CN111187261B - ATX inhibitor based on indole parent nucleus and preparation method and application thereof - Google Patents

ATX inhibitor based on indole parent nucleus and preparation method and application thereof Download PDF

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CN111187261B
CN111187261B CN202010043108.4A CN202010043108A CN111187261B CN 111187261 B CN111187261 B CN 111187261B CN 202010043108 A CN202010043108 A CN 202010043108A CN 111187261 B CN111187261 B CN 111187261B
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thiazol
methyl
indol
indole
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翟鑫
类红瑞
马恩龙
姜楠
贾芳
郭明
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Shenyang Pharmaceutical University
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Abstract

The invention belongs to the technical field of medicines, and relates to an ATX inhibitor based on an indole parent nucleus, an optical isomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, a preparation method of the ATX inhibitor and the optical isomer, the pharmaceutically acceptable salt, the solvate or the prodrug, and a pharmaceutical composition containing the ATX inhibitor. The indole derivative and the optical isomer, the pharmaceutically acceptable salt, the solvate or the prodrug thereof are shown as a general formula I. Wherein, L, X, R1‑R8As described in the claims and specification. The compound of the invention has strong ATX inhibitory activity in vitro, so the compound can be used for preparing medicines for treating and/or preventing cancers and fibrotic diseases.

Description

ATX inhibitor based on indole parent nucleus and preparation method and application thereof
Technical Field
The invention belongs to the technical field of medicines, and relates to an ATX inhibitor based on an indole parent nucleus, an optical isomer, a pharmaceutically acceptable salt, a solvate or a prodrug thereof, a preparation method of the ATX inhibitor and the optical isomer, the pharmaceutically acceptable salt, the solvate or the prodrug, and a pharmaceutical composition containing the ATX inhibitor.
Background
Autotaxin (ATX) can hydrolyze LPC (lysophosphatdylcholine) into choline and LPA (lysophosphatic acid) with extensive inflammation-mediating activity, the receptor LPAR of LPA is a G-protein coupled receptor with 6 subtypes, of which LPAR is a receptor1-3It is more closely related to fibrosis. The ATX-LPA functional axis plays an important role in fibrotic diseases, and inhibitors against this functional axis are mainly classified into ATX inhibitors, LPA receptor inhibitors, LPA monoclonal antibodies, and the like. The selective inhibition of ATX is to reduce the generation of LPA from the source, and can effectively control the progress of fibrosis. By inhibiting the ATX-mediated production of LPA, the biological effect produced is better than when LPA receptor antagonists are used alone.
At present, research aiming at ATX targets mostly focuses on in vitro pharmacological research (mainly enzyme activity test and molecular mechanism research), and indications aimed at inhibitors thereof are mainly tumors. At the same time, it has become widely recognized that ATX inhibitors have pulmonary fibrosis inhibitory effects. Especially, the compound GLPG-1690 developed by the company Galapagos for the treatment of pulmonary fibrosis is currently in the clinical stage of the third stage of research.
The invention designs and synthesizes a series of indole derivatives. In vitro activity screening shows that the compounds have excellent ATX inhibitory activity and show certain antitumor activity and fibrosis inhibitory activity.
Disclosure of Invention
The invention relates to indole derivatives shown in a general formula I, optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof,
Figure BDA0002368441140000011
wherein,
l is
Figure BDA0002368441140000012
R is H or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
x is O, S, NH;
R1and R2The substituents are the same or different and are respectively and independently selected from hydrogen, hydroxyl, carbamoyl, aminosulfonyl, (C1-C6) acyl and substituted sulfonyl, and the substituents are C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl;
or R1And R2Is (C1-C6) alkyl, C2-C6 alkenyl, C2-C6 alkynyl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, halogenated C1-C4 hydrocarbyl, halogenated C1-C4 alkoxy, amino, cyano, hydroxy, mercapto, carboxyl, carbamoyl, aminosulfonyl, NRnRo、ORn、C(O)Rn、C(O)ORn、OC(O)Rn、C(O)N(Ro)Rn、N(Ro)C(O)Rn、S(O)yRn(wherein y is 0, 1 or 2), SO2N(Ro)Rn、N(Ro)SO2RnOr (CH)2)zNRoRn(wherein z is 1,2 or 3) wherein RnAnd RoEach independently selected from H or (C1-C4) hydrocarbyl, halogen is fluorine, chlorine or bromine;
or R1And R2Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ring containing 1-3 heteroatoms N, O and/or S, which may be substituted by 1-3 identical or different R9Substitution;
R9is hydrogen, carboxyl, hydroxyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy, (C1-C6) hydrocarbyl or substituted C1-C6 alkyl, the substituents being: cyano, amino, C1-C4 alkylamino, C1-C4 sulfonyl and the like, and the hydrocarbon group is alkyl, C2-C6 alkenyl, C2-C6 alkynyl;
R3is hydrogen, (C1-C)6) Alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-6 membered saturated or unsaturated carbocyclic ring, C1-C6 alkoxy;
R4is absent or is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, substituted or unsubstituted 5-6 membered heteroaromatic ring, and the substituent is C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C3-C6) cycloalkyl, hydroxyl, cyano, C1-C4 alkoxy, halogen substituted (CH) alkyl2)nWherein n is 1,2 or 3, and the aromatic heterocyclic ring contains 1-3N, O and/or S;
R5、R6、R7、R8hydrogen, halogen, (C1-C4) alkyl, C2-C4 alkenyl, C2-C4 alkynyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, hydroxyl, carboxyl, cyano, C1-C4 amido, C1-C4 hydrocarbyl-substituted carbamoyl, C1-C4 hydrocarbyl-substituted sulfonamide, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide can be respectively and independently selected, and the number and the combination are not limited;
or R4And R5Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic, 4-7 membered unsaturated carbocyclic ring, said heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R5And R6Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R6And R7Together with the carbon atoms of the phenyl ring to which they are attached form a 3-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R7And R8Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof, wherein,
l is
Figure BDA0002368441140000021
R is H or C1-C4 alkyl;
x is O, S, NH;
R1and R2The substituents are (C1-C4) alkyl, C2-C4 alkenyl or C2-C4 alkynyl;
or R1And R2Is (C1-C6) alkyl, C2-C6 alkenyl, C2-C6 alkynyl, optionally substituted with one or more of the following substituents: hydrogen, halogen, halogeno C1-C4 hydrocarbon group, halogeno C1-C4 alkoxy group, amino group, cyano group, hydroxyl group, mercapto group, carboxyl group, carbamoyl group, aminosulfonyl group, NRnRo、ORn、C(O)Rn、C(O)ORn、OC(O)Rn、C(O)N(Ro)Rn、N(Ro)C(O)Rn、S(O)yRn(wherein y is 0, 1 or 2), SO2N(Ro)Rn、N(Ro)SO2RnOr (CH)2)zNRoRn(wherein z is 1,2 or 3) wherein RnAnd RoEach independently selected from H or (C1-C4) alkyl, halogen is fluorine, chlorine or bromine;
or R1And R2Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ring containing 1-3 heteroatoms N, O and/or S, which may be substituted by 1-3 identical or different R9Substitution;
R9is hydrogen, carboxyl, hydroxyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy, unsubstituted or substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and the substituent is cyano, amino, C1-C4 alkylamino, C1-C4 sulfonyl;
R3is hydrogen, (C1-C4) alkyl, C2-C4 alkenyl, or C2-C4 alkynyl;
R4is absent, orIs C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, substituted or unsubstituted 5-6-membered aromatic heterocycle, and the substituent is (C1-C4) alkyl, C2-C4 alkenyl or C2-C4 alkynyl, (C3-C6) cycloalkyl, cyano, C1-C4 alkoxy, halogen substituted (CH 1-C4 alkoxy)2)nWherein n is 1,2 or 3, and the aromatic heterocyclic ring contains 1-3N, O and/or S;
R5、R6、R7、R8hydrogen, halogen, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) alkylthio, hydroxyl, carboxyl, cyano, C1-C4 acylamino, C1-C4 alkyl or C2-C4 alkenyl or C2-C4 alkynyl substituted carbamoyl, C1-C4 alkyl or C2-C4 alkenyl or C2-C4 alkynyl substituted sulfonamide, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide can be respectively and independently selected, and the number and the combination are not limited;
or R4And R5Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring, 4-7 membered unsaturated carbocyclic ring, said heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R5And R6Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R6And R7Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R7And R8Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein,
l is
Figure BDA0002368441140000031
X is O, S, NH;
r is H or C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl;
R1and R2Is optionally hydroxyl-, carboxyl-substituted (C1-C6) alkyl, C2-C6 alkenyl, C2-C6 alkynyl, or R1And R2Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ring containing 1-3 heteroatoms N, O and/or S, which may be substituted with 1-3 identical or different R9Substitution;
R9sulfonyl substituted by hydrogen, carboxyl, hydroxyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy, (C1-C6) alkyl which is substituted or unsubstituted, C2-C6 alkenyl, C2-C6 alkynyl, and the substituent is cyano, amino, C1-C4 alkylamino, C1-C4 alkyl or C2-C4 alkenyl or C2-C4 alkynyl;
R3is hydrogen, (C1-C6) alkyl, C2-C6 alkenyl, C2-C6 alkynyl, 3-6 membered saturated or unsaturated carbocyclic ring, C1-C6 alkoxy;
R4is absent or is C1-C4 alkyl or alkenyl, substituted or unsubstituted 5-6 membered aromatic heterocycle, the substituent is (C1-C4) alkyl, (C3-C6) cycloalkyl, cyano, (C1-C6 alkoxy, halogen substituted (CH)2)nWherein n is 1,2 or 3, the aromatic heterocyclic ring contains 1-3N, O and/or S;
R5、R6、R7、R8hydrogen, halogen, halogenated (C1-C4) alkyl or C2-C4 alkenyl or C2-C4 alkynyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, hydroxyl, carboxyl, cyano, C1-C4 acylamino, C1-C4 hydrocarbyl-substituted carbamoyl, C1-C4 hydrocarbyl-substituted sulfonamide, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide can be respectively and independently selected, and the number and the combination are not limited;
or R4And R5Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring, 4-7 membered unsaturated carbocyclic ring, said heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R5And R6Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R6And R7Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R7And R8Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein,
l is
Figure BDA0002368441140000032
X is O, S, NH;
r is H or C1-C4 alkyl;
R1and R2Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ring, said heterocyclic or aromatic heterocyclic ring containing 1-3 heteroatoms of N, O and/or S, or said heterocyclic and heteroaromatic rings may be substituted by 1-3 identical or different R9Substitution;
R9hydrogen, carboxyl, hydroxyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy, substituted or unsubstituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, the substituents being cyano, amino, C1-C4 alkylamino, C1-C4 hydrocarbyl-substituted sulfonyl, etc.;
R3is hydrogen, (C1-C4) alkyl;
R4is absent;
R5、R6、R7、R8can be respectively and independently selected from hydrogen, halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, hydroxyl, carboxyl, amino,Cyano, C1-C4 acylamino, C1-C4 alkyl substituted carbamoyl, C1-C4 alkyl substituted sulfonamide, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide, and the number and combination thereof are not limited;
or R4And R5Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic, 4-7 membered unsaturated carbocyclic ring, said heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R5And R6Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R6And R7Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R7And R8Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein,
l is
Figure BDA0002368441140000041
X is O, S, NH;
r is H or C1-C4 alkyl;
R1and R2Together with the nitrogen atom to which they are attached to form
Figure BDA0002368441140000042
Figure BDA0002368441140000043
And may be substituted by 1 to 3 identical or different R9Substitution;
R9is hydrogen, carboxyl, hydroxyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy, (C1-C4) alkyl or substituted C1-C4 alkyl;
R3is hydrogen, C1-C4 alkyl;
R4is absent;
R5、R6、R7、R8hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, hydroxyl, carboxyl, cyano, C1-C4 acylamino, C1-C4 alkyl substituted carbamoyl, C1-C4 alkyl substituted sulfonamide, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide can be respectively and independently selected, and the number and the combination are not limited;
or R4And R5Together with the benzene ring to which they are attached
Figure BDA0002368441140000044
Or R4、R5Together with L and the benzene ring to which they are attached form
Figure BDA0002368441140000045
Or R6And R7Together with the benzene ring to which they are attached
Figure BDA0002368441140000051
The invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein,
l is
Figure BDA0002368441140000052
X is O, S, NH;
r is H or methyl;
R1and R2Together with the nitrogen atom to which they are attached to form
Figure BDA0002368441140000053
Figure BDA0002368441140000054
And may be substituted by 1 to 3 identical or different R9Substitution;
R9hydrogen, methyl, ethyl, hydroxymethyl, hydroxyethyl, carboxyl, hydroxyl;
R3hydrogen, methyl, ethyl;
R4is absent;
R5、R6、R7、R8hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy can be independently selected respectively, and the number and the combination are not limited;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
R1and R2Together with the nitrogen atom to which they are attached to form
Figure BDA0002368441140000055
R3Is methyl;
R4is absent;
R5、R6、R7、R8hydrogen and halogen can be respectively and independently selected, and the number and the combination are not limited;
or R6And R7Together with the benzene ring to which they are attached
Figure BDA0002368441140000056
The invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
r is H or methyl;
R1and R2Together with the nitrogen atom to which they are attached to form
Figure BDA0002368441140000057
Figure BDA0002368441140000058
R3Is ethyl;
R4is absent;
R5、R6、R7、R8hydrogen, halogen and methoxy can be respectively and independently selected, and the number and the combination are not limited;
or R4And R5Together with the benzene ring to which they are attached
Figure BDA0002368441140000059
Or R6And R7Together with the benzene ring to which they are attached
Figure BDA0002368441140000061
The invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein,
l is
Figure BDA0002368441140000062
X is O, S, NH;
R1and R2Is optionally hydroxyl-, carboxyl-substituted (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) alkynyl, or R1And R2Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ring containing 1-3 heteroatoms N, O and/or S, which may be substituted with 1-3 identical or different R9Substitution;
R9is hydrogen, carboxyl, hydroxyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy, (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) alkynyl which are substituted or not substituted, and the substituent is cyano, amino, C1-C4 alkylamino, sulfonyl substituted by C1-C4 hydrocarbyl；
R3Is hydrogen, (C1-C6) hydrocarbyl, (C2-C6) alkenyl or (C2-C6) alkynyl, 3-6 membered saturated or unsaturated carbocyclic ring, C1-C6 alkoxy;
R4is absent or is C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, substituted or unsubstituted 5-6 membered aromatic heterocycle, the substituent is (C1-C4) alkyl, C2-C4 alkenyl or C2-C4 alkynyl, (C3-C6) cycloalkyl, cyano, C1-C6 alkoxy, halogen substituted (CH)2)nWherein n is 1,2 or 3, the aromatic heterocyclic ring contains 1-3N, O and/or S;
R5、R6、R7、R8hydrogen, halogen, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, hydroxyl, carboxyl, cyano, C1-C4 acylamino, C1-C4 alkyl or C2-C4 alkenyl or C2-C4 alkynyl substituted carbamoyl, C1-C4 alkyl or C2-C4 alkenyl or C2-C4 alkynyl substituted sulfonamide, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide can be respectively and independently selected, and the number and the combination are not limited;
or R4And R5Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring, 4-7 membered unsaturated carbocyclic ring, said heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R5And R6Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R6And R7Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R7And R8Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein,
l is
Figure BDA0002368441140000063
X is O, S, NH;
R1and R2Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ring containing 1-3 heteroatoms N, O and/or S, which may be substituted with 1-3 identical or different R9Substitution;
R9is hydrogen, carboxyl, hydroxyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy, substituted or unsubstituted (C1-C4) alkyl or C2-C4 alkenyl or C2-C4 alkynyl, the substituents being cyano, amino, C1-C4 alkylamino, C1-C4 alkyl-substituted sulfonyl;
R3is hydrogen, C1-C4 alkyl;
R4absent, or C1-C4 alkyl;
R5、R6、R7、R8hydrogen, halogen, (C1-C4) alkoxy, (C1-C4) alkylthio, hydroxyl, carboxyl, cyano, C1-C4 acylamino, C1-C4 alkyl substituted carbamoyl, C1-C4 alkyl substituted sulfonamide, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide can be respectively and independently selected, and the number and the combination are not limited;
or R4And R5Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic, 4-7 membered unsaturated carbocyclic ring, said heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R5And R6Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R6And R7Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R7And R8Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein,
l is
Figure BDA0002368441140000071
X is O, S, NH;
R1and R2Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring containing 1-3 heteroatoms of N, O and/or S, or which may be interrupted by 1-3 identical or different R9Substitution;
R9hydrogen, methyl, ethyl, hydroxymethyl, hydroxyethyl, carboxyl, hydroxyl;
R3hydrogen, methyl, ethyl;
R4is absent, or is (CH)2)nWherein n is 1,2, 3;
R5、R6、R7、R8hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy can be independently selected respectively, and the number and the combination are not limited;
or R4And R5Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R5And R6Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring;
or R6And R7Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R7And R8Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
R1and R2Together with the nitrogen atom to which they are attached to form
Figure BDA0002368441140000072
Figure BDA0002368441140000073
R3Is ethyl;
R4is optionally (CH)2)nWherein n is 1;
R5、R6、R7、R8hydrogen, halogen and methyl can be respectively and independently selected, and the number and the combination are not limited;
or R6And R7Together with the benzene ring to which they are attached
Figure BDA0002368441140000081
The invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein,
l is
Figure BDA0002368441140000082
X is O, S, NH;
R1and R2Is optionally hydroxyl-, carboxyl-substituted (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) alkynyl, or R1And R2Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ringOr the aromatic heterocycle contains 1-3 heteroatoms of N, O and/or S, or the heterocycle and the aromatic heterocycle may be substituted by 1-3 identical or different R9Substitution;
R9is hydrogen, carboxyl, hydroxyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy, (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) alkynyl or substituted C1-C6 alkyl, the substituent is cyano, amino, C1-C4 alkylamino, C1-C4 alkyl substituted sulfonyl;
R3is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl 3-6 membered saturated or unsaturated carbocyclic ring, C1-C6 alkoxy;
R4is absent, or is a 5-6 membered heteroaromatic ring containing 1-3N, O and/or S, or is (CH) optionally substituted by (C1-C4) alkyl, (C3-C6) cycloalkyl, cyano, alkoxy, halogen2)nWherein n is 1,2, 3;
R5、R6、R7、R8hydrogen, halogen, (C1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, hydroxyl, carboxyl, cyano, C1-C4 acylamino, C1-C4 alkyl substituted carbamoyl, C1-C4 alkyl substituted sulphonamide, amino, C1-C4 alkyl sulphone, C1-C4 alkyl sulphoxide, the number and the combination of the above are not limited;
or R4And R5Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic, 4-7 membered unsaturated carbocyclic ring, said heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R5And R6Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R6And R7Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R7And R8To which they are connectedThe carbon atoms on the phenyl rings together form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or a heteroaromatic ring, said heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein,
l is
Figure BDA0002368441140000083
X is O, S, NH;
R1and R2Is optionally hydroxy-, carboxy-substituted (C1-C6) alkyl, or R1And R2Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ring, which heterocyclic or aromatic heterocyclic ring contains 1-3 heteroatoms N, O and/or S, and which heterocyclic and aromatic heterocyclic rings may be substituted by 1-3 identical or different R9Substitution;
R9hydrogen, carboxyl, hydroxyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy, (C1-C6) alkyl or substituted C1-C6 alkyl, the substituents being cyano, amino, C1-C4 alkylamino, C1-C4 alkyl substituted sulfonyl, etc.;
R3is hydrogen, C1-C4 alkyl;
R4(CH) is absent, or is a cyano-substituted thiazole ring, optionally substituted (CH) by (C1-C4) alkyl, (C3-C6) cycloalkyl, cyano, C1-C6 alkoxy, halogen2)nWherein n is 1,2, 3;
R5、R6、R7、R8hydrogen, halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, hydroxyl, carboxyl, cyano, C1-C4 amido, C1-C4 alkyl substituted carbamoyl, C1-C4 alkyl substituted sulfonamide, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide can be respectively and independently selected, and the number and the combination are not limited;
or R4And R5Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or aromatic ringA heterocycle, a 4-7 membered unsaturated carbocyclic ring, said heterocycle or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R5And R6Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R6And R7Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R7And R8Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein,
l is
Figure BDA0002368441140000091
X is O, S, NH;
R1and R2Is optionally hydroxy-, carboxy-substituted (C1-C6) alkyl, or R1And R2Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring containing 1-3 heteroatoms of N, O and/or S, or which may be interrupted by 1-3 identical or different R9Substitution;
R9hydrogen, methyl, ethyl, hydroxymethyl, hydroxyethyl, carboxyl, hydroxyl;
R3hydrogen, methyl, ethyl;
R4is absent, or is optionally (CH)2)nWherein n is 1,2, 3;
R5、R6、R7、R8each independently selected from hydrogen, halogen, (C1-C4) alkyl, (C1-C4) alkoxy, andthe number and the combination thereof are not limited;
or R4And R5Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R5And R6Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring;
or R6And R7Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R7And R8Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
R1and R2Together with the nitrogen atom to which they are attached to form
Figure BDA0002368441140000092
R3Is ethyl;
R4is optionally (CH)2)nWherein n is 1;
R5、R6、R7、R8hydrogen, halogen and methoxy can be respectively and independently selected, and the number and the combination are not limited;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein,
l is
Figure BDA0002368441140000101
X is O, S, NH;
R1and R2Is (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) alkynyl optionally substituted by hydroxyl or carboxyl, R1And R2Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ring, said heterocyclic or aromatic heterocyclic ring containing 1-3 heteroatoms of N, O and/or S, or said heterocyclic and aromatic heterocyclic rings may be substituted by 1-3 identical or different R9Substitution;
R9hydrogen, carboxyl, hydroxyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy, (C1-C6) alkyl, (C2-C6) alkenyl or (C2-C6) alkynyl or substituted C1-C6 alkyl, the substituent is cyano, amino, C1-C4 alkylamino, C1-C4 alkyl substituted sulfonyl and the like;
R3is hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, (C2-C6) alkynyl, 3-6 membered saturated or unsaturated carbocyclic ring, C1-C6 alkoxy;
R4is absent, or is a 5-6 membered heteroaromatic ring containing 1-3N, O and/or S, or is (CH 1-C4) alkyl, (C2-C4) alkenyl, (C2-C4) alkynyl, (C3-C6) cycloalkyl, cyano, alkoxy, halogen2)nWherein n is 1,2, 3;
R5、R6、R7、R8hydrogen, halogen, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C2-C4) alkenyl, (C2-C4) alkynyl, (C1-C4) alkylthio, hydroxyl, carboxyl, cyano, C1-C4 acylamino, C1-C4 alkyl substituted carbamoyl, C1-C4 alkyl substituted sulphonamide, amino, C1-C4 alkyl sulphone, C1-C4 alkyl sulphoxide, the number and the combination of the above are not limited;
or R4And R5Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S, a 4-7 membered saturated or partially unsaturated carbocyclic ring;
R5and R6Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R6And R7Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R7And R8Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein,
l is
Figure BDA0002368441140000102
X is O, S, NH;
R1and R2Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring or a 5-6 membered aromatic heterocyclic ring, said heterocyclic or aromatic heterocyclic ring containing 1-3 heteroatoms of N, O and/or S, or said heterocyclic and aromatic heterocyclic rings may be substituted by 1-3 identical or different R9Substitution;
R9hydrogen, carboxyl, hydroxyl, (C1-C4) hydroxyalkyl, (C1-C4) alkoxy, (C1-C6) alkyl;
R3is hydrogen, C1-C4 alkyl;
R4is absent, or is a 5-6 membered aromatic heterocycle (said aromatic heterocycle containing 1-3N, O and/or S), or is optionally substituted (CH 1-C4) alkyl, alkoxy, halogen2)nWherein n is 1,2, 3;
R5、R6、R7、R8hydrogen, halogen, (C1-C4) haloalkyl, (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) alkylthio, hydroxyl, carboxyl, cyano, C1-C4 amido, C1-C4 alkyl substituted carbamoyl, C1-C4 alkyl substituted sulfonamide, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide can be respectively and independently selected, and the number and the combination are not limited;
or R4And R5Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic, 4-7 membered unsaturated carbocyclic ring, said heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R5And R6Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R6And R7Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R7And R8Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein,
l is
Figure BDA0002368441140000111
X is O, S, NH;
R1and R2Together with the nitrogen atom to which they are attached form a 4-7 membered heterocyclic ring containing 1-3 heteroatoms of N, O and/or S, or which may be interrupted by 1-3 identical or different R9Substitution;
R9hydrogen, methyl, ethyl, hydroxymethyl, hydroxyethyl, carboxyl, hydroxyl;
R3hydrogen, methyl, ethyl;
R4absent, or a cyano-substituted thiazole ring, or optionally (CH)2)nWherein n is 1,2, 3;
R5、R6、R7、R8can respectively and independently select hydrogen,Halogen, (C1-C4) alkyl, (C1-C4) alkoxy, and the number and combination thereof are not limited;
or R4And R5Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R5And R6Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring;
or R6And R7Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R7And R8Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
R1and R2Together with the nitrogen atom to which they are attached to form
Figure BDA0002368441140000112
Figure BDA0002368441140000113
R3Is ethyl;
R4is a cyano-substituted thiazole ring;
R5、R6、R7、R8hydrogen, halogen and methoxy can be respectively and independently selected, and the number and the combination are not limited;
the invention preferably selects the indole derivative shown in the general formula I and optical isomer, pharmaceutically acceptable salt, solvate or prodrug thereof,
R1and R2Together with the nitrogen atom to which they are attached to form
Figure BDA0002368441140000114
R3Is ethyl;
R4is absent;
R5、R6、R7、R8hydrogen, halogen and methoxy can be respectively and independently selected, and the number and the combination are not limited;
or R4And R5Together with the benzene ring to which they are attached
Figure BDA0002368441140000121
The compounds of the present invention and optical isomers, pharmaceutically acceptable salts, solvates or prodrugs thereof are preferably the following compounds, but these compounds are not meant to limit the present invention in any way:
(Z) -2- (2- (1- (1-ethyl-5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
(Z) - ((2- (3- (1- (2- (5-cyano-4- (4-fluorophenyl) thiazol-2-yl) hydrazine) -2,2, 2-trifluoroethyl) -1-ethyl-1H-indol-5-yl) -thiazol-4-yl) -methyl) -L-proline
(Z) - ((2- (3- (1- (2- (5-cyano-4- (4-methoxyphenyl) thiazol-2-yl) hydrazine) -2,2, 2-trifluoroethyl) -1-ethyl-1H-indol-5-yl) -thiazol-4-yl) -methyl) -L-proline
(Z) -2- (2- (1- (1-ethyl-5- (4- (pyrrol-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
(Z) -2- (2- (1- (1-ethyl-5- (4- (piperidin-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
(Z) -2- (2- (1- (1-ethyl-5- (4- ((4-methylpiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-methoxyphenyl) thiazole-5-carbonitrile
(S, Z) -2- (2- (1- (1-ethyl-5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
(Z) -2- (2- (1- (1-ethyl-5- (4- ((3-hydroxyazetidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
(Z) -2- (2- (1- (1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
(Z) -2- (2- (1- (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
(Z) -4- ((2- (3- (1- (2- (benzo [ d ] thiazol-2-yl) hydrazine) -2,2, 2-trifluoroethyl) -1-ethyl-1H-indol-5-yl) -thiazol-4-yl) -methyl) morpholine
(Z) -2- (2- (1- (1-ethyl-5- (4- (piperidin-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) benzo [ d ] thiazole-5-carbonitrile
(Z) -1- ((2- (3- (1- (2- (benzo [ d ] thiazol-2-yl) hydrazono) -2,2, 2-trifluoroethyl) -1-ethyl-1H-indol-5-yl) thiazol-4-yl) methyl) piperidin-4-ol
(E) -1-ethyl-N' - (4-fluorobenzylidene) -5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-N '- (4-methoxybenzylidene) -5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide (E) -N' - (benzo [ d ] [1,3] dioxolan-5-ylmethylidene) -1-ethyl-5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-5- (4- (morpholinylmethyl) thiazol-2-yl) 5-N' - ((4-oxo-4H-chromone-3-yl) methylidene) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (4-fluorobenzylidene) -1-methyl-5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (benzo [ d ] [1,3] dioxolan-5-ylmethylidene) -1-methyl-5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-N' - (4-fluorobenzylidene) -5- (4- (piperidin-1-ylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-N' - (4-methoxybenzylidene) -5- (4- (tetrahydropyrrole-1-ylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (benzo [ d ] [1,3] dioxolan-5-ylmethylidene) -1-ethyl-5- (4- ((4-methylpiperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (4-chlorobenzylidene) -1-methyl-5- (4- ((4-methylpiperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-N '- (4-fluorobenzylidene) -5- (4- ((4-methylpiperidin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide (E) -1-ethyl-N' - (4-fluorobenzylidene) -5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (benzo [ d ] [1,3] dioxolan-5-ylmethylidene) -1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (4-chlorobenzylidene) -1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-N' - (4-fluorobenzylidene) -5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-N' - (1- (4-fluorophenyl) ethylidene) -5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (benzo [ d ] [1,3] dioxolan-5-ylmethylidene) -1-ethyl-5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (4-chlorobenzylidene) -1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-N' - (4-fluorobenzylidene) -5- (4- ((4- (2- (hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (benzo [ d ] [1,3] dioxolan-5-ylmethylidene) -1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
3, 5-dichlorobenzyl (1-ethyl-5- (4- (morpholinomethyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 5-dichlorobenzyl (1-ethyl-5- (4- (pyrrol-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
(R) -1- (4-methylphenyl) ethyl (1-ethyl-5- (4- (pyrrol-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 5-dichlorobenzyl (1-ethyl-5- (4- ((4-methylpiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 5-dichlorobenzyl (1-ethyl-5- (4- ((4-methylpiperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 5-dichlorobenzyl (S) - (1-ethyl-5- (4- (- (2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
(R) -1- (p-methylphenyl) ethyl (1-ethyl-5- (4- (((S) -2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
(R) -1- (2-chlorophenyl) ethyl (1-ethyl-5- (4- (((S) -2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
Benzyl (S) - (1-ethyl-5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
Benzo [ d ] [1,3] dioxolan-5-ylmethyl (S) - (1-ethyl-5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 5-dichlorobenzyl (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
Benzo [ d ] [1,3] dioxolan-5-ylmethyl (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 4-difluorobenzyl (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate (R) -1- (2-chlorophenyl) ethyl (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 5-dichlorobenzyl (5- (4- ((bis (2-hydroxyethyl) amino) methyl) thiazol-2-yl) -1-ethyl-1H-indol-3-yl) carbamate
3, 5-dichlorobenzyl (1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 4-Difluorobenzyl (1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
Benzyl (1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
1-benzyl-3- (1-ethyl-5- (4- (morpholinomethyl) thiazol-2-yl) -1H-indol-3-yl) urea
1- (1-ethyl-5- (4- ((4-methylpiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -3- (4-fluorobenzyl) urea
1- (4-chlorobenzyl) -3- (1-ethyl-5- (4- ((4-methylpiperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) urea
1- (3-chloro-4-methoxybenzyl) -3- (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) urea
1- (5- (4- ((bis (2-hydroxyethyl) amino) methyl) thiazol-2-yl) -1-ethyl-1H-indol-3-yl) -3- (3-chloro-4-methoxybenzyl) urea
Furthermore, the indole derivatives of the general formula I of the present invention may be used to form pharmaceutically acceptable salts with acids according to conventional methods in the art. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with salts formed with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like. Some of the derivatives may form pharmaceutically acceptable salts with bases, preferably with the following bases: triethylamine sodium hydroxide, lithium hydroxide, calcium hydroxide, and potassium hydroxide. Wherein, the example compound containing hydrazone structure can form salt with triethylamine, and the ratio of the two can be seen from nuclear magnetic spectrum diagram (corresponding products and triethylamine salt thereof in examples 1-10).
In addition, the present invention also includes prodrugs of the derivatives of the present invention. Prodrugs of the derivatives of the present invention are indole derivatives of formula i which may themselves be less active or even inactive, but which, upon administration, are converted under physiological conditions (e.g., by metabolism, solvolysis or otherwise) to the corresponding biologically active form. Among them, the derivative protected by acetyl group is the prodrug of indole derivative corresponding to the hydrolysis product (corresponding to the products and their acetyl group-protected prodrugs in examples 39-51).
"halogen" in the present invention means fluoro, chloro, bromo or iodo; "alkyl" refers to straight or branched chain alkyl; "alkylene" refers to straight or branched chain alkylene.
We have found that the compound of the present invention has strong ATX inhibitory activity in vitro, and therefore, it can be used for the preparation of a medicament for the treatment and/or prevention of cancer and fibrotic diseases, such as tumors mainly including breast, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, pancreas, bone marrow, testis, ovary, lymph, soft tissues, head and neck, thyroid, cancer of the tract and leukemia, neuroblastoma, etc.; the fibrotic diseases mainly include pulmonary fibrosis, hepatic fibrosis, myocardial fibrosis, renal fibrosis, etc.
Through in vitro experiments on MCF-7 breast cancer cell inhibition, the compound disclosed by the invention is found to have a better proliferation inhibition effect on breast cancer cells, and shows a certain selectivity (poorer inhibition activity) on A549 cells.
In vivo experiments preliminarily show that the preferred compound has better prognostic effect on myocardial fibrosis tissues after myocardial infarction, and show the possibility of the series of compounds as potential myocardial fibrosis treatment drugs.
The active compound or the medicinal salt and the solvate thereof can be used independently as a unique anti-tumor or anti-fibrosis drug or can be used together with the anti-tumor/anti-fibrosis drugs (such as pirfenidone, nintedanib, paclitaxel and the like) on the market. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations is not intended to limit the scope of the present invention in any way.
The following synthetic schemes outline and describe the preparation of the derivatives of formula I of the present invention, all starting materials being prepared by the means described in these schemes, by methods well known to those of ordinary skill in the art of organic chemistry or being commercially available. All final derivatives of the invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variables used in these routes are as defined below or in the claims.
Route 1
Figure BDA0002368441140000151
Route 2
Figure BDA0002368441140000152
Route 3
Figure BDA0002368441140000153
Route 4
Figure BDA0002368441140000154
Route 5
Figure BDA0002368441140000161
The derivatives of formula I according to the invention may each be according to scheme 1, scheme 2, scheme 3, scheme 4 and scheme5 from intermediate M1、M2、M3、M4、M5In a corresponding solvent, by rearrangement or condensation reactions. Wherein L, R in the compound1、R2、R3、R5、R6、R7And R8As defined in the claims.
Route 6
Figure BDA0002368441140000162
Route 7
Figure BDA0002368441140000163
Route 8
Figure BDA0002368441140000164
Route 9
Figure BDA0002368441140000165
Intermediate M1Intermediate IV can be obtained first by acylation of intermediate III and then by N-alkylation according to scheme 5. Wherein L, R in the compound1、R2And R3As defined in the claims.
Intermediate M2From intermediate M according to scheme 61Hydrolyzing to obtain the product. Wherein L, R in the compound1、R2And R3As defined in the claims.
Intermediate M3From intermediate M according to scheme 72The catalyst is subjected to esterification reaction with methanol under the catalysis of concentrated sulfuric acid, and then the catalyst is obtained through hydrazinolysis. Wherein L, R in the compound1、R2And R3As defined in the claims.
Intermediate VIII canVia a retaining ring from the intermediate according to scheme 8. Wherein L, R in the compound1、R2And R3As defined in the claims.
The intermediate X can be obtained from the intermediate VIII through a Sandmeyer reaction and a hydrazinolysis reaction according to a scheme 8. Wherein L, R in the compound1、R2And R3、R7As defined in the claims.
When L is
Figure BDA0002368441140000171
R1And R2Together with the nitrogen atom to which they are attached to form
Figure BDA0002368441140000172
R3Is ethyl, compound M1-1、I1-1And I2-1As shown in scheme 11, and the other substituents are as defined in the claims.
When L is
Figure BDA0002368441140000173
R1And R2Together with the nitrogen atom to which they are attached to form
Figure BDA0002368441140000174
R3Is ethyl, compound M1-1、I3-1And I4-1The process is as in scheme 12, and the other substituents are as defined in the claims.
When L is
Figure BDA0002368441140000175
R1And R2Together with the nitrogen atom to which they are attached to form
Figure BDA0002368441140000176
R3Is ethyl, compound I5-1The process is as in scheme 13, and the other substituents are as defined in the claims.
When L is
Figure BDA0002368441140000177
When R is H, R1And R2Together with the nitrogen atom to which they are attached to form
Figure BDA0002368441140000178
R3Is ethyl, compound M3-1、I6-1、I7-1The process is as in scheme 14, and the other substituents are as defined in the claims.
When L is
Figure BDA0002368441140000179
R is-CH3When R is1And R2Together with the nitrogen atom to which they are attached to form
Figure BDA00023684411400001710
R3Is ethyl, compound I8-1The process is as in scheme 15, and the other substituents are as defined in the claims.
When L is
Figure BDA00023684411400001711
When R forms a ring with the side chain to which it is attached, R1And R2Together with the nitrogen atom to which they are attached to form
Figure BDA00023684411400001712
R3Is ethyl, compound I9-1、I10-1The process is as in scheme 16, and the other substituents are as defined in the claims.
Route 10
Figure BDA00023684411400001713
Route 11
Figure BDA0002368441140000181
Route 12
Figure BDA0002368441140000182
Route 13
Figure BDA0002368441140000183
Route 14
Figure BDA0002368441140000191
Route 15
Figure BDA0002368441140000192
Route 16
Figure BDA0002368441140000193
Description of the drawings:
FIG. 1 improvement of MI model myocardial fibrotic tissue by Compound 34 of example 34;
where Ctrl is normal myocardial tissue, MI is myocardial fibrosis tissue of myocardial infarction model, and MI +34 is myocardial fibrosis tissue of MI model treated with the compound (34) in example 34.
The specific implementation mode is as follows:
the examples are intended to illustrate, but not to limit, the scope of the invention. The nuclear magnetic resonance hydrogen spectrum of the compound is measured by Bruker ARX-400, and the mass spectrum is measured by Agilent 1100 LC/MSD; all reagents used were analytically or chemically pure.
Figure BDA0002368441140000201
When L is
Figure BDA0002368441140000202
When Y is
Figure BDA0002368441140000203
Watch 1
Figure BDA0002368441140000204
When L is
Figure BDA0002368441140000205
When Y is
Figure BDA0002368441140000206
Watch two
Figure BDA0002368441140000211
When L is
Figure BDA0002368441140000221
When Y is
Figure BDA0002368441140000222
Watch III
Figure BDA0002368441140000223
When L is
Figure BDA0002368441140000231
When Y is
Figure BDA0002368441140000232
Watch four
Figure BDA0002368441140000233
Example 1
Step A1-Ethyl-1H-indole-5-carbonitrile (II)
100.2g (5.0mol) of 60% NaH are added to 1300ml LN, N-dimethylformamide at room temperature, stirred, slowly warmed to 40 ℃ and 5-cyanoindole 284.0g (2.0mol) is added until H reaches2After the evolution, the reaction mixture was cooled to 25 ℃ and 468.0g (3.0mol) of ethyl iodide was added to the reaction mixture to react at room temperature for 2 hours. After the reaction, 5000mL of water was added, and after stirring for 30min, 299.2g of a solid was obtained by suction filtration, with a yield of 88.0%.
Step B1-Ethyl-1H-indole-5-thiocarboxamide (III)
Sodium hydrosulfide (85.0g, 3.5mol), magnesium chloride hexahydrate (406.0g, 2.0mol) were added to 600ml of N, N-dimethylformamide at room temperature, and 170.0g (0.7mol) of intermediate 1-ethyl-1H-indole-5-carbonitrile (II) was added with stirring, followed by reaction at 25 ℃ for 3 hours. After the reaction, the reaction mixture was cooled to room temperature, poured into a large amount of water, stirred for 15min, filtered, the filter cake was added to 600mL of 1M hydrochloric acid, stirred for 20min, filtered, washed with a large amount of water, and dried to obtain 147.0g of yellow solid with a yield of 72.1%.
Step C4- (chloromethyl) -2- (1-ethyl-1H-indol-5-yl) thiazole (IV)
102.0g (0.5mol) of intermediate 1-ethyl-1H-indole-5-thiocarboxamide (III) and 63.0g (0.5mol) of 1, 2-dichloroacetone were added to 600mL of toluene at room temperature and refluxed for 2.5H. After the reaction, toluene was distilled off, 800mL of water was added, and after stirring for 30min, suction filtration, washing with water, and drying, 109.0g of a yellowish solid was obtained with a yield of 78.9%.
Step D1- (5- (4- (chloromethyl) thiazol-2-yl) -1-ethyl-1H-indol-3-yl) -2,2, 2-trifluoroethyl-1-one (V)
108.0g (0.4mol) of intermediate 4- (chloromethyl) -2- (1-ethyl-1H-indol-5-yl) thiazole (IV) was dissolved in 800mL of N, N-dimethylformamide at room temperature, stirred, and 83mL (0.6mol) of trifluoroacetic anhydride was added dropwise under ice bath conditions, and then the reaction was carried out for 1.5H at room temperature. After the reaction, the mixture was poured into 2500mL of water, stirred for 30min and filtered to obtain 113.5g of solid with a yield of 78.1%.
Step E1- (1-Ethyl-5- (4- (morpholinomethyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethyl-1-one (M)1)
Intermediate 37.0g (0.1mol) of V, 18mL (0.2mol) of morpholine and 28.0g (0.2mol) of potassium carbonate were dissolved in 200mL of acetonitrile at room temperature, and the mixture was stirred and reacted at room temperature for 2 hours. After the reaction, potassium carbonate was removed by suction filtration, acetonitrile was evaporated to dryness, 300mL of water was added, and after stirring for 20min, suction filtration was carried out to obtain 32.9g of a brown solid with a yield of 80.1%.
Step F (Z) -2- (2- (1- (1-ethyl-5- (4- (morpholinomethyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazone) -4- (4-fluorophenyl) thiazole-5-carbonitrile (example 1)
42.3g (0.1mol) of intermediate M are introduced at room temperature1To 150mL of toluene was added, followed by stirring, and 23.4g (0.1mol) of intermediate X and 34.5g (0.2mol) of p-toluenesulfonic acid were added to conduct a reflux reaction for 3 hours. After the reaction, toluene was distilled off, 100mL of dichloromethane was added to dissolve, saturated sodium bicarbonate solution was used for washing, the organic layer was evaporated to dryness, and a solid was obtained by column chromatography purification, with 13.4g of the yield being 21.0%. 213.8-214.2 ℃ in m.p.; MS (ESI) M/z 640.24[ M + H ]],638.20[M-H]；1H NMR(400MHz,DMSO)δ12.18(s,1H),8.07(s,1H),7.98(s,1H),7.95(dd,J＝8.8,5.5Hz,2H),7.86–7.83(m,1H),7.75(d,J＝8.7Hz,1H),7.47(s,1H),7.34(t,J＝8.9Hz,2H),4.35(q,J＝7.1Hz,2H),3.75(s,1H),3.58(s,4H),2.58(s,3H),1.44(t,J＝7.2Hz,3H).
The compounds of examples (Table I) 2 to 10 were prepared by the procedure of example 1, starting from example 1 and by condensation with hydrazine.
Example 2(Z) - ((2- (3- (1- (2- (5-cyano-4- (4-fluorophenyl) thiazol-2-yl) hydrazone) -2,2, 2-trifluoroethyl) -1-ethyl-1H-indol-5-yl) -thiazol-4-yl) -methyl) -L-proline
m.p.:183.0-184.2℃；MS(ESI)m/z:668.46[M+H],690.41[M+Na],666.24[M-H]；1H NMR(400MHz,DMSO)δ12.15(s,2H),8.07(s,1H),7.98(s,1H),7.95(dd,J＝8.7,5.6Hz,2H),7.87(d,J＝8.7Hz,1H),7.77(d,J＝8.7Hz,1H),7.59(s,1H),7.35(t,J＝8.8Hz,2H),4.36(q,J＝7.0Hz,2H),4.24(d,J＝13.9Hz,1H),4.10(d,J＝13.9Hz,1H),3.77–3.69(m,1H),3.28(d,J＝10.3Hz,1H),2.87(dd,J＝17.5,8.6Hz,1H),2.09(td,J＝17.1,8.4Hz,1H),1.94–1.81(m,1H),1.72(ddd,J＝28.8,14.2,8.1Hz,2H),1.45(t,J＝7.2Hz,3H).
Example 3(Z) - ((2- (3- (1- (2- (5-cyano-4- (4-methoxyphenyl) thiazol-2-yl) hydrazone) -2,2, 2-trifluoroethyl) -1-ethyl-1H-indol-5-yl) -thiazol-4-yl) -methyl) -L-proline
m.p.:129.7-131.1℃；MS(ESI)m/z:680.27[M+H],702.20[M+Na],678.27[M-H]；1H NMR(400MHz,DMSO)δ12.07(s,2H),8.05(s,1H),7.95(s,1H),7.88(s,2H),7.86(s,1H),7.78(d,J＝8.7Hz,1H),7.57(s,1H),7.05(d,J＝8.8Hz,2H),4.36(q,J＝7.1Hz,2H),4.20(d,J＝14.0Hz,1H),4.06(d,J＝13.9Hz,1H),3.80(s,3H),3.69–3.61(m,1H),3.23(s,1H),2.82(dd,J＝17.2,8.4Hz,1H),2.05(td,J＝16.8,8.3Hz,1H),1.90–1.79(m,1H),1.70(ddd,J＝29.1,14.6,8.4Hz,2H),1.45(t,J＝7.2Hz,3H).
Example 4(Z) -2- (2- (1- (1-Ethyl-5- (4- (pyrrol-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazone) -4- (4-fluorophenyl) thiazole-5-carbonitrile
m.p.:125.0-126.5℃；MS(ESI)m/z:624.31[M+H],622.27[M-H]；1H NMR(400MHz,DMSO)δ10.88(s,1H),8.17(s,1H),8.08(s,1H),7.95(dd,J＝8.8,5.5Hz,2H),7.83(d,J＝8.6Hz,1H),7.78(s,1H),7.72(d,J＝8.7Hz,1H),7.30(t,J＝8.8Hz,2H),4.44(s,2H),4.34(q,J＝7.1Hz,2H),3.27(s,4H),1.87(s,4H),1.43(t,J＝7.2Hz,3H).
Example 5(Z) -2- (2- (1- (1-Ethyl-5- (4- (piperidin-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazone) -4- (4-fluorophenyl) thiazole-5-carbonitrile
m.p.:120.0-121.3℃；ESI-MS[M+H](m/z):638.32；1H NMR(600MHz,CDCl3)δ8.04(s,1H),7.94(s,1H),7.89(d,J＝8.6Hz,1H),7.85(dd,J＝8.4,5.4Hz,2H),7.46(d,J＝8.7Hz,1H),7.41(s,1H),7.00(t,J＝8.5Hz,2H),4.23(q,J＝7.3Hz,2H),3.83(s,2H),2.64(s,4H),1.65(s,4H),1.52(t,J＝7.3Hz,3H),1.38(d,J＝21.7Hz,2H).
Example 6(Z) -2- (2- (1- (1-ethyl-5- (4- ((4-methylpiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazone) -4- (4-methoxyphenyl) thiazole-5-carbonitrile
m.p.:112.8-114.4℃；MS(ESI)m/z:664.18[M+H],662.23[M-H]；1H NMR(400MHz,DMSO)δ10.51(s,1H),8.14(s,1H),8.07(s,1H),7.89(s,1H),7.87(s,1H),7.80(dd,J＝8.6,1.2Hz,1H),7.70(d,J＝8.7Hz,1H),7.62(s,1H),7.01(s,1H),6.99(s,1H),4.34(q,J＝7.1Hz,2H),4.12(s,2H),3.79(s,3H),3.22(d,J＝11.2Hz,2H),2.65(s,2H),1.63(d,J＝12.9Hz,2H),1.43(t,J＝7.2Hz,3H),1.27(d,J＝11.7Hz,1H),1.23(s,2H),0.85(d,J＝6.4Hz,3H).
Example 7(S, Z) -2- (2- (1- (1-ethyl-5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazone) -4- (4-fluorophenyl) thiazole-5-carbonitrile
m.p.:128.4-129.3℃；MS(ESI)m/z:654.20[M+H],676.24[M+Na],652.23[M-H]；1H NMR(400MHz,DMSO)δ10.05(s,1H),8.19(s,1H),8.11(s,1H),7.95(s,2H),7.81(s,1H),7.71(s,1H),7.70–7.66(m,1H),7.29(s,2H),5.22(s,1H),4.49(s,1H),4.34(s,1H),4.33(s,2H),3.58(s,2H),3.08(s,2H),1.96(s,1H),1.74(s,2H),1.67(s,2H),1.42(s,3H).
Example 8(Z) -2- (2- (1- (1-ethyl-5- (4- ((3-hydroxyazetidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazone) -4- (4-fluorophenyl) thiazole-5-carbonitrile
m.p.:174.7-175.2℃；MS(ESI)m/z:626.47[M+H],624.27[M-H]；1H NMR(400MHz,DMSO)δ8.23(s,1H),8.19(s,1H),7.97(s,2H),7.79(d,J＝8.1Hz,1H),7.67(d,J＝8.6Hz,1H),7.53(s,1H),7.28(t,J＝8.5Hz,2H),5.74(s,1H),4.33(d,J＝6.7Hz,2H),4.12(s,2H),3.96(s,2H),3.86(s,1H),3.44(s,2H),1.42(t,J＝6.9Hz,3H).
Example 9(Z) -2- (2- (1- (1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazone) -4- (4-fluorophenyl) thiazole-5-carbonitrile
m.p.:102.4-103.6℃；MS(ESI)m/z:683.27[M+H],705.24[M+Na],681.31[M-H]；1H NMR(400MHz,DMSO)δ8.18(s,1H),8.17(s,1H),7.97(dd,J＝8.2,5.7Hz,2H),7.79(d,J＝8.6Hz,1H),7.65(d,J＝8.6Hz,1H),7.40(s,1H),7.28(t,J＝8.7Hz,2H),4.86(s,1H),4.33(dd,J＝14.2,7.0Hz,2H),3.72(s,2H),3.59(s,2H),2.86(s,4H),2.72(m,6H),1.42(t,J＝7.2Hz,3H).
Example 10(Z) -2- (2- (1- (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
m.p.:142.7-145.3℃；MS(ESI)m/z:654.27[M+H],652.31[M-H]；1H NMR(400MHz,DMSO)δ12.63(s,1H),10.65(s,1H),8.06(s,1H),7.98–7.94(m,2H),7.94(d,J＝4.6Hz,2H),7.91(s,1H),7.83(d,J＝8.6Hz,1H),7.37(t,J＝8.8Hz,2H),4.98(s,1H),4.40(s,2H),4.39–4.33(m,2H),3.35(s,2H),3.23(s,2H),3.01(s,1H),1.92(d,J＝11.4Hz,2H),1.70(d,J＝11.8Hz,2H),1.47(t,J＝7.2Hz,3H).
Example 11(Z) -4- ((2- (3- (1- (2- (benzo [ d ] thiazol-2-yl) hydrazone) -2,2, 2-trifluoroethylidene) -1-ethyl-1H-indol-5-yl) thiazol-4-yl) methyl) morpholine
4.3g (0.01mol) of intermediate M are reacted at room temperature130mL of toluene was added, followed by stirring, and 1.7g (0.01mol) of intermediate XI and 3.5g (0.02mol) of p-toluenesulfonic acid were added to the mixture to conduct a reflux reaction for 3 hours. After the reaction, toluene was distilled off, 100mL of dichloromethane was added to dissolve, saturated sodium bicarbonate solution was used for washing, the organic layer was evaporated to dryness, and the solid was purified by column chromatography to obtain 0.95g of a solid with a yield of 19.1%.
m.p.:120.0-122.1℃；MS(ESI)m/z:571.18[M+H],593.23[M+Na],569.20[M-H]；1H NMR(400MHz,DMSO)δ12.15(s,1H),8.03(s,2H),7.86–7.81(m,1H),7.72(t,J＝9.1Hz,2H),7.36(s,1H),7.29(t,J＝7.6Hz,1H),7.21(d,J＝7.8Hz,1H),7.13(t,J＝7.6Hz,1H),4.34(q,J＝7.1Hz,2H),3.58(s,3H),3.55–3.49(m,4H),2.42(s,4H),1.44(t,J＝7.2Hz,3H).
Following the procedure of example 11, intermediate M1The starting material was condensed with intermediate XI to give the compounds of examples 12-13.
Example 12(Z) -2- (2- (1- (1-Ethyl-5- (4- (piperidin-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) benzo [ d ] thiazole
m.p.:123.6-124.7℃；MS(ESI)m/z:569.20[M+H],567.23[M-H]；1H NMR(400MHz,DMSO)δ12.00(s,1H),8.03(s,1H),7.82(dd,J＝8.6,1.5Hz,1H),7.72(d,J＝4.1Hz,1H),7.70(d,J＝5.1Hz,1H),7.34(s,1H),7.28(t,J＝7.2Hz,1H),7.20(d,J＝7.8Hz,1H),7.12(t,J＝7.6Hz,1H),4.34(q,J＝7.1Hz,2H),3.59(s,1H),2.43(s,3H),1.43(t,J＝7.2Hz,3H),1.30(s,2H).
Example 13(Z) -1- ((2- (3- (1- (2- (benzo [ d ] thiazol-2-yl) hydrazone) -2,2, 2-trifluoroethylidene) -1-ethyl-1H-indol-5-yl) thiazol-4-yl) methyl) piperidin-4-ol
m.p.:79.4-81.8℃；MS(ESI)m/z:585.23[M+H],583.20[M-H]；1H NMR(400MHz,DMSO)δ12.13(s,1H),8.05(s,1H),8.02(s,1H),7.83(dd,J＝8.7,1.4Hz,1H),7.71(t,J＝6.8Hz,2H),7.33(s,1H),7.28(t,J＝7.6Hz,1H),7.21(d,J＝7.8Hz,1H),7.12(t,J＝7.6Hz,1H),4.54(s,1H),4.34(q,J＝7.1Hz,2H),3.58(s,2H),3.42(m,1H),2.76(d,J＝11.3Hz,2H),2.13(t,J＝10.0Hz,2H),1.68(d,J＝9.9Hz,2H),1.44(t,J＝7.2Hz,3H),1.41–1.33(m,2H).
Example 14
Step A1-Ethyl-5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid (M)2)
Intermediate 84.6g (0.2mol) M was added at room temperature2Adding into 4M NaOH solution, refluxing and reacting for 2 h. After the reaction, the reaction mixture was cooled to room temperature, the pH was adjusted to 3 with 6M HCl, and the reaction mixture was filtered and the filter cake was dried to obtain 70.1g of a solid with a yield of 79%.
Step B1-Ethyl-5- (4- (2- (piperidin-1-yl) ethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid methyl ester (VI)
Intermediate 70.0g (0.19mol) M2Dissolving in 200mL of methanol, adding concentrated sulfuric acid, and carrying out reflux reaction for 2 h. After the reaction, the solvent was distilled off, 60mL of water was added, extraction was performed with ethyl acetate (80mL), the mixture was washed with a saturated sodium bicarbonate solution, and the organic layer was evaporated to dryness to obtain a solid (54.4 g) with a yield of 75%.
Step C1-Ethyl-5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide (M)3)
3.85g (0.01mol) of intermediate VI and 15mL of hydrazine hydrate were added to 40mL of ethanol at room temperature, stirred, and reacted under reflux for 2.5 h. After the reaction, the solvent was distilled off, water and dichloromethane were added to separate the solution, and the organic layer was evaporated to dryness to obtain 2.5g of a pale yellow solid, with a yield of 64.9%.
Step D (E) -1-ethyl-N' - (4-fluorobenzylidene) -5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide (example 14)
1.9g (0.005mol) of intermediate M are reacted at room temperature3And 0.6g (0.005mol) of p-fluorobenzaldehyde were added to 15mL of anhydrous ethanol, and the reaction was refluxed for 3 hours. After the reaction, the reaction mixture was cooled to room temperature and filtered to obtain 1.4g of the final product with a yield of 48%.
m.p.:213.2-214.8℃；MS(ESI)m/z:492.24[M+H],514.27[M+Na],490.24[M-H]；1H NMR(400MHz,DMSO)δ8.60(s,1H),8.27(s,1H),7.84(dd,J＝8.6,1.5Hz,1H),7.72(d,J＝8.7Hz,1H),7.44(s,1H),4.32(q,J＝7.2Hz,2H),3.84(s,3H),3.66(s,2H),2.51(s,7H),2.22(s,3H),1.41(t,J＝7.2Hz,3H).
Following the procedure of example 14, intermediate M1The starting materials are subjected to a condensation reaction with aldehydes or ketones to give the compounds of examples 15 to 17.
Example 15(E) -1-Ethyl-N' - (4-methoxybenzylidene) -5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:223.2-225.0℃；MS(ESI)m/z:504.23[M+H],526.20[M+Na],502.20[M-H]；1H NMR(400MHz,DMSO)δ11.45(s,1H),8.85(s,1H),8.33(s,1H),7.84(d,J＝8.2Hz,1H),7.69(d,J＝7.7Hz,3H),7.45(s,1H),7.04(d,J＝7.9Hz,2H),4.35(s,2H),3.82(s,3H),3.66(s,2H),3.61(s,3H),2.51(s,3H),1.47(t,J＝6.6Hz,3H).
Example 16(E) -N' - (benzo [ d ] [1,3] Dioxolan-5-ylmethylidene) -1-ethyl-5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:209.0-211.3℃；MS(ESI)m/z:518.18[M+H],540.23[M+Na],516.23[M-H]；1H NMR(400MHz,DMSO)δ11.47(s,1H),8.85(s,1H),8.31(s,1H),7.76(d,J＝53.4Hz,2H),7.39(d,J＝41.6Hz,3H),7.09(d,J＝58.7Hz,2H),6.11(s,2H),4.34(s,2H),3.64(d,J＝11.1Hz,4H),3.64(d,J＝11.1Hz,3H),1.47(s,3H).
Example 17(E) -1-Ethyl-5- (4- (morpholinylmethyl) thiazol-2-yl) 5- -N' - ((4-oxo-4H-chromon-3-yl) methylidene) -1H-indole-3-carboxylic acid hydrazide
m.p.:217.6-217.4℃；MS(ESI)m/z:542.24[M+H],564.24[M+Na]；1H NMR(400MHz,DMSO)δ11.63(s,1H),8.86(s,2H),8.36(s,1H),8.17(s,1H),7.85(s,2H),7.73(m,2H),7.57(s,1H),7.45(s,1H),4.37(s,2H),3.65(s,2H),3.61(s,2H),2.50(s,4H),1.49(s,3H).
Example 18
Step A1-methyl-5- (4- (morpholinomethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid (M)2′)
Intermediate 84.6g (0.2mol) M was added at room temperature1′Adding into 4M NaOH solution, refluxing and reacting for 2 h. After the reaction, the reaction mixture was cooled to room temperature, the pH was adjusted to 5 with 6M HCl, and the reaction mixture was filtered and the filter cake was dried to obtain 53.7g of a solid with a yield of 79%.
Step B1-methyl-5- (4- (2- (piperidin-1-yl) ethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid methyl ester (VI')
Intermediate 53.6g (0.15mol) M was added at room temperature2′Dissolving in 200mL of methanol, adding concentrated sulfuric acid, and carrying out reflux reaction for 2 h. After the reaction, the solvent was distilled off, 60mL of water was added, extraction was performed with ethyl acetate (80mL), the mixture was washed with a saturated sodium bicarbonate solution, and the organic layer was evaporated to dryness to obtain a solid 42.3g, yielding 76%.
Step C1-methyl-5- (4- (morpholinomethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide (M)3′)
3.7g (0.01mol) of intermediate VI' and 15mL of hydrazine hydrate were added to 40mL of ethanol at room temperature, stirred, and reacted under reflux for 2.5 h. After the reaction, the solvent was distilled off, water and dichloromethane were added to separate the solution, and the organic layer was evaporated to dryness to obtain 2.4g of a pale yellow solid with a yield of 65%.
Step D (E) -N' - (4-fluorobenzylidene) -1-methyl-5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide (example 18)
1.85g (0.005mol) of intermediate M are reacted at room temperature3′And 0.6g (0.005mol) of p-fluorobenzaldehyde were added to 15mL of anhydrous ethanol, and the reaction was refluxed for 3 hours. After the reaction, the reaction mixture was cooled to room temperature and filtered to obtain 1.15g of the final product with a yield of 48%.
m.p.:222.3-223.2℃；MS(ESI)m/z:478.32[M+H],500.32,[M+Na],476.31[M-H]；1H NMR(600MHz,DMSO)δ11.57(s,1H),8.84(s,1H),8.36(s,2H),7.86(dd,J＝8.6,1.6Hz,1H),7.80(dd,J＝8.2,5.8Hz,2H),7.66(d,J＝8.6Hz,1H),7.46(s,1H),7.31(t,J＝8.6Hz,2H),3.94(s,4H),3.66(s,2H),3.61(m,6H).
Following the procedure of example 18, intermediate M1Is prepared from raw material and aldehyde or ketone through condensation reactionThe compounds of examples 19, 20 should be prepared.
Example 19(E) -N' - (benzo [ d ] [1,3] Dioxolan-5-ylmethylidene) -1-methyl-5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:173.9-174.4℃；MS(ESI)m/z:504.28[M+H],502.19[M-H]；1H NMR(600MHz,DMSO)δ11.47(s,1H),8.82(s,1H),8.28(m,2H),7.85(dd,J＝8.6,1.6Hz,1H),7.65(d,J＝8.6Hz,1H),7.45(s,1H),7.33(d,J＝1.4Hz,1H),7.17(d,J＝7.8Hz,1H),7.00(d,J＝7.9Hz,1H),6.10(s,2H),3.93(s,3H),3.65(s,2H),3.62–3.59(m,4H),2.49–2.47(m,4H).
Example 20(E) -N' - (4-chlorobenzylidene) -1-methyl-5- (4- ((4-methylpiperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:247.0-248.5℃；MS(ESI)m/z:507.23[M+H],505.19[M-H]；1H NMR(600MHz,DMSO)δ11.60(s,1H),8.82(s,1H),8.28(s,2H),7.86(dd,J＝8.6,1.8Hz,1H),7.78(s,1H),7.76(s,1H),7.66(s,1H),7.65(s,1H),7.54(s,1H),7.53(s,1H),7.42(s,1H),3.94(s,3H),3.64(s,2H),2.49–2.43(m,4H),2.39(s,4H),2.16(s,3H).
Example 21(E) -1-Ethyl-N' - (4-fluorobenzylidene) -5- (4- (piperidin-1-ylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
1.85g (0.005mol) of intermediate M are reacted at room temperature3And 0.6g (0.005mol) of p-fluorobenzaldehyde were added to 15mL of anhydrous ethanol, and the reaction was refluxed for 3 hours. After the reaction, the mixture was cooled to room temperature, water and dichloromethane were added to separate the liquid, the organic layer was evaporated to dryness and purified by column chromatography to obtain a solid 0.94g, with a yield of 33%.
m.p.:201.8-202.7℃；MS(ESI)m/z:490.45[M+H],488.37[M-H]；1H NMR(400MHz,DMSO)δ11.60(s,1H),8.84(s,1H),8.42(s,1H),7.84(dd,J＝8.6,1.5Hz,1H),7.80(dd,J＝8.5,5.7Hz,2H),7.70(d,J＝8.6Hz,1H),7.43(s,1H),7.31(t,J＝8.8Hz,2H),4.35(d,J＝6.3Hz,2H),3.68(s,2H),3.38(s,4H),1.54(d,J＝5.1Hz,3H),1.47(t,J＝7.2Hz,3H),1.40(d,J＝4.3Hz,2H).
Following the procedure of example 21, intermediate M1The starting materials are condensed with aldehydes or ketones to give the compounds of examples 22 to 33.
Example 22(E) -1-Ethyl-N' - (4-methoxybenzylidene) -5- (4- (tetrahydropyrrol-1-ylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:193.8-194.1℃；MS(ESI)m/z:542.24[M+H],564.24[M+Na]；1H NMR(400MHz,DMSO)δ11.81(s,1H),8.88(s,1H),8.49(s,1H),7.83(d,J＝8.4Hz,1H),7.75(d,J＝8.2Hz,2H),7.67(d,J＝8.6Hz,1H),7.51(d,J＝8.2Hz,2H),7.47(s,1H),4.32(d,J＝4.4Hz,3H),3.86(d,J＝21.1Hz,2H),2.69(s,5H),1.74(s,5H),1.46(t,J＝7.1Hz,4H).
Example 23(E) -N' - (benzo [ d ] [1,3] Dioxolan-5-ylmethylidene) -1-ethyl-5- (4- ((4-methylpiperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:204.9-205.2℃；MS(ESI)m/z:531.43[M+H],529.58[M-H]；1H NMR(400MHz,DMSO)δ11.44(s,1H),8.84(s,1H),8.32(s,1H),7.83(s,1H),7.71(s,1H),7.36(d,J＝24.2Hz,2H),7.18(s,1H),7.02(s,1H),6.11(s,2H),4.35(s,2H),3.62(s,2H),2.51(s,3H),2.46(s,3H),1.52(s,5H),1.40(s,3H).
Example 24(E) -1-Ethyl-N' - (4-fluorobenzylidene) -5- (4- ((4-methylpiperidin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:291.2-292.0℃；MS(ESI)m/z:MS(ESI)m/z:504.60[M+H],502.58[M-H]；1H NMR(400MHz,DMSO)δ11.63(s,1H),8.86(s,1H),8.44(s,2H),7.85(dd,J＝8.7,1.4Hz,1H),7.80(dd,J＝8.6,5.7Hz,2H),7.71(d,J＝8.6Hz,1H),7.52(s,1H),7.32(t,J＝7.2Hz,2H),4.35(d,J＝6.6Hz,2H),3.83(s,2H),3.03(d,J＝11.0Hz,2H),2.27(s,2H),1.64(d,J＝12.0Hz,2H),1.47(t,J＝7.2Hz,3H),1.40(m,1H)1.24(d,J＝11.0Hz,2H),0.90(d,J＝6.4Hz,3H).
Example 25(E) -1-Ethyl-N' - (4-fluorobenzylidene) -5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:163.5-165.6℃；MS(ESI)m/z:506.43[M+H],528.36[M+Na],504.41[M-H]；1H NMR(600MHz,DMSO)δ11.59(s,1H),8.86(s,1H),8.37(s,2H),7.84(dd,J＝8.6,1.6Hz,1H),7.80(dd,J＝8.5,5.7Hz,2H),7.70(d,J＝8.6Hz,1H),7.41(s,1H),7.32(t,J＝8.7Hz,2H),4.58(s,1H),4.35(s,2H),3.65(s,2H),3.47(s,1H),2.81(s,2H),2.18(s,2H),1.74(d,J＝9.7Hz,2H),1.47(t,J＝7.2Hz,3H),1.45–1.41(m,2H).
Example 26(E) -N' - (benzo [ d ] [1,3] Dioxolan-5-ylmethylidene) -1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:166.5-167.9℃；MS(ESI)m/z:532.45[M+H],554.38[M+Na],530.43[M-H]；1H NMR(600MHz,DMSO)δ11.52(s,1H),8.83(s,1H),8.34(s,2H),7.84(d,J＝8.5Hz,1H),7.70(d,J＝8.6Hz,1H),7.46(s,1H),7.33(s,1H),7.16(d,J＝7.4Hz,1H),7.01(d,J＝7.9Hz,1H),6.10(s,2H),4.63(s,1H),4.34(s,2H),3.72(s,2H),3.51(s,1H),3.35(s,2H),2.87(s,2H),2.26(s,2H),1.75(s,2H),1.47(t,J＝7.2Hz,3H).
Example 27(E) -N' - (4-chlorobenzylidene) -1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:143.6-144.7℃；MS(ESI)m/z:522.24[M+H],544.26[M+Na]；1H NMR(600MHz,DMSO)δ11.66(s,1H),8.84(s,1H),8.39(s,2H),7.84(d,J＝8.4Hz,1H),7.77(d,J＝6.9Hz,2H),7.70(d,J＝8.5Hz,1H),7.54(d,J＝6.9Hz,2H),7.42(s,1H),4.58(s,1H),4.35(s,2H),3.67(s,2H),3.48(s,1H),2.82(s,2H),2.20(s,2H),1.73(s,2H),1.47(t,J＝7.1Hz,3H),1.43(s,2H).
Example 28(E) -1-Ethyl-N' - (4-fluorobenzylidene) -5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:147.8-148.6℃；MS(ESI)m/z:506.43[M+H],504.41[M-H]；1H NMR(600MHz,DMSO)δ11.56(s,1H),8.83(s,1H),8.36(s,2H),7.84(dd,J＝8.6,1.7Hz,1H),7.80(dd,J＝8.6,5.6Hz,2H),7.70(d,J＝8.7Hz,1H),7.42(s,1H),7.32(t,J＝8.8Hz,2H),4.35(s,2H),4.13(d,J＝14.2Hz,1H),3.71(d,J＝14.2Hz,1H),3.47(dd,J＝10.6,4.7Hz,1H),3.32(dd,J＝10.6,6.4Hz,1H),3.03(dt,J＝9.2,4.6Hz,1H),2.71(s,1H),2.40(dd,J＝16.5,8.2Hz,1H),1.91(s,1H),1.84(dq,J＝12.2,8.2Hz,1H),1.69–1.62(m,2H),1.58(dt,J＝19.1,6.5Hz,1H),1.47(t,J＝7.3Hz,3H).
Example 29(E) -1-Ethyl-N' - (1- (4-fluorophenyl) ethylidene) -5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:185.7-186.4℃；MS(ESI)m/z:520.42[M+H],542.41[M+Na],518.46[M-H]；1H NMR(400MHz,DMSO)δ10.39(s,1H),8.83(s,1H),8.43(s,1H),7.93–7.87(m,2H),7.84(d,J＝8.7Hz,1H),7.70(d,J＝8.6Hz,1H),7.45(s,1H),7.28(t,J＝8.7Hz,2H),4.39–4.28(m,2H),4.17(d,J＝13.7Hz,1H),3.76(d,J＝12.3Hz,1H),3.49(d,J＝6.0Hz,1H),3.48(d,J＝4.3Hz,1H),3.06(s,1H),2.78(s,1H),2.39(s,3H),1.85(d,J＝9.7Hz,1H),1.67(s,2H),1.63–1.55(m,1H),1.46(t,J＝7.1Hz,3H).
Example 30(E) -N' - (benzo [ d ] [1,3] Dioxolan-5-ylmethylidene) -1-ethyl-5- (4- ((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:129.0-131.6℃；MS(ESI)m/z:532.45[M+H],530.43[M-H]；1H NMR(400MHz,DMSO)δ11.49(s,1H),8.85(s,1H),8.35(s,1H),7.85(d,J＝8.5Hz,1H),7.69(d,J＝8.6Hz,1H),7.44(s,1H),7.34(s,1H),7.17(d,J＝7.8Hz,1H),7.00(d,J＝7.9Hz,1H),6.11(s,2H),4.33(s,2H),4.18(d,J＝14.2Hz,1H),3.76(d,J＝14.1Hz,1H),3.50(dd,J＝10.6,4.5Hz,1H),3.40–3.32(m,1H),3.10–3.01(m,1H),2.78(s,1H),2.47(d,J＝8.3Hz,1H),1.92(s,1H),1.85(dd,J＝19.0,8.2Hz,1H),1.65(dd,J＝20.8,6.7Hz,2H),1.64–1.54(m,1H),1.47(t,J＝7.1Hz,3H).
Example 31(E) -N' - (4-chlorobenzylidene) -1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:157.9-158.8℃；MS(ESI)m/z:551.42[M+H],573.41[M+Na],549.46[M-H]；1H NMR(400MHz,DMSO)δ11.64(s,1H),8.83(s,1H),8.42(s,2H),7.84(d,J＝8.2Hz,1H),7.76(d,J＝8.3Hz,2H),7.70(d,J＝8.7Hz,1H),7.54(d,J＝8.3Hz,2H),7.41(s,1H),4.36(s,2H),3.64(s,2H),3.48(s,2H),2.45(s,2H),2.38(t,J＝6.2Hz,3H),1.47(t,J＝7.1Hz,3H).
Example 32(E) -1-Ethyl-N' - (4-fluorobenzylidene) -5- (4- ((4- (2- (hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:133.6-135.1℃；MS(ESI)m/z:535.41[M+H],557.40[M+Na],533.46[M-H]；1H NMR(400MHz,DMSO)δ11.55(s,1H),8.84(s,1H),8.38(s,1H),7.80(s,3H),7.70(d,J＝8.6Hz,1H),7.41(s,1H),7.31(s,2H),4.36(s,2H),3.65(s,2H),3.49(s,2H),2.50(s,4H),2.42(s,2H),1.47(s,3H).
Example 33(E) -N' - (benzo [ d ] [1,3] Dioxolan-5-ylmethylidene) -1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
m.p.:157.9-159.5℃；MS(ESI)m/z:561.44[M+H],583.43[M+Na],559.47[M-H]；1H NMR(600MHz,DMSO)δ11.47(s,1H),8.82(s,1H),8.31(s,2H),7.83(dd,J＝8.6,1.7Hz,1H),7.70(d,J＝8.7Hz,1H),7.42(s,1H),7.32(s,1H),7.16(d,J＝7.7Hz,1H),7.01(d,J＝8.0Hz,1H),6.10(s,2H),4.45(s,1H),4.34(s,2H),3.66(s,2H),3.50(s,2H),3.34(s,2H),2.52(m,4H),2.49–2.37(m,4H),1.47(t,J＝7.2Hz,3H).
Example 343, 5-dichlorobenzyl (1-ethyl-5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
Intermediate 3.5g (0.01mol) M at room temperature2Dissolved in dry toluene, 3mL of triethylamine and 3mL of diphenylphosphorylazide were added, and after stirring for 30min, 2.7g (0.015mol) of 3, 5-dichlorobenzyl alcohol was added, followed by reflux reaction for 3 hours. After the reaction, the solvent was distilled off, water and dichloromethane were added to separate the liquid, and the organic layer was evaporated to dryness to obtain a crude product. The crude product was purified by column chromatography to give the desired compound 2.2g in 42% yield.
m.p.:160.1-162.0℃；MS(ESI)m/z:545.47[M+H],568.39[M+Na],543.34[M-H]；1H NMR(400MHz,DMSO)δ9.95(s,1H),8.47(s,1H),7.74(d,J＝8.6Hz,1H),7.60(s,2H),7.54(s,2H),7.52(d,J＝8.9Hz,1H),7.39(s,1H),5.20(s,2H),4.20(q,J＝7.0Hz,2H),3.63(s,2H),3.61(d,J＝4.0Hz,4H),2.49(d,J＝10.6Hz,4H),1.34(t,J＝7.1Hz,3H).
Following the procedure of example 34, intermediate M2The starting material was subjected to Curtius rearrangement with an alcohol to afford the compounds of examples 35-38.
Example 353, 5-dichlorobenzyl (1-ethyl-5- (4- (pyrrol-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:183.5-184.8℃；MS(ESI)m/z:529.38[M+H],551.38[M+Na]；1H NMR(400MHz,DMSO)δ9.97(s,1H),8.51(s,1H),7.80(d,J＝8.8Hz,1H),7.74(s,1H),7.56(s,1H),7.23(s,1H),7.11(s,1H),6.95(t,J＝7.2Hz,2H),5.20(s,2H),4.40(s,2H),4.21(q,J＝7.1Hz,2H),3.25(s,4H),1.91(s,4H),1.34(t,J＝7.1Hz,3H).
Example 36(R) -1- (p-methylphenyl) ethyl (1-ethyl-5- (4- (pyrrol-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:127.6-129.4℃；MS(ESI)m/z:489.44[M+H],487.34[M-H]；1H NMR(400MHz,DMSO)δ9.83(s,1H),8.49(s,1H),7.73(d,J＝8.3Hz,1H),7.55(s,1H),7.49(d,J＝8.6Hz,1H),7.38(s,1H),7.34(d,J＝7.1Hz,2H),7.19(d,J＝6.7Hz,2H),5.79(d,J＝6.4Hz,1H),4.17(dd,J＝7.0Hz,2H),3.79(s,2H),2.62(s,4H),2.29(s,3H),1.73(s,4H),1.55(d,J＝6.1Hz,3H),1.32(t,J＝6.9Hz,3H).
Example 373, 5-dichlorobenzyl (1-ethyl-5- (4- ((4-methylpiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:125.2-127.1℃；MS(ESI)m/z:557.44[M+H],579.41[M+Na],555.48[M-H]；1H NMR(400MHz,DMSO)δ9.95(s,1H),8.46(s,1H),7.73(dd,J＝8.7,1.5Hz,1H),7.60(s,2H),7.54(s,2H),7.52(d,J＝8.9Hz,1H),7.36(s,1H),5.20(s,2H),4.20(q,J＝7.1Hz,2H),3.65(s,2H),2.93(d,J＝10.6Hz,2H),2.08(s,2H),1.59(d,J＝11.8Hz,2H),1.34(t,J＝7.1Hz,3H),1.23(s,1H),1.18(d,J＝9.7Hz,2H),0.89(d,J＝6.4Hz,3H).
Example 383, 5-dichlorobenzyl (1-ethyl-5- (4- ((4-methylpiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:137.5-139.6℃；MS(ESI)m/z:557.24[M+H],555.47[M-H]；1H NMR(400MHz,DMSO)δ9.95(s,1H),8.47(s,1H),7.73(dd,J＝8.7,1.5Hz,1H),7.60(s,2H),7.54(s,2H),7.52(d,J＝8.8Hz,1H),7.36(s,1H),5.20(s,2H),4.20(q,J＝7.1Hz,2H),3.62(s,2H),2.50(s,4H),2.41(s,4H),2.20(s,3H),1.34(t,J＝7.2Hz,3H).
Example 39
Step A methyl (S) - (1- ((2- (3- ((((3, 5-dichlorobenzyl) oxy) carbonyl) amino) -1-ethyl-1H-indol-5-yl) thiazol-4-yl) methyl) pyrrolidin-2-yl) acetate
Intermediate 4g (0.01mol) M at room temperature22mL of acetic anhydride, 3mL of triethylamine and 0.1g of 4-dimethylaminopyridine were added in this order to 25mL of dichloromethane and reacted at room temperature for 1.5 hours. After the reaction, water and dichloromethane were added to separate the reaction solution, and 3.2g of a yellow solid in the organic layer was evaporated to dryness, yielding 75%.
Step B methyl (S) - (1- ((2- (3- ((((3, 5-dichlorobenzyl) oxy) carbonyl) amino) -1-ethyl-1H-indol-5-yl) thiazol-4-yl) methyl) pyrrolidin-2-yl) acetate
3.2g (0.008mol) of the product obtained in step A was dissolved in dry toluene at room temperature, 2mL of triethylamine and 3mL of diphenylphosphorylazide were added, and after stirring for 30 minutes, 3, 5-dichlorobenzyl alcohol was added, and the mixture was refluxed for 2 hours. After the reaction, the reaction mixture was cooled to room temperature, toluene was evaporated, water and dichloromethane were added to separate the reaction mixture, and the organic layer was evaporated to dryness to obtain 3.6g of an oily substance with a yield of 72%.
Step C3, 5-dichlorophenyl (S) - (1-ethyl-5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate (example 39)
3.6g of the product from step B was dissolved in 15mL of dioxane at room temperature, and 20mL of 2M sodium hydroxide solution was added and reacted at 50 ℃ for 2 h. After the reaction, 30mL of water was added, the mixture was extracted with dichloromethane (25 mL. times.2), and the organic layer was evaporated to dryness to obtain a crude product. And purifying the crude product by column chromatography to obtain the target compound.
m.p.:60.2-62.9℃；MS(ESI)m/z:559.39[M+H]；1H NMR(600MHz,DMSO)δ10.40(s,1H),10.02(s,1H),8.52(s,1H),7.79(dd,J＝8.7,1.1Hz,1H),7.63(s,1H),7.60(s,1H),7.42(d,J＝6.8Hz,1H),7.30(s,1H),6.97(t,J＝7.2Hz,2H),5.67(s,1H),5.20(s,2H),4.85(s,1H),4.80(s,1H),4.63(s,1H),4.42(s,1H),4.21(q,J＝7.1Hz,2H),3.70(s,3H),3.42(s,1H),2.05(s,1H),1.86(d,J＝28.9Hz,2H),1.72(s,1H),1.34(t,J＝7.2Hz,3H).
Following the procedure of example 39, intermediate M2Esterification, rearrangement, hydrolysis reactions were performed on the starting materials to prepare the compounds of examples 40-51.
Example 40(R) -1- (p-methylphenyl) ethyl (1-ethyl-5- (4- (((S) -2- (hydroxymethyl l) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:63.0-65.4℃；ESI-MS(m/z):519.23[M+H]；1H NMR(400MHz,DMSO)δ9.82(s,1H),8.47(s,1H),7.76–7.71(m,1H),7.55(s,1H),7.49(d,J＝8.7Hz,1H),7.38(d,J＝11.2Hz,1H),7.34(d,J＝7.8Hz,2H),7.20(dd,J＝7.6,3.9Hz,2H),5.82–5.76(m,1H),4.48(s,1H),4.17(dd,J＝15.3,8.2Hz,2H),3.70(d,J＝14.1Hz,1H),3.47(dd,J＝10.6,4.7Hz,1H),3.32(dd,J＝10.5,6.3Hz,1H),3.03(dd,J＝8.4,4.4Hz,1H),2.73(s,1H),2.42(d,J＝7.7Hz,1H),2.30(s,4H),1.83(dt,J＝11.8,8.3Hz,1H),1.66(dd,J＝14.3,7.1Hz,2H),1.61(d,J＝6.5Hz,1H),1.55(d,J＝6.5Hz,3H),1.32(t,J＝7.1Hz,3H).
Example 41(R) -1- (2-chlorophenyl) ethyl (1-ethyl-5- (4- (((S) -2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:63.5-64.7℃；ESI-MS(m/z):539.17[M+H]；1H NMR(400MHz,DMSO)δ9.97(s,1H),8.48(s,1H),7.74(d,J＝8.6Hz,1H),7.62(d,J＝7.3Hz,1H),7.56(s,1H),7.52–7.46(m,2H),7.43(t,J＝7.3Hz,1H),7.36(d,J＝7.7Hz,2H),6.09(q,J＝6.4Hz,1H),4.47(s,1H),4.23–4.14(m,2H),4.10(s,1H),3.70(d,J＝14.1Hz,1H),3.47(dd,J＝10.4,4.4Hz,1H),3.32(d,J＝10.3Hz,1H),3.03(d,J＝4.0Hz,1H),2.72(s,1H),2.42(d,J＝7.6Hz,1H),1.84(dd,J＝19.0,8.2Hz,1H),1.64(td,J＝10.2,6.3Hz,2H),1.61(d,J＝6.5Hz,1H)1.56(d,J＝6.4Hz,3H),1.31(t,J＝7.0Hz,3H).
Example 42 phenyl (S) - (1-ethyl-5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:64.2-65.5℃；MS(ESI)m/z:491.32[M+H],513.35[M+Na],489.29[M-H]；1H NMR(400MHz,DMSO)δ9.87(s,1H),8.45(s,1H),7.73(d,J＝7.7Hz,1H),7.60(s,1H),7.51(d,J＝8.7Hz,1H),7.47(d,J＝6.9Hz,2H),7.44–7.39(m,2H),7.34(dd,J＝15.1,6.2Hz,2H),5.19(s,2H),4.45(s,1H),4.19(dd,J＝14.0,6.9Hz,2H),4.10(d,J＝14.2Hz,1H),3.68(d,J＝14.2Hz,1H),3.46(dd,J＝10.3,4.2Hz,1H),3.30(d,J＝10.5Hz,1H),3.05–2.98(m,1H),2.69(m,1H),2.44–2.33(m,1H),1.82(dd,J＝19.2,8.3Hz,1H),1.70–1.60(m,2H),1.57(dd,J＝12.0,6.0Hz,1H),1.34(t,J＝7.1Hz,3H).
EXAMPLE 43 benzo [ d ] [1,3] Dioxolan-5-ylmethyl (S) - (1-ethyl-5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:129.7-131.8℃；ESI-MS[M+H](m/z):535.26；1H NMR(400MHz,DMSO)δ9.81(s,1H),8.44(s,1H),7.74(d,J＝8.5Hz,1H),7.59(s,1H),7.51(d,J＝8.7Hz,1H),7.39(s,1H),7.03(s,1H),6.95(d,J＝3.5Hz,2H),6.03(s,2H),5.08(s,2H),4.57–4.47(m,1H),4.23–4.18(m,2H),4.15(d,J＝16.0Hz,1H),3.76(s,1H),3.48(m,2H)3.07(d,J＝6.1Hz,1H),2.78(s,1H),1.85(dd,J＝19.1,8.2Hz,1H),1.67(d,J＝6.8Hz,2H),1.58(dd,J＝11.8,6.1Hz,2H),1.34(t,J＝7.1Hz,3H).
Example 443, 5-dichlorobenzyl (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:67.9-69.6℃；MS(ESI)m/z:559.39[M+H],581.41[M+Na]；1H NMR(600MHz,DMSO)δ9.96(s,1H),8.47(s,1H),7.73(dd,J＝8.6,1.6Hz,1H),7.60(s,2H),7.54(s,2H),7.52(d,J＝8.7Hz,1H),7.35(dd,J＝3.3,2.5Hz,1H),5.20(s,2H),4.56(s,1H),4.20(q,J＝7.2Hz,2H),3.60(s,2H),3.46(s,1H),2.79(s,2H),2.15(s,2H),1.73(d,J＝9.9Hz,2H),1.42(dd,J＝13.1,5.9Hz,2H),1.34(t,J＝7.2Hz,3H).
EXAMPLE 45 benzo [ d ] [1,3] Dioxolan-5-ylmethyl (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:64.3-65.9℃；ESI-MS[M+H](m/z):535.31；1H NMR(400MHz,DMSO)δ9.82(s,1H),8.46(s,1H),7.73(d,J＝8.5Hz,1H),7.59(s,1H),7.50(d,J＝8.6Hz,1H),7.35(s,1H),7.04(s,1H),6.94(s,2H),6.03(s,2H),5.08(s,2H),4.57(s,1H),4.26–4.10(m,2H),3.63(s,2H),3.47(s,1H),2.80(s,2H),2.18(s,2H),1.73(d,J＝10.0Hz,2H),1.43(d,J＝9.2Hz,2H),1.34(t,J＝7.0Hz,3H).
Example 463, 4-difluorobenzyl (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:60.0-62.4℃；MS(ESI)m/z:527.26[M+H],525.18[M-H]；1H NMR(400MHz,DMSO)δ9.91(s,1H),8.46(s,1H),7.73(d,J＝8.5Hz,1H),7.60(s,1H),7.51(dd,J＝19.8,10.9Hz,3H),7.35(s,2H),5.17(s,2H),4.56(s,1H),4.20(d,J＝6.8Hz,2H),3.61(s,2H),3.47(s,1H),2.79(m,2H),2.16(m,2H),1.72(m,2H),1.42(d,J＝9.4Hz,2H),1.34(t,J＝6.9Hz,3H).
Example 47(R) -1- (2-chlorophenyl) ethyl (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:103.1-105.6℃；MS(ESI)m/z:539.28[M+H],537.31[M-H]；1H NMR(400MHz,DMSO)δ9.98(s,1H),8.50(s,1H),7.73(d,J＝8.6Hz,1H),7.62(d,J＝7.4Hz,1H),7.56(s,1H),7.51–7.46(m,2H),7.43(t,J＝7.5Hz,1H),7.34(d,J＝8.7Hz,2H),6.09(q,J＝6.5Hz,1H),4.57(d,J＝2.8Hz,1H),4.16(dd,J＝14.0,6.9Hz,2H),3.62(s,2H),3.48(s,1H),2.81(d,J＝10.3Hz,2H),2.17(s,2H),1.74(d,J＝9.8Hz,2H),1.56(d,J＝6.4Hz,3H),1.43(m,2H),1.31(t,J＝7.1Hz,3H).
Example 483, 5-dichlorobenzyl (5- (4- ((bis (2-hydroxyethyl) amino) methyl) thiazol-2-yl) -1-ethyl-1H-indol-3-yl) carbamate
m.p.:112.7-113.6℃；1H NMR(400MHz,DMSO)δ7.73(t,J＝12.3Hz,1H),7.60(s,1H),7.53(d,J＝8.7Hz,1H),7.45(d,J＝1.9Hz,1H),7.42(s,2H),7.35(s,1H),7.16(s,1H),6.97(s,1H),4.89(s,2H),4.85(s,2H),4.51(d,J＝5.6Hz,2H),4.25–4.13(m,2H),3.89(s,2H),3.53(s,2H),3.51(s,2H),2.70(s,2H),1.34(t,J＝5.7Hz,3H).
Example 493, 5-dichlorobenzyl (1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:80.5-81.7℃；MS(ESI)m/z:588.13[M+H]；1H NMR(400MHz,DMSO)δ9.96(s,1H),8.47(s,1H),7.73(d,J＝8.7Hz,1H),7.60(s,2H),7.54(s,2H),7.52(d,J＝9.0Hz,1H),7.36(s,1H),5.20(s,2H),4.44(s,1H),4.20(q,J＝6.9Hz,2H),3.62(s,2H),3.49(t,J＝6.1Hz,2H),3.42(s,2H),2.49–2.45(m,4H),2.42(t,J＝6.1Hz,4H),1.34(t,J＝7.1Hz,3H).
Example 503, 4-Difluorobenzyl (1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:83.1-85.0℃；MS(ESI)m/z:556.12[M+H]；1H NMR(400MHz,DMSO)δ9.91(s,1H),8.46(s,1H),7.73(dd,J＝8.7,1.3Hz,1H),7.59(d,J＝6.5Hz,1H),7.56(s,1H),7.52(s,1H),7.50(s,1H),7.35(s,2H),5.17(s,2H),4.40(s,1H),4.20(q,J＝7.1Hz,2H),3.62(s,2H),3.49(t,J＝6.0Hz,2H),2.49–2.43(m,6H),2.39(t,J＝6.1Hz,4H),1.34(t,J＝7.2Hz,3H).
Example 51 benzyl (1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
m.p.:88.2-89.6℃；MS(ESI)m/z:519.76[M+H]；1H NMR(400MHz,DMSO)δ9.88(s,1H),8.47(s,1H),7.73(d,J＝8.6Hz,1H),7.60(s,1H),7.50(d,J＝8.7Hz,1H),7.46(s,2H),7.41(s,2H),7.35(s,2H),5.19(s,2H),4.41(s,1H),4.19(d,J＝6.9Hz,2H),3.61(s,2H),3.49(s,2H),2.48–2.45(m,6H),2.40(m,4H),1.34(t,J＝6.9Hz,3H).
Example 521-phenyl-3- (1-ethyl-5- (4- (morpholinomethyl) thiazol-2-yl) -1H-indol-3-yl) urea
Intermediate 3.5g (0.01mol) M at room temperature2Dissolved in dry toluene, 3mL of triethylamine and 3mL of diphenylphosphorylazide were added, and after stirring for 30min, 1.6g (0.015mol) of benzylamine was added, and the reaction was refluxed for 3 hours. After the reaction, the solvent was distilled off, water and dichloromethane were added to separate the liquid, and the organic layer was evaporated to dryness to obtain a crude product. The crude product was purified by thin layer chromatography to give 0.71g of the target compound in 15% yield.
m.p.:102.9-103.7℃；MS(ESI)m/z:476.75[M+H],474.73[M-H]；1H NMR(400MHz,DMSO)δ8.66(s,1H),8.22(s,1H),7.67(d,J＝8.6Hz,1H),7.58(s,1H),7.50(d,J＝8.7Hz,1H),7.39(s,1H),7.37–7.30(m,5H),7.25(d,J＝4.5Hz,1H),6.54(t,J＝5.9Hz,1H),4.34(d,J＝5.9Hz,2H),4.17(q,J＝7.1Hz,2H),3.62(s,2H),3.61–3.58(m,4H),2.47(m,4H),1.33(t,J＝7.1Hz,3H).
Following the procedure of example 52, intermediate M2The starting materials were subjected to Curtius rearrangement with benzylamine to afford the compounds of examples 53-54.
Example 531- (1-Ethyl-5- (4- ((4-methylpiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -3- (4-fluorobenzene) urea
m.p.:104.7-105.2℃；MS(ESI)m/z:506.83[M+H]；1H NMR(400MHz,DMSO)δ8.70(s,1H),8.22(s,1H),7.67(dd,J＝8.6,1.5Hz,1H),7.57(s,1H),7.49(d,J＝8.7Hz,1H),7.37(dd,J＝8.4,5.7Hz,2H),7.32(s,1H),7.16(t,J＝8.9Hz,2H),6.59(t,J＝6.0Hz,1H),4.32(d,J＝5.8Hz,2H),4.16(q,J＝7.1Hz,2H),3.58(s,2H),2.88(d,J＝11.3Hz,2H),2.00(t,J＝10.7Hz,2H),1.57(d,J＝11.9Hz,2H),1.33(t,J＝7.1Hz,3H),1.21(m,J＝12.9,3.2Hz,1H),1.14(m,J＝17.4,8.2Hz,2H),0.88(d,J＝6.4Hz,3H).
Example 541- (4-Chlorobenzene) -3- (1-ethyl-5- (4- ((4-methylpiperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) urea
m.p.:102.1-103.9℃；MS(ESI)m/z:523.86[M+H]；1H NMR(400MHz,DMSO)δ8.70(s,1H),8.22(s,1H),7.67(dd,J＝8.7,1.3Hz,1H),7.57(s,1H),7.50(d,J＝8.7Hz,1H),7.40(d,J＝7.3Hz,1H),7.39(s,1H),7.36(s,2H),7.34(s,1H),6.60(t,J＝6.0Hz,1H),4.33(d,J＝5.9Hz,2H),4.17(q,J＝7.1Hz,2H),3.62(s,2H),2.50–2.44(m,3H),2.37(m,4H),2.17(s,3H),1.33(t,J＝7.2Hz,3H).
Example 55
Step A5- (4- ((4-acetoxypiperidin-1-yl) methyl) thiazol-2-yl) -1-ethyl-1H-indole-3-carboxylic acid
Intermediate 3.85g (0.01mol) M was added at room temperature22mL of acetic anhydride, 3mL of triethylamine and 0.1g of 4-dimethylaminopyridine were added in this order to 25mL of dichloromethane and reacted at room temperature for 1.5 hours. After the reaction, water and methylene chloride were added to separate the reaction solution, and 3.3g of a yellow solid in the organic layer was evaporated to dryness, whereby the yield was 77%.
Step B1- ((2- (3- (3- (3-chloro-4-methoxyphenyl) ureido) -1-ethyl-1H-indol-5-yl) thiazol-4-yl) methyl) piperidin-4-yl acetate
At room temperature, 3.3g (0.008mol) of the product obtained in step A was dissolved in dry toluene, 2mL of triethylamine and 3mL of diphenylphosphorylazide were added, and after stirring for 30 minutes, 3-chloro-4-methoxybenzylamine was added, and the reaction was refluxed for 2 hours. After the reaction, the reaction mixture was cooled to room temperature, toluene was evaporated, water and dichloromethane were added to separate the reaction mixture, and the organic layer was evaporated to dryness to obtain an oily substance (3.57 g) in a yield of 75%.
Step C1- (3-chloro-4-methoxyphenyl) -3- (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) urea (example 55)
3.57g of the product from step B was dissolved in 15mL of dioxane at room temperature, and 20mL of 2M sodium hydroxide solution was added and reacted at 50 ℃ for 2 h. After the reaction, 30mL of water was added, the mixture was extracted with dichloromethane (25 mL. times.2), and the organic layer was evaporated to dryness to obtain a crude product. The crude product was purified by thin layer chromatography to give the target compound in 19% yield.
m.p.:103.5-104.6℃；MS(ESI)m/z:555.86[M+H]；1H NMR(400MHz,DMSO)δ8.69(s,1H),8.22(s,1H),7.67(dd,J＝8.6,1.4Hz,1H),7.57(s,1H),7.49(d,J＝8.7Hz,1H),7.38(d,J＝1.8Hz,1H),7.33(s,1H),7.26(dd,J＝8.4,1.9Hz,1H),7.10(d,J＝8.5Hz,1H),4.55(s,1H),4.27(d,J＝5.8Hz,2H),4.17(q,J＝7.1Hz,2H),3.83(s,3H),3.59(s,2H),3.46(s,1H),2.78(d,J＝11.3Hz,2H),2.13(t,J＝9.8Hz,2H),1.72(d,J＝9.5Hz,2H),1.41(dd,J＝18.6,8.8Hz,2H),1.33(t,J＝7.2Hz,3H).
Example 56
3, 5-dichlorobenzyl (5- (4- ((bis (2-hydroxyethyl) amino) methyl) thiazol-2-yl) -1-ethyl-1H-indol-3-yl) carbamate
m.p.:109.5-110.3℃；1H NMR(400MHz,DMSO)δ8.65(s,1H),8.18(s,1H),7.69(dd,J＝8.6,1.4Hz,1H),7.57(s,1H),7.50(d,J＝8.7Hz,1H),7.43(s,1H),7.38(d,J＝1.8Hz,1H),7.27(dd,J＝8.5,1.8Hz,1H),7.11(d,J＝8.5Hz,1H),6.55(t,J＝5.9Hz,1H),4.44(s,2H),4.26(d,J＝5.8Hz,2H),4.17(dd,J＝14.3,7.1Hz,2H),3.86(s,2H),3.83(s,3H),3.51(t,J＝6.0Hz,4H),2.67(t,J＝6.2Hz,4H),1.33(t,J＝7.2Hz,3H).
Study of ATX inhibitory Activity of the product of the present invention
The inhibition of the compounds of the invention on ATX was tested using an ATX detection kit with FS-3 as substrate.
Starting from the highest concentration of 20 micromolar, 10 microliters of serial dilution compound were added to each well. Glycosylated human ATX protein) was used at a final concentration of 0.4 or 0.64 μ g/mL, diluted in 50mM Tris-HCl (2-amino-2-hydroxymethyl-1, 3-propanediol hydrochloride), pH 8, and sodium chloride 250 mmol, potassium chloride 5 mmol, magnesium chloride 1 mmol, calcium chloride 1 mmol and fatty acid free BSA (bovine serum albumin) were added to maintain a total volume of 20 μ L. The compound was added to the enzyme mixture and the resulting mixture was shaken at room temperature and incubated for 30 minutes. Fluorescence was excited by adding 20. mu.L of 0.75. mu.M FS-3 diluted in the same buffer. After 30min incubation at room temperature (excitation wavelength 485nm, emission wavelength 520nm), fluorescence values were read from a fluorescence excitation device (Perkinelmer).
Research on antitumor activity of product of the invention
In vitro antitumor cell Activity
The indole derivative of the formula I is subjected to in vitro MCF-7 breast cancer cell activity test and EGFR high-expression human lung adenocarcinoma cell A549 activity screening.
(1) After cells were thawed and passaged for 2-3 stabilities, they were digested from the bottom of the flask with trypsin solution (0.25%). After pouring the cell digest into the centrifuge tube, the culture medium is added to stop the digestion. Centrifuging the centrifuge tube at 800r/min for 10min, discarding supernatant, adding 5mL culture solution, blowing and beating the mixed cells, sucking 10 μ L cell suspension, adding into a cell counting plate, counting, and adjusting cell concentration to 104 cells/hole. 100. mu.L of the cell suspension was added to the 96-well plate except that the A1 well was a blank well and no cells were added. The 96-well plate was placed in an incubator for 24 h.
(2) The test sample was dissolved in 50. mu.L of dimethyl sulfoxide, and then an appropriate amount of culture medium was added to dissolve the sample to 2mg/mL of the liquid, and then the sample was diluted to 20, 4, 0.8, 0.16, 0.032. mu.g/mL in a 24-well plate. 3 wells were added for each concentration, two rows and two columns of cells around the wells were greatly affected by the environment and only used as blank wells. The 96-well plate was placed in an incubator for 72 h.
(3) The drug-containing culture medium in the 96-well plate was discarded, the cells were washed twice with Phosphate Buffered Saline (PBS), 100. mu.L of MTT (0.5mg/mL) was added to each well, and the mixture was placed in an incubator for 4 hours, and then the MTT solution was discarded, and 100. mu.L of dimethyl sulfoxide was added thereto. And oscillating on a magnetic oscillator to fully dissolve the viable cells and the MTT reaction product formazan, and putting the formazan into an enzyme labeling instrument to measure the result. Determination of drug IC by Bliss method50The value is obtained.
The results of the ATX inhibitory activity of the compounds and the activity of the breast cancer cells MCF-7 and lung adenocarcinoma cells A549 are shown in Table 1.
TABLE 1
Figure BDA0002368441140000341
Figure BDA0002368441140000351
Figure BDA0002368441140000361
Research on in vivo anti-fibrosis activity of compound of the invention
The inhibition effect of the lead compound 34 on an MI model is examined by adopting a Masson staining experimental method, and the anti-myocardial tissue fibrosis capacity of the lead compound is evaluated.
Dewaxing the myocardial tissue slices to distilled water, dyeing with hematoxylin for 5-10 min, differentiating with hydrochloric acid and alcohol, bluing with running water, washing with distilled water, dyeing with ponceau red acid red liquor for 5-8 min, washing with distilled water, dyeing with 1% phosphomolybdic acid for 1-3 min, directly introducing aniline blue liquor or brilliant green liquor for 5min without washing with water, washing with water quickly, drying in a 60 ℃ incubator, and sealing and fixing with transparent xylene. Collagen fibers were blue (counterstained with aniline blue) or green (counterstained with light green), cytoplasm, muscle fibers and erythrocytes were red, and nuclei were blue-brown.
As shown in FIG. 1, the collagen tissue was significantly increased in the Myocardial Infarction (MI) model, and when treated with 34, the collagen tissue was significantly decreased as compared to the MI group. The experimental result proves that 34 has the function of reducing the generation of collagen tissue and inhibiting fibrosis.

Claims (13)

1. Indole derivatives represented by general formula I and pharmaceutically acceptable salts thereof,
Figure FDA0003248148760000011
wherein,
l is
Figure FDA0003248148760000012
R is H or C1-C6 alkyl;
x is O, S, NH;
R1、R2is C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of hydrogen, halogen, halogenated C1-C4 hydrocarbyl, halogenated C1-C4 alkoxy, amino, cyano, hydroxy;
or R1And R2Together with the nitrogen atom to which they are attached to form
Figure FDA0003248148760000013
Figure FDA0003248148760000014
And may be substituted by 1 to 3 identical or different R9Substitution;
R9is hydrogen, carboxyl, hydroxyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkyl or substituted C1-C6 alkyl, and the substituent is: cyano, amino, C1-C4 alkylamino, C1-C4 sulfonyl;
R3is hydrogen, C1-C6 alkyl;
R4is absent;
R5、R6、R7、R8hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxyl, carboxyl, cyano, C1-C4 acylamino, C1-C4 hydrocarbyl-substituted carbamoyl, C1-C4 hydrocarbyl-substituted sulfonamide, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide can be respectively and independently selected, and the number and the combination are not limited;
or R4And R5Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered heterocyclic or heteroaromatic, 4-7 membered unsaturated carbocyclic ring, said heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R5And R6Together with the carbon atoms of the phenyl ring to which they are attached form a 4-to 7-membered ringAn unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or a heteroaromatic ring, said heterocyclic or heteroaromatic ring containing 1-3 heteroatoms of N, O and/or S;
or R6And R7Together with the carbon atoms of the phenyl ring to which they are attached form a 3-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S;
or R7And R8Together with the carbon atoms of the phenyl ring to which they are attached form a 4-7 membered unsaturated carbocyclic ring, a 4-7 membered heterocyclic ring or an aromatic heterocyclic ring, said heterocyclic or heteroaryl group containing 1-3 heteroatoms of N, O and/or S.
2. Indole derivatives of the general formula I according to claim 1,
wherein,
R1、R2is C1-C6 alkyl optionally substituted with one or more substituents selected from amino, hydroxy;
or R1And R2Together with the nitrogen atom to which they are attached to form
Figure FDA0003248148760000021
Figure FDA0003248148760000022
And may be substituted by 1 to 3 identical or different R9Substitution;
R9is hydrogen, carboxyl, hydroxyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C6 alkyl or substituted C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, and the substituent is: cyano, amino, C1-C4 alkylamino, C1-C4 sulfonyl.
3. Indole derivatives of the general formula I according to claim 1,
wherein R is9Is hydrogen, carboxyl, hydroxyl, C1-C4 alkoxyl, C1-C4 hydroxyalkyl.
4. Indole derivatives of the general formula I according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof,
wherein,
R3hydrogen, C1-C4 alkyl.
5. Indole derivatives of the general formula I according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof
Wherein,
R3is methyl or ethyl.
6. Indole derivatives of the general formula I according to any one of claims 1 to 3 and pharmaceutically acceptable salts thereof,
wherein,
R5、R6、R7、R8hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxyl, carboxyl, cyano, C1-C4 acylamino, C1-C4 hydrocarbyl-substituted carbamoyl, C1-C4 sulfonamido, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide can be respectively and independently selected, and the number and the combination are not limited.
7. Indole derivatives of the general formula I according to claim 4,
wherein,
R5、R6、R7、R8hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxyl, carboxyl, cyano, C1-C4 acylamino, C1-C4 hydrocarbyl-substituted carbamoyl, C1-C4 sulfonamido, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide can be respectively and independently selected, and the number and the combination are not limited.
8. Indole derivatives of the general formula I according to claim 5,
wherein,
R5、R6、R7、R8hydrogen, halogen, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C1-C4 haloalkyl, C1-C4 alkoxy, C1-C4 alkylthio, hydroxyl, carboxyl, cyano, C1-C4 acylamino, C1-C4 hydrocarbyl-substituted carbamoyl, C1-C4 sulfonamido, amino, C1-C4 alkyl sulfone, C1-C4 alkyl sulfoxide can be respectively and independently selected, and the number and the combination are not limited.
9. Indole derivatives and pharmaceutically acceptable salts thereof,
(Z) -2- (2- (1- (1-ethyl-5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
(Z) - ((2- (3- (1- (2- (5-cyano-4- (4-fluorophenyl) thiazol-2-yl) hydrazine) -2,2, 2-trifluoroethyl) -1-ethyl-1H-indol-5-yl) -thiazol-4-yl) -methyl) -L-proline
(Z) - ((2- (3- (1- (2- (5-cyano-4- (4-methoxyphenyl) thiazol-2-yl) hydrazine) -2,2, 2-trifluoroethyl) -1-ethyl-1H-indol-5-yl) -thiazol-4-yl) -methyl) -L-proline
(Z) -2- (2- (1- (1-ethyl-5- (4- (pyrrol-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
(Z) -2- (2- (1- (1-ethyl-5- (4- (piperidin-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
(Z) -2- (2- (1- (1-ethyl-5- (4- ((4-methylpiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-methoxyphenyl) thiazole-5-carbonitrile
(S, Z) -2- (2- (1- (1-ethyl-5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
(Z) -2- (2- (1- (1-ethyl-5- (4- ((3-hydroxyazetidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
(Z) -2- (2- (1- (1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
(Z) -2- (2- (1- (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) -4- (4-fluorophenyl) thiazole-5-carbonitrile
(Z) -4- ((2- (3- (1- (2- (benzo [ d ] thiazol-2-yl) hydrazine) -2,2, 2-trifluoroethyl) -1-ethyl-1H-indol-5-yl) -thiazol-4-yl) -methyl) morpholine
(Z) -2- (2- (1- (1-ethyl-5- (4- (piperidin-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) -2,2, 2-trifluoroethylidene) hydrazine) benzo [ d ] thiazole-5-carbonitrile
(Z) -1- ((2- (3- (1- (2- (benzo [ d ] thiazol-2-yl) hydrazono) -2,2, 2-trifluoroethyl) -1-ethyl-1H-indol-5-yl) thiazol-4-yl) methyl) piperidin-4-ol
(E) -1-ethyl-N' - (4-fluorobenzylidene) -5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (benzo [ d ] [1,3] dioxolan-5-ylmethylidene) -1-ethyl-5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-5- (4- (morpholinylmethyl) thiazol-2-yl) 5-N' - ((4-oxo-4H-chromone-3-yl) methylidene) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (4-fluorobenzylidene) -1-methyl-5- (4- (morpholinylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-N' - (4-fluorobenzylidene) -5- (4- (piperidin-1-ylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-N' - (4-methoxybenzylidene) -5- (4- (tetrahydropyrrole-1-ylmethyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (benzo [ d ] [1,3] dioxolan-5-ylmethylidene) -1-ethyl-5- (4- ((4-methylpiperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (4-chlorobenzylidene) -1-methyl-5- (4- ((4-methylpiperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-N' - (4-fluorobenzylidene) -5- (4- ((4-methylpiperidin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-N' - (4-fluorobenzylidene) -5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (benzo [ d ] [1,3] dioxolan-5-ylmethylidene) -1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (4-chlorobenzylidene) -1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-N' - (4-fluorobenzylidene) -5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-N' - (1- (4-fluorophenyl) ethylidene) -5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (benzo [ d ] [1,3] dioxolan-5-ylmethylidene) -1-ethyl-5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (4-chlorobenzylidene) -1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -1-ethyl-N' - (4-fluorobenzylidene) -5- (4- ((4- (2- (hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
(E) -N' - (benzo [ d ] [1,3] dioxolan-5-ylmethylidene) -1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indole-3-carboxylic acid hydrazide
3, 5-dichlorobenzyl (1-ethyl-5- (4- (morpholinomethyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 5-dichlorobenzyl (1-ethyl-5- (4- (pyrrol-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
(R) -1- (4-methylphenyl) ethyl (1-ethyl-5- (4- (pyrrol-1-ylmethyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 5-dichlorobenzyl (1-ethyl-5- (4- ((4-methylpiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 5-dichlorobenzyl (1-ethyl-5- (4- ((4-methylpiperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 5-dichlorobenzyl (S) - (1-ethyl-5- (4- (- (2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
(R) -1- (p-methylphenyl) ethyl (1-ethyl-5- (4- (((S) -2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
(R) -1- (2-chlorophenyl) ethyl (1-ethyl-5- (4- (((S) -2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
Benzyl (S) - (1-ethyl-5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
Benzo [ d ] [1,3] dioxolan-5-ylmethyl (S) - (1-ethyl-5- (4- ((2- (hydroxymethyl) pyrrol-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 5-dichlorobenzyl (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
Benzo [ d ] [1,3] dioxolan-5-ylmethyl (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 4-Difluorobenzyl (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
(R) -1- (2-chlorophenyl) ethyl (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 5-dichlorobenzyl (5- (4- ((bis (2-hydroxyethyl) amino) methyl) thiazol-2-yl) -1-ethyl-1H-indol-3-yl) carbamate
3, 5-dichlorobenzyl (1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
3, 4-Difluorobenzyl (1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
Benzyl (1-ethyl-5- (4- ((4- (2-hydroxyethyl) piperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) carbamate
1-benzyl-3- (1-ethyl-5- (4- (morpholinomethyl) thiazol-2-yl) -1H-indol-3-yl) urea
1- (1-ethyl-5- (4- ((4-methylpiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) -3- (4-fluorobenzyl) urea
1- (4-chlorobenzyl) -3- (1-ethyl-5- (4- ((4-methylpiperazin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) urea
1- (3-chloro-4-methoxybenzyl) -3- (1-ethyl-5- (4- ((4-hydroxypiperidin-1-yl) methyl) thiazol-2-yl) -1H-indol-3-yl) urea
1- (5- (4- ((bis (2-hydroxyethyl) amino) methyl) thiazol-2-yl) -1-ethyl-1H-indol-3-yl) -3- (3-chloro-4-methoxybenzyl) urea.
10. A pharmaceutical composition comprising the indole derivative of any one of claims 1 to 9, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier.
11. Use of the indole derivatives as claimed in any one of claims 1 to 9 and pharmaceutically acceptable salts thereof or the pharmaceutical composition as claimed in claim 10 for the preparation of an ATX inhibitor.
12. Use of the indole derivatives as claimed in any one of claims 1 to 9 and pharmaceutically acceptable salts thereof or the pharmaceutical composition as claimed in claim 10 for the manufacture of an anti-tumour or anti-fibrotic medicament.
13. The use of claim 12, wherein the tumor is breast cancer or glioma and the fibrosis is pulmonary fibrosis, hepatic fibrosis or myocardial fibrosis.
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