 to 36 prepared by route 3, according to the procedure of example 27, the following results were obtained:
Figure GPA0000233715180000453
Figure GPA0000233715180000461
Figure GPA0000233715180000471
route 4
Figure GPA0000233715180000481
Preparation of examples 37 to 39 by following the procedure of example 27, starting from the compound of example 3D, prepared by acylation reaction of scheme 4, the results are as follows:
Figure GPA0000233715180000482
route 5
Figure GPA0000233715180000491
In the same manner as in example 27, starting from example 3D, the acylation reaction was carried out, purified to give example 40 as follows:
Figure GPA0000233715180000492
route 6
Figure GPA0000233715180000493
Example 50
Figure GPA0000233715180000501
Example 6A
Figure GPA0000233715180000502
To the compound of example 2A (300.0 mm)G, 629.0 micromoles) was added to thionyl chloride (1.3 g, 11.0 mmol) in toluene (5.0 ml) and reacted at 100 ℃ for 2 hours. The solution was then rotary evaporated to dryness and dissolved in 10ml of tetrahydrofuran and then again rotary dried. The resulting product was dissolved in 10ml of tetrahydrofuran, an aqueous solution (5.0 ml) of sodium azide (122.8 mg, 1.9 mmol) was added thereto at 0 to 10 ℃, and after reacting for 2 hours at 10 ℃, the reaction was quenched with ice water (20 ml), and the aqueous layer was extracted with ethyl acetate (30 ml). The combined organic layers were dried over sodium sulfate, filtered and spun to give about 300 mg of a red oily product, 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 ℃ for 10 hours. After completion of the reaction, the solvent was evaporated to dryness, the reaction was quenched with water (20 ml), and the aqueous layer was extracted with ethyl acetate (20 ml). The combined organic layers were 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 give the compound of example 6A (150.0 mg, 240.3 micromoles, 80.1% yield, 90% purity).1H 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).
Example 50
Figure GPA0000233715180000503
To a solution of the compound from example 6A (150.0 mg, 267 micromoles) in tetrahydrofuran/water (5 ml/3 ml) was added lithium hydroxide monohydrate (11.2 mg, 267 micromoles) and reacted at 40 degrees celsius for 5 hours. After the reaction was complete, ethyl acetate (15 ml) was extracted, the combined organic layers were dried over sodium sulfate, filtered and the crude product obtained was isolated by preparative thin layer chromatography (dichloromethane: ethyl acetate 1: 1) to afford the compound of example 50 (49.0 mg, yield 34.2%, purity 95%).1H 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).
Preparation of examples 41-49 prepared by route 6, reference example 50 was conducted to the procedure of example 50, and the results were as follows:
Figure GPA0000233715180000511
Figure GPA0000233715180000521
Figure GPA0000233715180000531
route 7
Figure GPA0000233715180000541
Example 53
Figure GPA0000233715180000542
Example 7A
Figure GPA0000233715180000543
To a solution of the compound of example 2A (300.0 mg, 629.4 micromoles) in toluene (5.0 ml) was added thionyl chloride (1.3 g, 11.0 mmol) and reacted at 100 degrees celsius for 2 hours. The solution was then spun dry, dissolved in 10ml of tetrahydrofuran and spun dry again. The resulting product was dissolved in 10ml of tetrahydrofuran, to which was added an aqueous solution (5.0 ml) of sodium azide (122.8 mg, 1.9 mmol) at 0-10 ℃. After 2 hours at 10 ℃ the reaction was quenched with ice water (20 ml) and the aqueous layer was washed with brineEthyl acetate (30 ml) was extracted. The combined organic layers were dried over sodium sulfate, filtered and evaporated to give 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 ℃ for 1 hour, then the solvent was spun off, and the product was dissolved in a mixed solution of dichloromethane/tetrahydrofuran (1 ml/1 ml) and (3S) -3-hydroxypyrrole (500.0 mg, 4.1 mmol, hydrochloride) and triethylamine (453.9 mg, 4.5 mmol) were added, respectively, and reacted at 10 ℃ for 10 hours. After the reaction was completed, the reaction was quenched with water (30 ml), extracted with ethyl acetate (30 ml), and the combined organic layers were dried over sodium sulfate, filtered, and the crude product obtained was spin-dried and separated by column chromatography (dichloromethane: methanol ═ 20: 1) to give the compound of example 7A (160.0 mg, yield 86.2%, purity 90%).1H 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).
Example 53
Figure GPA0000233715180000551
To a solution of the compound from example 7A (150.0 mg, 267.5 micromoles) in tetrahydrofuran/water (5 ml/3 ml) was added lithium hydroxide monohydrate (33.7 mg, 802.5 micromoles) and reacted at 40 degrees celsius for 5 hours. After the reaction was complete, extraction was performed with ethyl acetate (20 ml), the combined organic layers were dried over sodium sulfate, filtered and the crude product obtained was isolated by preparative thin layer chromatography (dichloromethane: methane: 20: 1) to give the compound of example 53 (90.0 mg, yield 34%, purity 95%).1H 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).
Preparation of examples 51-58 prepared by route 7, with reference to the procedure of example 53, the results are as follows:
Figure GPA0000233715180000552
Figure GPA0000233715180000561
Figure GPA0000233715180000571
route 8
Figure GPA0000233715180000581
Example 59
Figure GPA0000233715180000582
Example 8A
Figure GPA0000233715180000583
Reference example 1a mixture of the 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 ℃ for 0.5 hour, and then O-benzotriazol-N, N' -tetramethyluronium tetrafluoroborate (95.0 mg, 0.3 mmol) was added. The resulting mixture was stirred at 25 ℃ for 12 hours. After removal of the solvent by rotary evaporation in vacuo, the residue was purified by column chromatography to give the compound of example 8A, (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).
Example 59
Figure GPA0000233715180000584
To a solution of the compound from example 8A (100.0 mg, 0.2 mmol) in tetrahydrofuran (5 ml) was added a solution of methyl magnesium bromide (0.4 ml, 1.1 mmol, 3N) in diethyl ether at 0 degrees celsius and stirring continued at 0 degrees celsius for 30 minutes, then warmed to room temperature and stirred for 12 hours, quenched by addition of ice water and extracted with ethyl acetate (60 ml × 2), the organic phase washed with water was dried over anhydrous sodium sulfate, filtered, the solvent removed in vacuo and the residue purified by preparative TLC to give the compound from example 59 (6.0 mg, 66.0% yield).1H 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)，1.99-1.79(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).
Route 9
Figure GPA0000233715180000591
Example 60
Figure GPA0000233715180000592
Example 9A
Figure GPA0000233715180000593
A solution of potassium monomethyl malonate (2.4 g, 15.1 mmol) and magnesium chloride (479.4 mg, 5.0 mmol) in tetrahydrofuran (20 ml) was stirred at 60 ℃ for 3 hours, cooled to 20 ℃; to a solution of the compound of example 2A (2.4 g, 5.0 mmol) in tetrahydrofuran (8 ml) was added a solution of carbonyldiimidazole (816.5 mg, 5.0 mmol) in tetrahydrofuran (8 ml) and stirred at 25 ℃ for 2 hours; this solution was then added to the previous reaction solution and stirred at 35 ℃ for 10 hours. After completion of the reaction, tetrahydrofuran was dried under reduced pressure, extracted with ethyl acetate (100 ml × 3), the combined organic layers were washed 2 times with saturated brine (10 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20: 1) to give the compound of example 9A (2.2g, 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).
Example 60
Figure GPA0000233715180000601
A solution of hydrogen chloride (200.0 mg, 375.4 micromoles) 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 ℃. After stirring for 30 minutes, the above mixed solution was added to a mixed solution of hydroxylamine hydrochloride (52.2 mg, 750.9. mu. mol) and sodium hydroxide (45 mg) in methanol and water (0.6 ml/0.6 ml) at-30 ℃ for 1 hour with continued stirring, and 36.5% hydrochloric acid (0.6 ml) was added and then stirred for 10 hours while warming to 80 ℃. The reaction was concentrated, extracted with dichloromethane (10 ml × 3), the combined organic layers were washed 2 times with saturated brine (10 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated, and the residue was purified by plate preparation (dichloromethane: methanol ═ 10: 1) to give the compound of example 60 (20.00 mg, 43.5 micromoles, 11.6% yield). 1H NMR (400MHz, CHLOROFORM-d) delta ppm 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).
Example 61
Figure GPA0000233715180000602
To a solution of the compound from example 62 (23.0 mg, 50.0 micromoles) and potassium carbonate (13.8 mg, 100.1 micromoles) in dimethylformamide (2.0 ml) was added iodomethane (8.5 mg, 60.0 micromoles, 3.7 μ l) at 20 degrees celsius under nitrogen protection, after stirring for 3 hours, 5 ml of water was added, extraction was performed with ethyl acetate (10 ml × 3), the combined organic layers were washed 2 times with saturated brine (10 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated, and the residue was purified by preparative plate (ethyl acetate: petroleum ether ═ 10: 1) to give the compound of example 61 (9.0 mg, 34.2% yield).1HNMR(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).
Route 10
Figure GPA0000233715180000611
Example 62
Figure GPA0000233715180000612
Example 10A
Figure GPA0000233715180000613
The compound from example 9A (200.0 mg, 365.8 micromoles) was dissolved in ethanol (3 ml), hydrazine monohydrate (23.8 mg, 475.6 micromoles in ethanol 2 ml) was added dropwise over a minute at 0 ℃, the ice bath was removed and the reaction stirred at 25 ℃ for four hours. The solvent was removed by concentration and the residue was isolated by thin layer chromatography to give the compound of example 10A (90.0 mg, 184.9 micromoles, 50.6% yield).1H 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).
Example 62
Figure GPA0000233715180000614
The compound from example 10A (90.0 mg, 184.9 micromoles) was dissolved in tetrahydrofuran (1.0 ml), methanol (1.0 ml) and water (1.0 ml), lithium hydroxide monohydrate (77.6 mg, 1.9 mmol) was added, and the reaction was stirred at 25 ℃ for twelve hours. The reaction solution was neutralized with 1 mol of hydrochloric acid to pH 5-6, and the solution was extracted with ethyl acetate (10 ml × 3). The resulting organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to thin layer chromatography to give 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，5H)，1.05-1.00(m，4H)，0.93(br.s.，5H)，0.90(br.s.，5H)，0.70(s，3H).
Route 11
Figure GPA0000233715180000621
Example 63
Figure GPA0000233715180000622
Example 11A
Figure GPA0000233715180000623
Preparation of the compound of reference example 1(35.0 g, 83.2 mmol) and p-toluenesulfonic acid (1.4g, 8.3 mmol)The methanol (350 ml) mixture was stirred at 80 ℃ for 2 hours. After cooling filtration and spin-drying of the solvent, the residue was purified by silica gel chromatography to give compound 11A, (30 g, yield 82%).1H 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).
Example 11B
Figure GPA0000233715180000631
To a solution of the compound (200.0 mg, 460.0. mu. mol) of example 11A in methanol (10 ml) was added hydrazine hydrate (515.0 mg, 10.3 mmol), and the reaction was allowed to react at 25 ℃ for 12 hours. The solvent was spun off and the residue was washed with ethyl acetate solution (5 ml) to give the compound of example 11B (120.0 mg, 60.2% yield).1H 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).
Example 63
Figure GPA0000233715180000632
To a solution of compound 11B (180.0 mg, 414.1 micromoles) and carbonyldiimidazole (100.7 mg, 621.2 micromoles) in dimethylformamide (2.00 ml), tetrahydrofuran (2 ml) at 20 ℃ under nitrogen, triethylamine (83.8 mg, 828.2 micromoles, 114.8 microliters) was added, after stirring at 70 ℃ for 12 hours, cooled to 20 ℃, water was added at 20 ml, ethyl acetate (20 ml) was added, extraction was performed 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 (dichloromethane: methanol 50: 1) to give the compound of example 63 (72.0 mg, 35.9% yield).1HNMR(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)。
Route 12
Figure GPA0000233715180000641
Example 64
Figure GPA0000233715180000642
Example 12A
Figure GPA0000233715180000643
The compound of example 11A (1.1 g, 2.5 mmol) was dissolved in methanolic ammonia (14 ml) and stirred at 60-70 ℃ for 18 h. The crude product after lyophilization was purified by column chromatography to give the compound of example 12A (200.0 mg, 19.0% yield).1HNMR(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).
Example 12B
Figure GPA0000233715180000651
Burgess reagent (85.0 mg, 357.5 micromoles) was added to a solution of Compound 12A (150.0 mg, 357.4 micromoles) in tetrahydrofuran (3 ml) at 0 deg.C. The reaction solution was stirred at 10-15 ℃ for 3 hours, washed with saturated brine (15 ml. times.2), and extracted with ethyl acetate (10 ml. times.2). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was vacuum-dried. The crude product was isolated on a thin layer chromatography prep. plate to give the compound of example 12B (30.0 mg, 21.0% yield).1H 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).
Example 64
Figure GPA0000233715180000652
Dibutyltin oxide (40.0 mg, 74.7. mu. mol) and trimethylsilylazide (52.0 mg, 451.4. mu. mol) were added to a solution of the compound from example 12B (30.0 mg, 74.7. mu. mol) in toluene (2 mL) and stirred at 100 ℃ 110 ℃ for 18 h. After completion of the reaction, the reaction solution was cooled to 25 to 30 ℃, washed with saturated brine (15 ml × 2), and extracted with ethyl acetate (8 ml × 2). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was vacuum-dried. The crude product was isolated by thin layer chromatography preparative plate to give the compound of example 64 (7.0 mg, 21.0% yield). 1H NMR (400MHz, CHLOROFORM-d) delta 3.65-3.81(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, 1H)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).
Route 13
Figure GPA0000233715180000661
Example 65
Figure GPA0000233715180000662
Example 13A
Figure GPA0000233715180000663
3, 4-dihydropyran (1.6 g, 18.4 mmol), the compound of example 12A (1.0 g, 2.3 mmol) and p-toluenesulfonic acid (35.9 mg, 0) were reacted.2 mmol) of 1, 4-dioxane (20 ml) was stirred at 25 ℃ for 0.5 h. After cooling and spin-drying, the residue was extracted with ethyl acetate, washed successively with water, saturated brine, and the organic phase was spin-dried and purified by silica gel chromatography to give the compound of example 13A (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，2H)，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).
Example 13B
Figure GPA0000233715180000671
A solution of the compound from example 13A (500 mg, 0.8 mmol) in tetrahydrofuran (5 ml) was added lithium aluminium hydride (94.4 mg, 2.5 mmol) at 0 degrees celsius and after stirring the mixture at 0 degrees celsius for a further 1 hour 94.4 ml water was added, filtered, the filtrate diluted with ethyl acetate and washed with aqueous sodium bicarbonate to give the compound from example 13B (400 mg, 84% yield) after the organic phase was spun off which was used directly in the next reaction.1H 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).
Example 13C
Figure GPA0000233715180000672
Pyridine chromate (215.0 mg, 997.4 micromoles) was added in one portion to a solution of the compound of example 13B (230.0 mg, 400.1 micromoles) in dichloromethane (10 ml) and the mixture was reacted at 18 degrees celsius for 2 hours. After the reaction was filtered and spun dry, the residue was purified by prep. plate to give the compound of example 13C (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).
Example 13D
Figure GPA0000233715180000673
To an ethanol solution (500 ml) of the compound from example 13C (150.0 mg, 233.3 micromoles) were 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). After stirring at 60 ℃ for 6 hours, the reaction solution was poured into ice water (50 ml), and the aqueous layer was extracted with ethyl acetate (50 ml. times.3). The combined organic layers were washed with brine (50 ml × 2), the organic layer was dried over sodium sulfate, filtered and evaporated, and the residue was purified by preparative plate to give the compound of example 13D (80.0 mg, yield 72.1%).1H 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).
Example 65
Figure GPA0000233715180000681
To a solution of acetyl chloride (320.5 mg, 4.1 mmol) in methanol (2 ml) at 0 deg.c was added dropwise a solution of the compound from example 13D (75.0 mg, 116.7 μmol) in methanol (1 ml). After stirring at 0 ℃ for 4h, the reaction was spin dried and the residue was purified by preparative plate to give the compound of example 65 (55.0 mg, 99.0% yield).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).
Route 14
Figure GPA0000233715180000682
Examples 66A and 66B
Figure GPA0000233715180000691
Example 14A
Figure GPA0000233715180000692
To a solution of the compound from 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), stirred at 0 ℃ for 1 hour, and after removal of the solvent in vacuo, the residue was purified by column chromatography on silica gel to give the compound from example 14A (60.0 mg, 33.1% yield).1H NMR(400MHz，CHLOROFORM-d)δ4.73(d，J＝3.8Hz，1H)，4.03-3.78(m，2H)，3.70(br.s.，1H)，3.58-3.35(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).
Examples 66A and 66B
Figure GPA0000233715180000693
The procedure was as in example 65, starting from the title compound 14A and purifying to give the compound of example 66A and the compound of example 66B (27.0 mg, yield 61.0%).1H NMR (400MHz, CHLOROFORM-d) δ 3.92(dd, J ═ 4.0, 9.0Hz, 1H), 3.71(br.s., 1H), 3.46-3.35(m, 1H), 2.86-2.65(m, 1H), 2.14(dt, J ═ 3.8, 12.8Hz, 1H), 1.98(d, J ═ 11.8Hz, 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%).1H NMR(400MHz，CHLOROFORM-d)δ4.00-3.80(m，1H)，3.70(br.s.，1H)，3.48-3.34(m，1H)，2.72(br.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).
Route 15
Figure GPA0000233715180000701
Example 67
Figure GPA0000233715180000702
Example 15A
Figure GPA0000233715180000703
To a solution of the compound of example 2A (100.0 mg, 0.2 mmol) and lead acetate (186.0 mg, 0.4 mmol) in carbon tetrachloride (2 ml) was added elemental iodine (106 mg, 0.4 mmol), and the reaction system was reacted under light for 12 hours. The reaction was quenched by addition of sodium thiosulfate solution (1 ml), the aqueous layer was extracted with dichloromethane (10 ml × 3), dried over sodium sulfate, filtered and spun dry, and the residue was purified by preparative thin layer plate (petroleum ether: ethyl acetate ═ 5: 1) to give the compound of example 15A (50.0 mg, 38.0% yield).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).
Example 15B
Figure GPA0000233715180000711
A mixture of the compound from example 15A (100.0 mg, 179. mu. mol) in triethylphosphite (149.0 mg, 895. mu. mol) was stirred at 160 deg.C for 6 hours. After dilution with water (5 ml), extraction with ethyl acetate (10 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and spin-dried, and the residue was purified byPreparative thin layer plate purification (petroleum ether: ethyl acetate 1: 1) gave the compound of example 15B (90.0 mg, 84.1% yield).1H-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).
Example 67
Figure GPA0000233715180000712
Referring to example 53, starting from compound 15B (40.0 mg, 70.3 micromoles), the compound of example 67 was obtained (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).
Route 16
Figure GPA0000233715180000713
Example 68
Figure GPA0000233715180000721
Example 16A
Figure GPA0000233715180000722
To a solution of N-tert-butoxycarbonyl-1, 2, 5-thiadiazoline 1, 1-dioxide (20.0 mg, 89.5 micromoles) in N, N-dimethylformamide (1 ml) was added sodium hydrogen (7.0 mg, 179 micromoles) at zero degrees. Half an hour later, the compound of example 15A (50.0) is added dropwiseMg, 89.5 micromoles) of N, N-dimethylformamide (1 ml). After the dropwise addition, the reaction system was slowly warmed to room temperature and reacted for another 1 hour. The reaction was quenched with water (5 ml), the aqueous layer was extracted with ethyl acetate (10 ml × 3), the organic layers were combined, dried over sodium sulfate, filtered and spun dry, and the residue was purified by preparative thin layer plate (petroleum ether: ethyl acetate ═ 1: 1) to give compound 16A compound (30.0 mg, yield 57.5%).1H-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).
Example 68
Figure GPA0000233715180000723
Referring to example 53, the compound of example 16A was used as starting material (30.0 mg, 57 micromoles) to provide the compound of example 68 (20.0 mg, 67.1% yield).1H-NMR(CDCl3，400MHz)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)，1.80(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).
Preparation of examples 69 and 70 prepared by route 16, reference example 68 was run, and the results were as follows:
Figure GPA0000233715180000724
Figure GPA0000233715180000731
route 17
Figure GPA0000233715180000732
Example 71
Figure GPA0000233715180000733
Example 17A
Figure GPA0000233715180000741
Silver carbonate (197.5 mg, 716.2 micromoles) was added to a solution of the compound of example 15A (200.0 mg, 200.0 micromoles) in a mixture of acetone (2.8 ml) and water (150.0 μ l) at 25 ℃. Stirring was carried out at 25 ℃ for 30 minutes, followed by warming to 80 ℃ and stirring was continued for 12 hours. Thin layer chromatography (petroleum ether: ethyl acetate 2: 1) detects that the new compound with increased polarity is generated. The reaction suspension was filtered, and the solvent was removed from the filtrate under reduced pressure to obtain a residue. The residue was purified using a thin layer prep plate (petroleum ether: ethyl acetate 2: 1) to give the compound of example 17A (46.0 mg, 27.2% yield, 95% purity).1H 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).
Example 17B
Figure GPA0000233715180000742
To a solution of the compound from example 17A (40.0 mg, 89.2 micromoles) in toluene (3 ml) was added ethyl isocyanate (13.0 mg, 178.4 micromoles) and the reaction was stirred at 110 degrees celsius for 12 hours. The solvent was spun dry and the residue was purified by preparative thin layer plate (petroleum ether: ethyl acetate 2: 1) to give the compound of example 17B (5 mg, 9.7% yield).1H-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，2H)，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).
Example 71
Figure GPA0000233715180000743
Referring to example 53, starting from the compound of example 17B, purification gave the compound of example 71 (5.0 mg, yield 53.0%).1H-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，7H)，1.14(s，3H)，0.97(d，J＝6.3Hz，3H)，0.89-0.93(m，6H)，0.67(s，3H).
Route 18
Figure GPA0000233715180000751
Example 72
Figure GPA0000233715180000752
Example 18A
Figure GPA0000233715180000753
Formic acid (8.2 mg, 8.2 micromoles) was added dropwise to a round bottom flask charged with chlorosulfonic isocyanate (24.1 mg, 24.1 micromoles) at 0 degrees celsius and stirred for 5 minutes at 0 degrees celsius, yielding a white solid. Dichloromethane (3.0 ml) was added to the reaction and stirring was continued at 0 ℃ for 1 hour, followed by warming to 25 ℃ and stirring continued for 4 hours. The reaction was cooled to 0 ℃ and the compound from example 17A (50.0 mg, 111.5. mu. mol) and pyridine (13.5 mg, 13.5. mu.M)Micromoles) of the mixture is added to the reaction system. The reaction mixture was warmed to 25 ℃ and stirred for an additional 12h, the solvent was distilled off under reduced pressure and the residue was purified using a thin layer prep plate (petroleum ether: ethyl acetate 2: 1) to give the compound of example 18A (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).
Example 72
Figure GPA0000233715180000761
In the same manner as in example 53, the compound of example 18A was used as a starting material and was purified to obtain the compound of example 72 (10.0 mg, yield 56.0%, purity 90%).1H 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).
Route 19
Figure GPA0000233715180000762
Example 73
Figure GPA0000233715180000763
Example 19A
Figure GPA0000233715180000771
The compound (1.5g, 2.7 mmol) of example 15A was dissolved in N-methylpyrrolidone (8.0 ml), sodium azide (1.5g, 23.1 mmol) and acetic acid (1.9 g, 32.3 mmol) were added in this order, and the reaction mixture was stirred at 20 ℃ for 2 minutes0 hour. The reaction was quenched by addition of saturated aqueous sodium bicarbonate (5 ml) and extracted with ethyl acetate (20 ml × 3). The organic layer was washed with water (10 ml. times.4), dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was isolated by column chromatography (silica gel) to give the compound of example 19A (1.2 g, 89.0% yield).1H 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).
Example 19B
Figure GPA0000233715180000772
The compound (1.0 g, 2.1 mmol) of example 19A was dissolved in tetrahydrofuran (20.0 ml), triphenylphosphine (1.7 g, 6.3 mmol) and water (1.0 ml) were added sequentially under nitrogen, and the reaction was stirred at 20 ℃ for twelve 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, 50.3% yield).1HNMR(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(br.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).
Example 19C
Figure GPA0000233715180000773
The compound of example 19B (50.0 mg, 111.7 micromoles) was dissolved in N, N-dimethylformamide (1.0 ml) and dichloromethane (2.0 ml), an aqueous solution of sodium bicarbonate (28.2 mg, 335.1 micromoles) (1.0 ml) and thiophosgene (15.4 mg, 134.0 micromoles) were added sequentially at 0 ℃, the reaction was reacted at 20 ℃ for thirty minutes, water (10 ml) was added, and dichloromethane was extracted (10 ml × 3). The organic layer was washed successively with water (10 ml) and saturated brine (10 ml), and the filtrate wasDried over anhydrous sodium sulfate, filtered and concentrated, the resulting residue was dissolved in tetrahydrofuran (4.0 ml), and (3R) -3-hydroxypyrrole hydrochloride (11.7 mg, 94.5 micromoles) and triethylamine (13.6 mg, 134.0 micromoles) were added in this order at 20 degrees celsius, and the reaction 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. times.3). The organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was chromatographed by thin layer chromatography to give the compound of example 19C (40.0 mg, 62.0% yield).1H 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).
Example 73
Figure GPA0000233715180000781
Referring to example 53, starting from the compound of example 19C, purification gave the compound of example 73 (27.0 mg, 71% yield).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).
Route 20
Figure GPA0000233715180000782
Example 74
Figure GPA0000233715180000783
Example 20A
Figure GPA0000233715180000791
The compound of example 19B (80.0 mg, 178.7 micromoles) was dissolved in dichloromethane (4.0 ml) and diisopropylethylamine (34.6 mg, 268.1 micromoles) and 2-isopropyl isocyanate (27.1 mg, 268.1 micromoles) were added in that order and the reaction was stirred at 20 ℃ 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 20A (60.0 mg, 58.0% yield).1H 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).
Example 74
Figure GPA0000233715180000792
Referring to example 53, starting from the compound of example 20A, the compound of example 74 was obtained (48.0 mg, 85.0% yield).1H 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).
Route 21
Figure GPA0000233715180000801
Example 75
Figure GPA0000233715180000802
Example 21A
Figure GPA0000233715180000803
The compound of example 12A (5.0 g, 11.5 mmol) was dissolved in anhydrous toluene (80.0 ml) and silver carbonate/celite (12.6 g, 46.0 mmol) was added and the reaction was stirred at 130 degrees celsius for twelve hours. After cooling to room temperature, the solvent was removed by concentration. Column chromatography (silica gel) of the residue gave the compound of example 21A (3.6 g, 69.0% yield).1H 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).
Example 21B
Figure GPA0000233715180000804
Under nitrogen, a toluene solution (3 ml) of the compound (601.4 mg, 1.4 mmol) of example 21A was added dropwise to a suspension (20 ml) of anhydrous toluene containing sodium hydrogen (40.0 mg, 1.7 mmol), followed by dropwise addition of a toluene solution (2 ml) of ethyl formate (308.9 mg, 4.2 mmol), and the mixture was stirred at 20 ℃ for 1 hour. Absolute ethanol (76.8 mg, 1.7 mmol) was then added and stirring continued for 11 hours. The reaction was poured into ice water, extracted with ethyl acetate (20 ml × 3), and the combined organic phases were washed with saturated brine (10 ml × 2), dried over anhydrous sodium sulfate, filtered and concentrated to give the compound of example 21B (500.0 mg, 72.0% yield).1H 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).
Example 21C
Figure GPA0000233715180000811
The compound of example 21B (100.0 mg, 210.7 micromoles) was dissolved in ethanol (3.00 ml), hydrazine hydrate (21.1 mg, 421.4 micromoles) was added to the resulting solution, and the reaction was stirred at 80 ℃ for 1 hour. The solvent was removed by concentration, and the resulting residue was subjected to 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)，2.43-2.26(m，1H)，2.23-2.09(m，3H)，1.96-1.73(m，7H)，1.67-1.52(m，4H)，1.46-1.35(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).
Example 75
Figure GPA0000233715180000812
The compound from example 21C (65.0 mg, 138.1 micromoles) was dissolved in tetrahydrofuran (4.0 ml) and then an aqueous solution of sodium hydroxide (55.2 mg, 1.4 mmol) (2.0 ml) was added and the reaction was stirred at 30 degrees celsius for 12 hours. Acidification to pH 2-3 with 1N dilute hydrochloric acid, extraction with ethyl acetate (10 ml. times.3), washing of the organic layer with water (10 ml), drying over anhydrous sodium sulfate, filtration and concentration gave a residue which was chromatographed by thin layer chromatography to give the compound of example 75 (14.0 mg, 22.0% yield).1H 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).
Route 22
Figure GPA0000233715180000821
Example 76
Figure GPA0000233715180000822
Example 22A
Figure GPA0000233715180000823
The compound of example 21C (90.0 mg, 191.2 micromoles) was dissolved in N, N-dimethylformamide (4.0 ml), then dimethyl sulfate (440.0 mg, 3.5 mmol) and potassium carbonate (79.3 mg, 573.6 micromoles) were added and the reaction 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).1H 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).
Example 76
Figure GPA0000233715180000831
By following the procedure of example 53, starting from the compound of example 22A (20.0 mg, 37.1. mu. mol), the ethoxylation was removed by LiOH and the compound of example 76 (10.0 mg, 50% yield) was isolated by thin layer chromatography.1HNMR(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)，2.58-2.20(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).
Route 23
Figure GPA0000233715180000832
Example 77
Figure GPA0000233715180000833
Example 23A
Figure GPA0000233715180000834
After the compound of example 21B (400.0 mg, 895.6 μmol) was dissolved in methanol (10.0 ml), sodium borohydride (203.3 mg, 5.4 mmol) was added and the reaction was stirred at 0 ℃ for 1 hour. The reaction was quenched by the addition of saturated ammonium chloride solution (5 ml), concentrated to remove the solvent, and water (5 ml) was added to the residue, which was extracted with ethyl acetate (10 ml × 3). The organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and the resulting residue was subjected to thin layer chromatography to give the compound of example 23A (120.0 mg, yield 28.0%, colorless oil).1H 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).
Example 77
Figure GPA0000233715180000841
Using the compound of example 23A as a starting material (100.0 mg, 208.9 μmol), prepared according to the method described in example 65, example 77 was isolated by thin layer chromatography to give the compound of example 77 (20.0 mg, 20.0% yield).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).
Route 24
Figure GPA0000233715180000842
Example 78
Figure GPA0000233715180000843
Example 24A
Figure GPA0000233715180000851
The compound of example 21A (10.0 g, 23.1 mmol) was dissolved in pyridine (100 ml), acetic anhydride (28.3 g, 277.4 mmol) and 4-N, N-dimethylaminopyridine (282.4 mg, 2.3 mmol) were added, reflux was carried out at 110 ℃ for 6 hours, the TLC run was complete, the solvent was removed by concentration, and the residue was chromatographed by thin layer chromatography to give the compound of example 24A (9.2 g, 84.0% yield).1H 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).
Example 24B
Figure GPA0000233715180000852
Diethylaminosulfur trifluoride (132.4 mg, 821.6 micromoles) was added dropwise to a solution of the compound from example 24A (130.0 mg, 273.9 micromoles) in dichloromethane (3.0 ml) and stirred at 25-30 ℃ for 18 hours. After completion of the reaction, the reaction solution was quenched with ice water, extracted with ethyl acetate (10 ml × 2), and 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 isolated and purified by thin layer chromatography preparative plate (petroleum ether/ethyl acetate 10/1) to give the compound of example 24B (75.0 mg, 50.1 yield%, purity 90%).1H 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)1.57-1.69(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).
Example 78
Figure GPA0000233715180000853
The same procedure as for the title compound 53, starting from compound 24B (75.0 mg, 151.0 micromoles), was worked up and purified to give the title compound 78(55.0 mg, 74.0% yield, 90% purity).1H 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).
Route 25
Figure GPA0000233715180000861
Examples 79A and 79B
Figure GPA0000233715180000862
Example 25A
Figure GPA0000233715180000863
Lithium hydroxide monohydrate (35.3 mg, 1.5 mmol) was added to a mixed solution of the compound of example 24A (100.0 mg, 0.2 mmol) in methanol (2 ml) and water (0.5 ml) and stirred at 20-25 ℃ for 18 hours. After completion of the reaction, the reaction solution was acidified with 2M diluted hydrochloric acid, washed with saturated brine (15 ml × 2), and extracted with ethyl acetate (10 ml × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure. The crude product is separated by thin layer chromatography preparative plate (dichloromethane/methanol ═ dichloromethane)20/1) gave the compound of example 25A (60.0 mg, 88.0% yield).1H 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).
Example 25B
Figure GPA0000233715180000871
A solution of methylmagnesium bromide (0.4 mL, 651.2 μm, 3N) in diethyl ether was added dropwise to a solution of the compound from example 25A (60.0 mg, 130.2 μm) in tetrahydrofuran (4 mL) at 0 deg.C under nitrogen and stirred for 2 hours. After completion of the reaction, it was quenched with a saturated ammonium chloride solution and extracted with ethyl acetate (10 ml × 2). The organic phase was washed with saturated brine (15 ml. times.2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was isolated by preparative thin layer chromatography on plate (dichloromethane/methanol-20/1) to afford the compound of example 25B.
The compound of example 25B 1(35.0 mg, 56.0% yield).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).
The compound of example 25B2 (15.0 mg, 24.0% yield).1H 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).
Examples 79A and 79B
Figure GPA0000233715180000872
Sodium hydroxide (1.5g, 37.5 mmol) was added to example 25B1A solution of compound (35.0 mg, 73.4. mu. mol) in methanol (2.0 ml) was stirred at 70-80 ℃ for 55 hours. After completion of the reaction, the reaction mixture was acidified to a pH of about 5 with 2N diluted hydrochloric acid, extracted with ethyl acetate (8 ml. times.2), and the organic phase was washed with saturated brine (10 ml. times.2), dried over anhydrous sodium sulfate, filtered, and evaporated to dryness under reduced pressure. The crude product was purified on a thin layer chromatography plate (dichloromethane/methanol ═ 15/1) to afford the compound of example 79A (20.0 mg, 63.0% yield).1H 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).
The same procedure as for the compound of example 79A was followed, starting from the compound of example 25B2 (15.0 mg, 31.5 μm), and the crude product was purified by thin layer chromatography (dichloromethane/methanol 15/1) to afford the compound of example 79B (6.0 mg, 44.0% yield).1HNMR(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).
Route 26
Figure GPA0000233715180000881
Example 80
Figure GPA0000233715180000882
Example 26A
Figure GPA0000233715180000883
Tebbe reagent (0.5M in toluene, 0.1 mmol) was added to a solution of the compound from example 24A (60.0 mg, 0.1 μmol) in tetrahydrofuran (2.0 ml) at 0 degrees celsius under nitrogen. After stirring at 0 ℃ for 4 hours, the temperature is raised to 25-30 ℃ and stirring is carried out for 16 hours. 2 ml of 2M sodium hydroxide solutionThe reaction solution was added to the reaction solution and filtered, the filtrate was extracted with ethyl acetate (10 ml. times.2), and the organic phase was washed with saturated brine (15 ml. times.2), dried over anhydrous sodium sulfate, filtered, and spin-dried under reduced pressure. The crude product was purified by thin layer chromatography (petroleum ether/ethyl acetate 5/1) to give the compound of example 26A (33.0 mg, 55.0% yield).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)2.10-2.20(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).
Example 26B
Figure GPA0000233715180000891
Diethyl zinc (22.9 mg, 185.8 μm) and diiodomethane (79.6 mg, 297.2 μm) were added sequentially to a solution of the compound from example 26A (40.0 mg, 92.9 μm) in toluene (2.0 ml) under nitrogen. Stirring for 0.5 hour at 25-30 deg.C, and gradually turning the reaction solution into white suspension. The nitrogen was then replaced by oxygen, during which the suspension turned from white to pink. The reaction was then stirred at 65-75 ℃ for 3.5 hours, during which time the suspension changed from pink to light yellow. After completion of the reaction, 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 spin-dried under reduced pressure. The crude product was purified by thin layer chromatography (petroleum ether/ethyl acetate 10/1) to give the compound of example 26B (30.0 mg, 69% yield).1H 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).
Example 80
Figure GPA0000233715180000892
The procedure was as in example 53 starting from compound 26B (30.0 mg, 67.5 μm) and purified by thin layer chromatography (petroleum ether/ethyl acetate 3/1) to give the title compound 80(20.0 mg, 65% yield).1H 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，4H)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).
Route 27
Figure GPA0000233715180000901
Example 81
Figure GPA0000233715180000902
Example 27A
Figure GPA0000233715180000903
Dry palladium on carbon (5.0 mg) was added to a solution of compound 26A (33.0 mg, 69.8 μm) in methanol (4 ml) under nitrogen and replaced three times with a hydrogen balloon, and then the reaction was stirred at 20-28 ℃ under 1 atm of hydrogen for 18 hours. The reaction was then filtered and the solvent was dried under reduced pressure to give the compound of example 27A (25.0 mg, 75% yield).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，2H)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).
Example 81
Figure GPA0000233715180000904
The same procedure as in example 53 was followed, starting from compound 27A (50.0 mg, 105.3 μmol), and the crude product was purified by thin layer chromatography (petroleum ether/ethyl acetate 1/1) to give the title compound 81(30.0 mg, 68% yield).1H 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).
Route 28
Figure GPA0000233715180000911
Examples 82A and 82B
Figure GPA0000233715180000912
Example 28A
Figure GPA0000233715180000913
Borane in tetrahydrofuran solution (1M, 58.0 μ M) was added to a solution of the compound from example 26A (25.0 mg, 58.0 μ M) in tetrahydrofuran (1.5 ml) and stirred at 25-30 ℃ for 4 h. After completion of the reaction, the reaction solution was cooled to 0 ℃, and water (0.1 ml), a 5 mol aqueous solution of sodium hydroxide (0.2 ml) and hydrogen peroxide (30% aqueous solution, 6.9 mmol) were sequentially added. Stirring for 3 hours at 25-30 ℃. After completion of the reaction, 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 spin-dried under reduced pressure. The crude product was purified by thin layer chromatography (petroleum ether/ethyl acetate 3/1) to give the compound of example 28a1 (6.0 mg, 14% yield, 60% purity).1H NMR(400MHz，CHLOROFORM-d)δ3.70-3.75(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 the compound of example 28A1 (9.0 mg, 28% yield, 80% purity).1H 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).
Examples 82A and 82B
Figure GPA0000233715180000921
The same procedure as in example 53, starting from compound 28a1(35.0 mg, 78.0 μm) and 28a2(25.0 mg, 55.7 μm), was followed and the crude product was purified by thin layer chromatography (20 ml/1 drop petroleum ether/ethyl acetate/acetic acid) to afford the compound of example 82A and the compound of example 82B.
EXAMPLE 82A Compound (15.0 mg, 44% yield)1H 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).
The compound of example 82B (10.0 mg, 39% yield, 95% purity).1H 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).
Route 29
Figure GPA0000233715180000922
Example 83
Figure GPA0000233715180000931
After sodium hydrogen (13.2 mg, 552.2 micromoles) was added to a mixed solution of compound 11A (40.0 mg, 92.0 micromoles) in N, N-dimethylformamide (1 ml) and tetrahydrofuran (2 ml) at 0 ℃ and stirred for 5 minutes, methyl iodide (270.0 mg, 1.9 mmol) was added to the reaction solution and stirred at 25-30 ℃ for 18 hours. After completion of the reaction as monitored by a thin layer preparative chromatography plate, the reaction solution was extracted with ethyl acetate (10 ml. times.2), the organic phase was washed with saturated brine (15 ml. times.2), dried over anhydrous sodium sulfate, and filtered. The crude filtrate, concentrated under reduced pressure, was purified by thin layer chromatography (petroleum ether/ethyl acetate 7/3) to afford the compound of example 83 (20 mg, 48% yield, 95% purity).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).
Route 30
Figure GPA0000233715180000932
Example 84
Figure GPA0000233715180000933
Example 30A
Figure GPA0000233715180000941
After n-butyllithium (0.1 ml, 2.5 moles per liter of n-hexane solution) was added to a solution of methoxymethyl triphenyl phosphonium chloride (151.7 mg, 442.4 micromoles) in diethyl ether (5.0 ml) at-60 deg.C under nitrogen, the reaction solution was stirred at 25-30 deg.C for half an hour during which a reddish-red phosphine ylide was formed. Then, a solution of the compound (70.0 mg, 147.5. mu. mol) prepared in example 24A in tetrahydrofuran (2.0 ml) was added dropwise to the reaction solution while cooling on ice, and the mixture was stirred at 25 to 30 ℃ for 3 hours. Reaction solutionAfter quenching with saturated ammonia chloride solution, extraction was performed with ethyl acetate (10 ml. times.2). The organic phase was washed with saturated brine (15 ml. times.2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was isolated and purified by thin layer chromatography preparative plate to give the compound of example 30A (30.0 mg, 38% yield, 95% purity).1H 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).
Example 30B
Figure GPA0000233715180000942
Concentrated hydrochloric acid (12M, 200.0. mu.l) was added dropwise to a solution of the compound from example 30A (30.0 mg, 59.7. mu. mol) in dioxane (2.0 ml) and stirred at 25-30 ℃ for 2 hours. After completion of the reaction, the reaction solution was extracted with ethyl acetate (10 ml × 2), and 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 isolated and purified by thin layer chromatography preparative plate (petroleum ether/ethyl acetate 8/1) to give the compound of example 30B (15.0 mg, 42% yield, 85% purity).1H 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).
Example 30C
Figure GPA0000233715180000951
Diethylaminosulfur trifluoride (82.5 mg, 511.6. mu.mol) was added dropwise to the compound of example 30B (50.0 mg, 102.3. mu.mol) in dichloromethane (2)0 ml) and stirred at 25-30 ℃ for 36 hours. After completion of the reaction, 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 isolated and purified by thin layer chromatography preparative plate (petroleum ether/ethyl acetate 8/1) to give the compound of example 30C (40.0 mg, 69% yield, 90% purity).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)1.75-1.87(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).
Example 84
Figure GPA0000233715180000952
The same procedure as in example 53 was repeated, using compound 30C (40.0 mg, 78.33 μmol) as a starting material, and the crude product obtained by the reaction workup was isolated and purified by thin layer chromatography preparative plate (petroleum ether/ethyl acetate: 3/1) to give the compound of example 84 (25.0 mg, yield 67%, purity 95%) as a white solid.1H 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，1H)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).
Route 31
Figure GPA0000233715180000953
Example 85
Figure GPA0000233715180000961
Example 31A
Figure GPA0000233715180000962
Compound 19B (20.0 mg, 44.7 mmol) was dissolved in dichloromethane (3.0 ml), and a solution of N, N-dimethyl-4-aminopyridine (1.1 mg, 9.0 mmol) and phenylsulfonyl chloride (11.8 mg, 67.0 mmol) in dichloromethane (1 ml) was added sequentially and stirred at 20 ℃ 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 31A (12.0 mg, yield 48%, near colorless liquid).1H 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)，3.08-2.99(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).
Example 85
Figure GPA0000233715180000963
By following the same procedure as in example 53, starting from compound 31A (42.0 mg, 75.0 mmol), purification was carried out to give the compound of example 85 (15.0 mg, 37.59% yield).1H 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，11H)，1.20-1.06(m，5H)，0.89(s，4H)，0.85(d，J＝6.5Hz，3H)，0.66-0.55(m，3H).
Preparation of examples 86 and 87 prepared by route 31, reference example 85 was conducted to the procedure for preparation of example 85, and the results were as follows:
Figure GPA0000233715180000971
route 32
Figure GPA0000233715180000972
Example 88
Figure GPA0000233715180000981
Potassium carbonate (27.8 mg, 27.8 micromoles) and dimethyl sulfate (25.3 mg, 25.3 micromoles) were added to a solution of the compound of example 2 (40.0 mg, 80.4 micromoles) in acetone (1.0 ml) at 20 degrees celsius. The mixture was stirred for 12 hours. The completion of the reaction was checked by thin layer chromatography (petroleum ether/ethyl acetate 1/2). The solvent was evaporated under reduced pressure and isolated and purified using a thin layer prep plate (petroleum ether/ethyl acetate 1/2) to give the compound of example 88 (23.0 mg, yield 13%, white solid).1HNMR(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).
Route 33
Figure GPA0000233715180000982
Example 89
Figure GPA0000233715180000983
Example 33A
Figure GPA0000233715180000991
To a solution of the compound of example 11A (5.0 g, 11.5 mmol) in pyridine (20 ml) were added acetic anhydride (7.1 g, 69.1 mmol) and N, N-dimethylaminopyridine (140.5 mg, 1.2 mmol) and the reaction was stirred at 80 degrees celsius for 12 hours. The solvent was spun dry and the system was washed with saturated aqueous sodium bicarbonate (10 ml), the reaction was extracted with ethyl acetate (15 ml × 3), the combined organic layers were 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)。
Example 33B
Figure GPA0000233715180000992
To a solution of the compound from example 33A (100.0 mg, 193.0 micromoles) in methanol was added a mixture of hydrochloric acid (12M, 0.2 ml) and stirred at 20 degrees celsius for 12 hours. The solvent was dried, the system was washed with saturated aqueous sodium bicarbonate (10 ml), the reaction was extracted with ethyl acetate (15 ml × 3), the combined organic layers were dried over sodium sulfate, filtered and evaporated to give the compound of example 33B (90.0 mg, 98% yield).1H-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)。
Example 33C
Figure GPA0000233715180000993
To a solution of the compound from example 33B (100.0 mg, 209.0 μmol), triphenylphosphine (304.0 mg, 1.2 μmol) and imidazole (83.0 mg, 1.2 μmol) in toluene (8 ml) and acetonitrile (2 ml) was added iodine (266.0 mg, 1.1 mmol). After reacting at 20 ℃ for 1 hour, a 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 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，5H)，1.17-1.06(m，4H)，1.03(s，3H)，0.93-0.87(m，6H)，0.68-0.61(m，3H)。
Example 33D
Figure GPA0000233715180001001
To the compound of example 33C (2.3 g, 3.9 mmol), pyrazole (534.0 mg, 7.8 mmol) in DMF (30 ml) was added potassium carbonate (1.0 g, 7.8 mmol). After 12 hours at 60 ℃, water (50 ml) was added to the reaction system, the aqueous layer was extracted with ethyl acetate (30 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 compound of example 33D (1.4g, 78%).1H 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)。
Example 33E
Figure GPA0000233715180001002
Diethyl zinc (1M, 3.3 ml) was added dropwise to a solution of diiodomethane (438.0 mg, 1.6 mmol) in dichloromethane under nitrogen atmosphere at zero temperature, and after 30 minutes, a solution of the compound of example 33D (150.0 mg, 327.0 micromoles) in dichloromethane (2 ml) was added dropwise at zero temperature, and the reaction was carried out at 20 ℃ for 12 hours. Water (5 ml) was added to the reaction, the system was adjusted to Ph 6 with hydrochloric acid solution (1M), the aqueous layer was extracted with dichloromethane (10 ml × 3), the organic layers were combined, dried over sodium sulfate, filtered and evaporated to give the compound of example 33E (110.0 mg, 71%).1H 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)。
Example 89
Figure GPA0000233715180001011
To an ethanol solution (1 ml) of the compound (40.0 mg, 84.3. mu. mol) of example 33E was added a 10% by mass aqueous solution (1 ml) of potassium hydroxide, and the mixture was reacted at 70 ℃ for 12 hours. The system was adjusted to Ph 2 with hydrochloric acid solution (1M), the aqueous layer was extracted with ethyl acetate (10 ml × 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%).1H 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)。
Route 34
Figure GPA0000233715180001012
Example 34A
Figure GPA0000233715180001013
To a dry 25 ml round bottom flask was added dry palladium on carbon (50 mg, water < 1%) and the compound from example 33D (600.0 mg, 720.1 micromoles), then anhydrous methanol (5.0 ml) and tetrahydrofuran (5.0 ml) were added and the reaction was purged three times with nitrogen and then three times with hydrogen and the reaction was stirred at 25 ℃ for 48 hours under an atmosphere of hydrogen (15 psi). The reaction was filtered through celite, washed with dichloromethane/methanol (10/1, 20 ml) and the filtrate was concentrated to give the compound of example 34A (550.0 mg, 91% yield).1H 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).
Example 34B
Figure GPA0000233715180001021
The compound of example 34B (400.0 mg, 75.3% yield) was synthesized as in example 53, starting from example 35A (550.0 mg, 1.3 mmol). 1H NMR (400MHz, CHLOROFORM-d) δ 3.72(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), 1.77-1.60(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).
Example 90
Figure GPA0000233715180001022
The same procedure as in example 2A was followed, starting from example 34B (100.0 mg, 247.2 micromoles), and carrying out the acylation reaction to purify the compound of example 90 (20.0 mg, 16.8% yield). 1H NMR (400MHz, 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).
Route 35
Figure GPA0000233715180001023
Example 91
Figure GPA0000233715180001031
Example 35A
Figure GPA0000233715180001032
Sodium hydroxide (79.6 mg, 2.0 mmol) was added to a solution of the compound of example 13A (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 completion of the reaction, the solvent was concentrated to 5 ml, and diluted with ethyl acetate to 12 ml, and then acidified to pH 5-6 with 2M dilute hydrochloric acid and citric acid, after separation of layers, the organic phase was washed with saturated brine (25 ml × 3), extracted with ethyl acetate (20 ml × 3), dried over anhydrous sodium sulfate, filtered and concentrated to give the compound of example 35A (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)
Example 35B
Figure GPA0000233715180001033
Dicyclohexylcarbodiimide (1.3 g, 6.4 mmol) was added to a solution of the compound from example 35A (1.4g, 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 completion of the reaction, the mixture was filtered and the filtrate was spin-dried in vacuo. The resulting crude product was dissolved in 12 ml of N, N-dimethylformamide, and aqueous ammonia (910.0 mg, 7.3 mmol) was added thereto. The reaction solution was stirred at 50-60 ℃ for 20 minutes. After completion of the reaction, the reaction solution was cooled to room temperature, washed with saturated brine (35 ml × 2), extracted with ethyl acetate (20 ml × 2), and the organic phase was dried over anhydrous sodium sulfate, filtered and then spin-dried under low pressure to obtain the compound of example 35B (1.8 g, yield 94.8%, purity 67%).1H 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)
Example 35C
Figure GPA0000233715180001041
The compound of example 35B (2.0 g, 3.4 mmol) was dissolved in tetrahydrofuran (20.0 ml) and at zero degrees centigrade, lithium aluminum hydride (1.0 g, 27.2 mmol) was added in portions and the reaction was stirred at seventy degrees centigrade for twelve hours. Cooled to zero degrees centigrade, water (2 ml) was added dropwise to the reaction solution, and 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 subjected to silica gel column chromatography (previously 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).1HNMR(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，2H)，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).
Example 35D
Figure GPA0000233715180001042
The compound from example 35C (200.0 mg, 348.5 micromoles) was dissolved in dichloromethane (4.0 ml), triethylamine (70.5 mg, 697.0 micromoles) and phenylsulfonyl chloride (123.1 mg, 697.0 micromoles) were added in that order, and the reaction was stirred at twenty degrees celsius for twelve hours. Concentration to remove the solvent and thin layer chromatography of the residue afforded the compound of example 35D (180.0 mg, 72.3% yield)Rate).1H NMR(400MHz，CHLOROFORM-d)δ7.89(d，J＝7.3Hz，2H)，7.62-7.52(m，3H)，4.75(d，J＝3.3Hz，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，1H)，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).
Example 91
Figure GPA0000233715180001043
The compound of example 35D (140.0 mg, 196.06 micromoles) was dissolved in methanol (5.0 ml), p-toluenesulfonic acid monohydrate (37.3 mg, 196.0 micromoles) was added, and the reaction was stirred at twenty degrees celsius for twelve hours. The solvent was removed by concentration and the residue was subjected to thin layer chromatography to give the compound of example 91 (92.0 mg, 85.9% yield). H NMR (400MHz, CHLOROFORM-d) δ 7.89(d, J ═ 7.3Hz, 2H), 7.62-7.56(m, 1H), 7.56-7.49(m, 2H), 4.95(d, J ═ 5.5Hz, 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, 3H), 4H, 1H, 1.85H, 4H, and 4H.
Preparation of example 92 and example 93 prepared by route 35, reference example 91, the procedure was as follows:
Figure GPA0000233715180001051
route 36
Figure GPA0000233715180001061
Example 94
Figure GPA0000233715180001062
Example 36A
Figure GPA0000233715180001063
Trimethylsilyl isocyanate (361.3 mg, 3.1 mmol, 415.35 μ l) was added to a solution of example 35C (1.5g, 2.61 mmol) in dichloromethane (10.0 ml). The reaction solution was stirred at 25 ℃ for 12 hours. TLC (dichloromethane/methanol-10/1) showed the reaction was complete. To the reaction solution was added 5 ml of water and extracted with dichloromethane (5 ml × 3), and the combined organic layers were washed with 10ml (5 ml × 2) of brine, dried over anhydrous sodium sulfate, filtered and concentrated to give example 36A (1.4g, yield 86.9%).1H 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)
Example 94
Figure GPA0000233715180001064
By reference to the procedure for example 65, starting from example 36A, purification gave the compound of example 94 (692.0 mg, 67.8% yield).1H 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)
Route 37
Figure GPA0000233715180001071
Example 95
Figure GPA0000233715180001072
Example 37A
Figure GPA0000233715180001073
The compound from example 35C (200.0 mg, 357.2 μmol) was dissolved in dichloromethane (2 ml), triethylamine (72.3 mg, 714.5 μmol, 99.0 μ l) was added, ethyl mono-oxalyl chloride (97.6 mg, 714.5 μmol, 79.9 μ l) was added at 0 ℃ and dissolved in dichloromethane (1 ml) and the reaction was stirred at 30 ℃ for twelve hours. The solvent was removed by concentration, water (5 ml) was added to the residue, and extracted with ethyl acetate (10 ml. times.3). The organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was subjected to thin layer chromatography to give the compound of example 37A (130.0 mg, 54.0% yield).1H NMR(400MHz，CHLOROFORM-d)δ7.11(d，J＝4.8Hz，1H)，4.77-4.64(m，1H)，4.53-4.41(m，1H)，4.37-4.25(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).
Example 95
Figure GPA0000233715180001081
Working example 53 and the compound of example 65, example 37A (150.0 mg, 222.6 micromoles) was synthesized in two steps and purified to give the compound of example 95 (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).
Route 38
Figure GPA0000233715180001082
Example 38A
Figure GPA0000233715180001083
To a 100 ml three-neck-flask was added dichloromethane (10 ml), aqueous sodium bicarbonate (292.8 mg, 3.5 mmol), dissolved in water (5.0 ml) and the compound of example 35C (100.0 mg, 174.2 μmol), triphosgene (103.4 mg, 348.5 μmol) was added in one portion at zero degrees centigrade and the reaction was stirred for one hour at zero degrees centigrade. The reaction solution was poured into a separatory funnel, the organic layer was separated, and the aqueous layer was extracted with dichloromethane (20 ml. times.2). The organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated to give intermediate a. At zero degrees centigrade, (3S) -hydroxypyrrole (43.1 mg, 348.5 micromole) and triethylamine (35.2 mg, 348.5 micromole) were added to the dichloromethane solution of intermediate a (5 ml), the ice bath was removed after two hours, and the reaction was stirred at thirty degrees centigrade for two hours. The solvent was removed by concentration and the residue was chromatographed by thin layer chromatography to give the compound of 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)，2.06-1.93(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).
Example 96
Figure GPA0000233715180001091
Using example 38A (76.0 mg, 110.6. mu. mol) as starting material and the procedure described in reference example 65, thin layer chromatography isolation was performed to give the compound of example 96 (40.0 mg, 6. mu.M)9.7% yield).1H 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)，1.80-1.72(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).
Route 39
Figure GPA0000233715180001092
Example 97
Figure GPA0000233715180001093
Example 39A
Figure GPA0000233715180001101
Example 35C (1.3 g, 2.3 mmol) was dissolved in tetrahydrofuran (12 ml), triethylamine (458.4 mg, 4.5 mmol) was added, chloroethyl isocyanate (478.1 mg, 4.5 mmol) was added dropwise and dissolved in tetrahydrofuran (3 ml) and the reaction was stirred at thirty degrees celsius for twelve hours. Water (5 ml) was added and extracted with ethyl acetate (10 ml × 3). The organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was isolated by thin layer chromatography to give the compound of example 39A (1.2 g, 77.8% yield).1H 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).
Example 39B
Figure GPA0000233715180001102
Sodium hydride (63.6 mg, 2.6 mmol) (65% in mineral oil) was suspended in tetrahydrofuran (25 ml) and the compound from example 39A (600.0 mg, 883.1 μmol) was added dropwise under a zero degree centigrade nitrogen blanket and dissolved in tetrahydrofuran (5 ml). After one hour the ice bath was removed and stirring continued for an additional eleven hours at thirty degrees celsius. Water (5 ml) was added, acidified with one mol of 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 isolated by thin layer chromatography to give the compound of 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，1H)，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)。
Example 97
Figure GPA0000233715180001111
The compound of example 97 (200.0 mg, 75.2% yield) was purified from the compound of example 39B (360.0 mg, 559.9 micromoles) by the same synthetic procedures as example 65.1H NMR(400MHz，METHANOL-d4)δ4.62(br.s.，1H)，3.67(br.s.，1H)，3.51-3.44(m，2H)，3.43-3.37(m，2H)，3.32-3.29(m，1H)，3.13(t，J＝7.0Hz，2H)，2.03(d，J＝12.3Hz，1H)，1.97-1.72(m，6H)，1.68-1.42(m，11H)，1.32(d，J＝12.3Hz，6H)，1.23-1.07(m，4H)，0.99(d，J＝6.5Hz，3H)，0.93(s，3H)，0.90(d，J＝3.3Hz，2H)，0.72(s，3H).
Route 40
Figure GPA0000233715180001112
Example 98
Figure GPA0000233715180001113
Example 40A
Figure GPA0000233715180001114
The compound of example 19B (100.0 mg, 223.4 micromoles) was dissolved in dichloromethane (2.0 ml), triethylamine (33.9 mg, 335.1 micromoles) was added at 0 ℃, ethyl monochloroacetate (61.0 mg, 446.7 micromoles) was added, and the reaction was stirred at 20 ℃ for 16 hours. The solvent was removed by concentration and the residue was chromatographed by thin layer chromatography to give the compound of example 40A (50.0 mg, 91.29 micromoles, 40.7% yield).1H 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，3H)，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).
Example 98
Figure GPA0000233715180001121
The compound of example 40A (50.0 mg, 91.2 micromoles) was dissolved in tetrahydrofuran (1.0 ml), methanol (1.0 ml) and water (1.0 ml), lithium hydroxide monohydrate (76.6 mg, 1.8 mmol) was added, and the reaction was stirred at 25 ℃ for twelve hours. The reaction was extracted with dichloromethane/methanol (10/1, 10ml × 3), 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) δ 7.32(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).
Preparation of example 99 prepared by route 40 according to the procedure of example 98, the results are as follows:
Figure GPA0000233715180001122
Figure GPA0000233715180001131
route 41
Figure GPA0000233715180001132
Example 100
Figure GPA0000233715180001133
Example 41A
Figure GPA0000233715180001134
To a solution of the compound (500.0 mg, 1 mmol) of example 2A 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 was allowed to react at 25 degrees celsius for 2 hours. The system was cooled to temperature, and a solution of sodium borohydride (210.0 mg, 5.5 mmol) in methanol (5 ml) was slowly added to the reaction system, reacted at 0 ℃ for 15 minutes and 25 ℃ for 15 minutes. The reaction was quenched with 0.2M dilute hydrochloric acid, and the aqueous layer was washed with ethyl acetate (10 ml. times.3)) Extraction and combination of organic layers were 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 the compound of example 41A (600.0 mg, crude).1H 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).
Example 41B
Figure GPA0000233715180001141
To a solution of the compound of example 41A (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 degrees, and the reaction was allowed to react at 25 ℃ 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%).1H-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).
Example 41C
Figure GPA0000233715180001142
To a solution of the compound (400.0 mg, 699 μmol) obtained in example 41B in N, N-dimethylformamide (5 ml) was added sodium cyanide (171.0 mg, 3.5 mmol), and the reaction was allowed to react at 100 ℃. Water (10 mL) was added to the reaction, the aqueous layer was extracted with ethyl acetate (10 mL. times.3), the organic layers were combined, dried over sodium sulfate, filtered and evaporated to give the title compound 41C (225.0 mg, 68%),1h NMR (400MHz, CHLOROFORM-d) δ 8.15(d, J ═ 3.0Hz, 1H), 8.04(s, 1H), 5.19(br.s., 1H), 4.77-4.66(m, 1H), 3.46(d, J ═ 4.5Hz, 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 ═ 1.5Hz, 3H) and the product of the 3-position deacylation (75 mg, 24%),1H 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)。
example 41D
Figure GPA0000233715180001151
A solution of the compound of example 41C (100.0 mg, 212. mu. mol) in 30% potassium hydroxide in methanol to water (1: 1 by volume) (10 ml) was reacted at 90 ℃ for 16 hours. Water (10 ml) and ethyl acetate (10 ml) were added to the reaction, the organic layer was washed with saturated potassium hydroxide solution (20 ml), the aqueous layers were combined, the aqueous layer was adjusted to Ph 4 with 4M hydrochloric acid, the aqueous layer was extracted with ethyl acetate (20 ml × 3), the organic layers were combined, dried over sodium sulfate, filtered and evaporated to give the title compound 41D (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)。
example 100
Figure GPA0000233715180001152
Cyclohexylcarbodiimides (36.0 mg, 172. mu. mol), N, N-lutidine (14.0 mg, 115. mu. mol) and methylsulfonamide (16.0 mg, 172. mu. mol) were added to a solution of the compound of example 41D (50.0 mg, 115.0. mu. mol) in methylene chloride (1 ml) at 25 ℃ and the reaction was allowed to react for 12 hours at 25 ℃. Water (5 ml) was added to the reaction system, which was adjusted to Ph 2 with hydrochloric acid (1M), ethyl acetate (10 ml in a crude extract)3) Extraction, drying the organic layer over anhydrous sodium sulfate, filtration and concentration. The residue was purified by preparative thin layer plate (dichloromethane/methanol-20/1) to give the compound of example 100 (15.0 mg, 25% yield).1H 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)。
Route 42
Figure GPA0000233715180001153
Example 101
Figure GPA0000233715180001161
Example 42A
Figure GPA0000233715180001162
To a solution of the compound of reference example 1A (35.0 g, 89.6 mmol) in dioxane (550 ml) was added p-toluenesulfonic acid monohydrate (1.5g, 8.9 mmol) and dihydropyran (11.3 g, 134.4 mmol) under nitrogen. The TLC check reaction was complete and hydrogenated at 50 deg.C for 2 hours (50 psi). The solvent portion was evaporated, water (50 ml) was added, and extraction was performed with ethyl acetate (50 ml × 3). The combined organic layers were washed with brine (50 ml), dried over sodium sulfate, filtered and evaporated, and the residue was purified by column chromatography to give the title compound 42A compound (33.0 g, 77.5% yield).1H 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).
Example 42B
Figure GPA0000233715180001163
To tetrahydrofuran (100.0 ml) was added dropwise lithium diisopropylamide (2 mol per liter, 6.74 ml) and hexamethylphosphoric triamide (2.4 g, 13.4 mmol, 2.4 ml) under nitrogen protection at-78 deg.c, and after the addition was completed, the solution was kept at-78 deg.c for 30 minutes, then a tetrahydrofuran solution of compound 42A (2.0 g, 4.2 mmol) was added dropwise to the solution and kept at-78 deg.c for 30 minutes, and finally a tetrahydrofuran (8 ml) solution of iodomethane (4.9 g, 34.5 mmol) was slowly added to the reactor, and then allowed to warm to room temperature and stirred overnight. Saturated ammonium chloride (10 ml) was added to quench, the pH was adjusted to 4 with 10% citric acid, water was added, 20 ml was extracted with ethyl acetate (200 ml × 3), the combined organic layers were washed once with saturated brine (100 ml), the organic phase was dried over anhydrous sodium sulfate, filtered and evaporated to give the title compound 42B (2.1 g, crude) which was used directly in the next reaction.
Example 42C
Figure GPA0000233715180001171
To a solution of the compound from example 42B (2.1 g, 4.2 mmol) in methanol was added p-toluenesulfonic acid (73.1 mg, 424.0 micromoles). The reaction was heated to 80 ℃ and stirred for 2h, the main solvent was evaporated by rotary evaporation (50 ℃) and water was added in 2 ml, extracted with ethyl acetate (5 ml × 3), the combined organic layers were washed with saturated sodium bicarbonate (2 ml) and saturated brine (5 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 ═ 10/1 to 3/1) to give the title compound 42C (350.0 mg, 17.7% yield). 1HNMR (400MHz, CHLOROFORM-d) δ 0.61-0.73(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).
Example 42D
Figure GPA0000233715180001172
To the compound of example 42C (340.0 mg, 812.21 micromoles) was added a solution of sodium hydroxide (105.5 mg, 2.6 micromoles) in water (60.0 ml), heated to 80 ℃, sodium borohydride (184.3 mg, 4.8 mmol) added in portions, the reaction was warmed to 100 ℃ and stirred for 8 hours, cooled to 15 ℃, saturated ammonium chloride (100 ml) was added to quench, the pH was adjusted to 2-3 with 1 mol per liter of 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 column purified (petroleum ether/ethyl acetate 2/1 → 1/2, 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)
Example 101
Figure GPA0000233715180001181
The mixture of methanesulfonamide (16.4 mg, 172.1 micromoles), the compound of example 42D (70.0 mg, 172.1 micromoles), dicyclohexylcarbodiimide (71.0 mg, 344.3 micromoles) and diisopropylethylamine (22.2 mg, 172.1 micromoles) was stirred in dichloromethane (2 ml) for 10 hours at 20 ℃ under nitrogen, 10ml of water was added, 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 give the compound of example 101 (15.0 mg, 16.2% yield).1HNMR(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＝15.75，9.72，6.15Hz，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)。
Route 43
Figure GPA0000233715180001182
Example 102
Figure GPA0000233715180001183
Example 43A
Figure GPA0000233715180001184
To a solution of the compound from example 17A (240.0 mg, 534.9 micromoles) in anhydrous tetrahydrofuran (15 ml) was added tetrachlorophosphate (200 mg, 803.6 micromoles) at-30 degrees celsius under nitrogen and stirred for 2.5 hours. After the solvent was spun down, water (10 ml) was added, filtered, and the filter cake was dissolved in methanol and spun down under reduced pressure to give the crude compound of example 43A (240.0 mg, 80.6% yield).1H 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)
Example 102
Figure GPA0000233715180001191
With reference to the procedure of example 2, purification starting from the compound of example 43A (240.0 mg, 479.4 micromoles) gave the compound of example 102 (200.0 mg, 79.4% yield).1H 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).
Route 44
Figure GPA0000233715180001192
Example 103
Figure GPA0000233715180001193
Example 44A
Figure GPA0000233715180001201
The compound from 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 and the reaction stirred at 25 ℃ for twelve hours the solvent was removed by concentration and the residue was chromatographed on silica gel to give the compound from example 44A (700.0 mg, 32.9% yield).1H 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).
Example 44B
Figure GPA0000233715180001202
The compound of example 44A (80.0 mg, 173.6 micromoles) was dissolved in dichloromethane (3.0 ml), pyridinium tribromide (55.5 mg, 173.6 micromoles) was added to the solution at 25 ℃ under nitrogen, and the reaction was stirred at 40 ℃ 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 subjected to thin layer chromatography to give the compound of example 44B (40.0 mg, 42.69% yield).1H NMR(400MHz，CHLOROFORM-d)δ8.13(s，1H)，5.34-5.21(m，1H)，4.79(dd，J＝5.1，14.2Hz，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).
Example 44C
Figure GPA0000233715180001203
The compound of example 44B (100.0 mg, 185.3 micromoles) and thiourea (28.2 mg, 370.6 micromoles) were dissolved in pyridine (2.0 ml) and the reaction was stirred at 90 degrees celsius for twelve hours. The solvent was removed, water (5 ml) was added to the residue, and extraction was performed with ethyl acetate (10 ml × 3). The resulting organic layer was washed with water (10 ml), dried over anhydrous sodium sulfate and concentrated. The residue was subjected to thin layer chromatography to give the compound of example 44C (45.0 mg, 47.0% yield).1H 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).
Example 103
Figure GPA0000233715180001211
With reference to the procedure of example 2, the compound of example 44C was purified starting from (45.0 mg, 87.1 micromoles) to give the compound of example 103 (19.0 mg, 45.9% yield, yellow solid).1H 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)，1.95-1.88(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).
Experimental example 1: in vitro study
FXR Biochemical experiment
Purpose of the experiment:
activation of FXR binding response by compounds was detected by homogeneous proximity luminescence amplification assay (alphascreen).
Experimental materials:
1. protein: glutathione-S-transferase-labeled FXR human protein (Invitrogen)
2. Co-activator: biotin-labeled steroid receptor co-activators (Anaspec)
3. Detection reagent: homogeneous proximity luminescence amplification (alphascreen) assay kit (PerkinElmer)
The experimental method comprises the following steps:
1. compound dilution: test compounds were prepared as 40 μ L DMSO solutions, followed by 3-fold dilution of the compounds to 10 concentration points. The reference compound was prepared as a 400 μ M DMSO solution, followed by 1.5-fold dilution to 10 concentration points. The diluted DMSO solution was added to the microwells of 384-well plates at a volume of 150nL per well.
2. glutathione-S-transferase-labeled FXR human protein and biotin-labeled steroid receptor co-activator are prepared into mixed solutions with the concentrations of 0.4nM and 30nM respectively. Add to the microwells of a 384 well plate in a volume of 15. mu.L per well. Incubate at room temperature for 1 hour.
4. The receptor bead mixture in the homogeneous proximity luminescence amplification assay (alphascreen) assay kit was diluted 125-fold and added to the microwells of a 384-well plate at a volume of 7.5ul per well. The experimental process was carried out in the dark. Incubate at room temperature for 1 hour.
5. The donor pellet mix in the homogeneous proximity luminescence amplification (alphascreen) assay kit was diluted 125-fold and added to the wells of a 384-well plate at a volume of 7.5ul per well. The experimental process was carried out in the dark. Incubate at room temperature for 1 hour.
EC50 test: and (3) reading the absorption signals at 520-620nm by adopting Envision to excite at 680 nm.
7. Analyzing data: data were analyzed using Prism 5.0 and EC50 values for compound activation were calculated. The percent activation potency (Efficacy) of a compound is then determined by the ratio of the highest signal value for the compound to the highest signal value for the reference compound.
FXR cell assay
Purpose of the experiment:
the effect of the compounds on the functional activity of the cells was examined by β -lactamase reporter gene technology.
Experimental materials:
1. cell line: FXR HEK 293T DA
2. Cell culture medium: DMEM Medium supplemented with 10% serum and Penicilin/Streptomyces (1X)
3. Detection reagent:
Figure GPA0000233715180001222
reporter gene detection kit (Invitrogen)
The experimental method comprises the following steps:
1. compound dilution: test compounds were prepared as 100 μ M DMSO solutions, followed by 3-fold dilution of the compounds to 10 concentration points. The reference compound was prepared as a 100 μ M DMSO solution, which was then diluted 1.3-fold to 10 concentration points. The diluted DMSO solution was added to the microwells of the 384-well plate in a volume of 200 μ L per well.
2. Cell inoculation: resuscitating FXR HEK 293T DA cells, resuspending with culture medium, and diluting to density of 5 × 105one/mL, at a volume of 40. mu.L per well, was added to the microwells of a 384-well plate.
3. The 384 micro-porous plate is heated at 37 ℃ and 5% CO2Incubated under conditions for 16 hours.
4. mu.L of 1mM LiveBLAzerTMThe FRET B/G (CCF4-AM) substrate was mixed with 60. mu.L of the B solution and 934. mu.L of the C solution and added to the microwells of a 384-well plate in a volume of 8. mu.L per well.
5. The 384 microwell plates were incubated for 2 hours at room temperature in the dark.
EC50 test: the absorption signals at 460 and 530nm were read using Envision excitation at a wavelength of 409 nm.
7. Analyzing data: data were analyzed using Prism 5.0 and EC50 values for compound activation were calculated. The percent activation potency (Efficacy) of the compound was then determined by the ratio of the highest signal value for the test compound to the highest signal value for the reference compound (chenodeoxycholic acid).
TABLE 1 test results of biochemical and cellular experiments50：
Figure GPA0000233715180001221
Figure GPA0000233715180001231
Figure GPA0000233715180001241
Figure GPA0000233715180001251
Experimental example 2: in vivo studies
Mouse drug administration alone:
12C 57BL/6J male mice were randomly divided into two groups, 6 per group. The first group is a vein group which is injected and administrated by 2mg/kg for tail vein, (the solvent is 10% HPbCD water solution, and when the solubility of the medicine is not ideal, the cosolvent is added); the second group is oral group, and the administration is performed by intragastric administration of 10mg/kg and 10mL/kg (the solvent is 0.5% HPMC aqueous solution). Plasma (K) was collected at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours post intravenous group administration2-EDTA is anticoagulant) sample; plasma samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours after oral group administration. Blood samples were taken from 6 animals per group at 3 time points, 3 animals from batch 1 were interleaved with 3 animals from batch 2. Plasma sample analysis was performed using LC-MS/MS. Plasma concentrations were plotted against time and PK parameters were calculated using Phoenix WinNonlin 6.3.
TABLE 2
Figure GPA0000233715180001261
ah，L/kg，mL/min/kg，nM.h；bnM，h，nM.h，％
Box type administration mouse liver blood ratio experiment:
one group of 6 male mice C57BL/6J was used as an oral group, the preparation contained 5 drugs for development, and 2 mg/kg/compound (vehicle is 0.5% HPMC aqueous solution) was administered by gavage. The 5 compounds were first dissolved separately in the vehicle to form 1mg/mL solutions (clear solutions or suspensions), either by sonication or vortexing, and then the five compound solutions were mixed in equal volumes (1: 1, v: v) in a glass bottle. After oral administration by gavage, plasma and liver tissue samples were collected at 0.5 hours after administration in 3 animals; the other 3 animals received corresponding samples 3 hours after dosing. After liver tissue harvest, homogenization was performed using ice-cold homogenization buffer (methanol: 15mM PBS buffer (pH 7.4) ═ 1: 2, v: v) at a liver weight: homogenization buffer volume of 1: 3. Plasma and liver tissue sample analysis was performed using a five-in-one LC-MS/MS analysis method developed in advance. Plasma concentrations were obtained as well as liver tissue homogenate concentrations and ratios of liver tissue to plasma concentrations were calculated using Excel.
TABLE 3
Figure GPA0000233715180001271
And (4) conclusion: as shown in table 3, the compounds of the present invention in the same dose list were orally administered, and the liver concentrations were higher than the control compound for both 0.5 hour and 3 hours, and the liver/blood concentration ratio was also higher than the control compound, showing significant effects.

Claims (15)

1. A compound of formula V, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0002257345120000011
wherein,
R4is selected from C1-3An alkyl group;
R5is selected from H、Me、Et、
Figure FDA0002257345120000012
R6Selected from H or OH;
n is selected from 0, 1 or 2;
l is selected from: -NHC (═ O) N (R)L) -, or-NHC (═ S) N (R)L)-；
RLIs selected from C1-3An alkyl group;
and
RLand R4Taken together to form a 4-6 membered ring optionally substituted with 1, 2, or 3R, said ring selected from heterocycloalkyl, said heterocycloalkyl heteroatom selected from nitrogen, said heteroatom number selected from 1, 2, or 3; r is respectively and independently selected from F, Cl, Br, I, OH, CN and NH2、SH、Me、Et、
Figure FDA0002257345120000013
Or CF3。
2. The compound of claim 1, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the stereoisomer of the compound of formula v is represented by the following formula v':
Figure FDA0002257345120000014
3. the compound, its tautomer, its stereoisomer, or its pharmaceutically acceptable salt according to claim 1, wherein R is5Selected from H, Me or Et.
4. The compound, its tautomer, its stereoisomer, or its pharmaceutically acceptable salt according to claim 1, wherein R isLAnd R4When taken together to form a 4-to 6-membered ring optionally substituted with 1, 2, or 3R, structural units-L-R4Selected from optionally substituted by 1 or 2R
Figure FDA0002257345120000015
5. The compound, its tautomer, its stereoisomer, or its pharmaceutically acceptable salt according to claim 4, wherein R isLAnd R4When joined together to form a 4-to 6-membered ring optionally substituted with 1, 2, or 3R, the structural unit-L-R4Is selected from
Figure FDA0002257345120000021
6. The compound, its tautomer, its stereoisomer, or its pharmaceutically acceptable salt according to claim 1, characterized by-L-R4Selected from:
Figure FDA0002257345120000022
7. the compound according to claim 1, selected from:
Figure FDA0002257345120000023
8. a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-7, a tautomer thereof, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients.
9. Use of a compound according to any one of claims 1 to 7, a tautomer thereof, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, for the preparation of a medicament for the prophylaxis or treatment of diseases which benefit from FXR agonism.
10. Use according to claim 9, characterized in that the diseases benefiting from FXR agonism are selected from cardiovascular diseases, diseases of the liver/biliary system, obesity, diabetes, lower urinary tract symptoms and benign prostatic hyperplasia or ureteral calculi.
11. Use according to claim 10, characterized in that the cardiovascular disease comprises cardiovascular diseases associated with hypertriglyceridemia and/or hypercholesterolemia.
12. The use according to claim 10, wherein the cardiovascular disease comprises atherosclerosis, arteriosclerosis, hypercholesterolemia, hyperlipidemia, thrombosis, coronary artery disease, stroke, or hypertension.
13. Use according to claim 10, wherein said diseases of the liver/gall bladder system include cholestatic liver diseases, and high HDL cholesterol diseases, high triglyceride diseases or fibrotic diseases.
14. The use according to claim 10, wherein the diseases of the liver/biliary system include non-alcoholic steatohepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, gallstones, non-alcoholic cirrhosis, biliary atresia, cholestatic liver disease, chronic liver disease, hepatitis infection, alcoholic liver disease, hepatic fibrosis.
15. The use of claim 14, wherein the hepatitis infection is hepatitis B infection or hepatitis C infection.
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Families Citing this family (37)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
MX2017005935A (en) * 2014-11-06 2018-01-11 Enanta Pharm Inc Bile acid analogs an fxr/tgr5 agonists and methods of use thereof.
AU2015353473A1 (en) 2014-11-26 2017-06-08 Enanta Pharmaceuticals, Inc. Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
US11578097B2 (en) 2014-11-26 2023-02-14 Enanta Pharmaceuticals, Inc. Tetrazole derivatives of bile acids as FXR/TGR5 agonists and methods of use thereof
US10208081B2 (en) 2014-11-26 2019-02-19 Enanta Pharmaceuticals, Inc. Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
CA2975257A1 (en) 2015-02-11 2016-08-18 Enanta Pharmaceuticals, Inc. Bile acid analogs as fxr/tgr5 agonists and methods of use thereof
CN107427527B (en) 2015-03-31 2021-01-26 英安塔制药有限公司 Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
CN107250150B (en) * 2015-04-28 2019-11-22 江苏豪森药业集团有限公司 Chlolic acid derivatives and preparation method thereof and medical usage
MX2017016611A (en) * 2015-06-19 2018-05-15 Intercept Pharmaceuticals Inc Tgr5 modulators and methods of use thereof.
DK3310801T3 (en) 2015-06-19 2021-06-21 Intercept Pharmaceuticals Inc TGR5 MODULATORS AND METHODS FOR USING IT
CN106478756A (en) * 2015-09-02 2017-03-08 中美华世通生物医药科技（武汉）有限公司 OCA-E monocrystalline and its production and use
WO2017147159A1 (en) 2016-02-23 2017-08-31 Enanta Pharmaceuticals, Inc. Deuterated bile acid derivatives as fxr/tgr5 agonists and methods of use thereof
US10323060B2 (en) 2016-02-23 2019-06-18 Enanta Pharmaceuticals, Inc. Benzoic acid derivatives of bile acid as FXR/TGR5 agonists and methods of use thereof
US10323061B2 (en) 2016-02-23 2019-06-18 Enanta Pharmaceuticals, Inc. Heteroaryl containing bile acid analogs as FXR/TGR5 agonists and methods of use thereof
TW201802103A (en) * 2016-07-13 2018-01-16 江蘇恆瑞醫藥股份有限公司 Preparation method of obeticholic acid and intermediates thereof
WO2018102418A1 (en) * 2016-11-29 2018-06-07 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonylurea bile acid derivatives
CN108218945B (en) * 2016-12-15 2021-05-28 宁波百纳西药业有限公司 Deoxycholic acid derivative, preparation method, pharmaceutical composition and application thereof
CN106749472B (en) * 2016-12-30 2019-02-22 江苏开元医药化工有限公司 A kind of -6 α of 3 Alpha-hydroxy--5 β of ethyl -7- ketone-cholane -24- acid preparation method
WO2018152171A1 (en) 2017-02-14 2018-08-23 Enanta Pharmaceuticals, Inc. Bile acid derivatives as fxr agonists and methods of use thereof
CA3058754A1 (en) 2017-04-07 2018-10-11 Enanta Pharmaceuticals, Inc. Process for preparation of sulfonyl carbamate bile acid derivatives
CN106986910A (en) * 2017-04-19 2017-07-28 成都百特万合医药科技有限公司 The preparation method of shellfish cholic acid intermediate difficult to understand
CN109134572A (en) * 2017-06-19 2019-01-04 中国科学院上海药物研究所 Chlolic acid derivatives and its preparation method and application
EP3431486A1 (en) * 2017-07-18 2019-01-23 Bionice, S.L.U. Process and intermediates for the synthesis of obeticholic acid and derivatives thereof
CN110869381B (en) * 2017-07-26 2021-11-19 正大天晴药业集团股份有限公司 Preparation method of steroid derivative FXR agonist
CN107383139A (en) * 2017-08-09 2017-11-24 杭州和泽医药科技有限公司 The method that a kind of β cholanic acid new derivatives of 7 oxo of 3 α hydroxyls 5 prepare shellfish cholic acid difficult to understand
WO2019085963A1 (en) 2017-11-02 2019-05-09 正大天晴药业集团股份有限公司 Method for preparing cholic acid compound
EP3730509A4 (en) * 2017-12-19 2021-09-01 Xi' An Biocare Pharma Compound for treating metabolic diseases and preparation method and use thereof
CN107987116B (en) * 2018-01-17 2021-01-05 中国药科大学 Chenodeoxycholic acid derivatives, preparation method and medical application thereof
GB201812382D0 (en) 2018-07-30 2018-09-12 Nzp Uk Ltd Compounds
CN111285914B (en) * 2018-12-10 2023-02-17 江西青峰药业有限公司 Preparation method of obeticholic acid
CN109762043B (en) * 2019-03-06 2020-07-24 华南理工大学 Chenodeoxycholic acid and preparation method thereof
US20220204548A1 (en) * 2019-05-10 2022-06-30 President And Fellows Of Harvard College Small molecule modulators of gut bacterial bile acid metabolism
CN112824425B (en) * 2019-11-21 2023-10-03 成都西岭源药业有限公司 6-alkenyl substituted cholic acid compound and preparation method and application thereof
CN112898368B (en) * 2019-12-03 2023-08-18 中国科学院成都有机化学有限公司 Preparation method of obeticholic acid intermediate
CN113493485A (en) * 2020-04-08 2021-10-12 西安奥立泰医药科技有限公司 Bile acid derivative salt, crystal form structure thereof, and preparation method and application thereof
TW202333741A (en) * 2021-11-15 2023-09-01 大陸商海湃泰克（北京）生物醫藥科技有限公司 Polycyclic compounds and methods thereof
WO2023192221A1 (en) * 2022-03-29 2023-10-05 Bilayer Therapeutics, Inc. Forms and compositions of sodium chenodeoxycholate
CN116497082B (en) * 2023-06-27 2023-09-29 华南理工大学 Method for synthesizing 3 alpha, 7 alpha, 24R-trihydroxy cholesterol by chemical-enzymatic method

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016045480A1 (en) * 2014-09-28 2016-03-31 上海源力生物技术有限公司 Method for preparing obeticholic acid

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1568706A1 (en) * 2004-02-26 2005-08-31 Intercept Pharmaceuticals, Inc. Novel steroid agonist for FXR
AU2007215207A1 (en) * 2006-02-14 2007-08-23 Intercept Pharmaceuticals, Inc. Bile acid derivatives as FXR ligands for the prevention or treatment of FXR-mediated diseases or conditions
JP2013206716A (en) * 2012-03-28 2013-10-07 Fujifilm Corp Photoelectric conversion element and dye-sensitized solar cell
US11578097B2 (en) * 2014-11-26 2023-02-14 Enanta Pharmaceuticals, Inc. Tetrazole derivatives of bile acids as FXR/TGR5 agonists and methods of use thereof
CN104672290B (en) * 2015-01-05 2017-06-06 北京普禄德医药科技有限公司 A kind of medicine of disease for preventing or treating FXR mediations and its production and use

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016045480A1 (en) * 2014-09-28 2016-03-31 上海源力生物技术有限公司 Method for preparing obeticholic acid

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