CN112300134B - ASK1 inhibitor and derivative thereof, preparation method, pharmaceutical composition and application - Google Patents

ASK1 inhibitor and derivative thereof, preparation method, pharmaceutical composition and application Download PDF

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CN112300134B
CN112300134B CN202011186652.0A CN202011186652A CN112300134B CN 112300134 B CN112300134 B CN 112300134B CN 202011186652 A CN202011186652 A CN 202011186652A CN 112300134 B CN112300134 B CN 112300134B
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triazol
isopropyl
phenyl
indazole
cyclopropyl
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陈亚东
侯少华
佟宇
杨玥婧
陈泉威
万勃亨
魏然
陆涛
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China Pharmaceutical University
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Abstract

The invention discloses an ASK1 inhibitor and a derivative thereof, a preparation method, a pharmaceutical composition and application. The structure of the compound is shown as a formula I, and the ASK1 inhibitor derivative relates to an isomer, a diastereoisomer, an enantiomer, a tautomer, a solvate, a salt of the solvate, a pharmaceutically acceptable salt or a mixture of the isomers, the diastereoisomer, the enantiomer, the tautomer, the solvate and the salt of the solvate. The ASK1 inhibitor and the derivatives thereof have high-efficiency inhibition effect on ASK1 kinase, can be used for preparing medicines for diseases related to ASK1 kinase, can exert medicine effect on molecular level and cellular level, and have wide application, and the synthesis method of the compounds is simple and convenient and easy to operate.
Figure DDA0002751617350000011

Description

ASK1 inhibitor and derivative thereof, preparation method, pharmaceutical composition and application
Technical Field
The invention relates to an ASK1 inhibitor and a derivative thereof, a preparation method, a pharmaceutical composition and application thereof, in particular to an ASK1 inhibitor which can be prepared into ASK1 inhibitor medicines and a derivative thereof, a preparation method, a pharmaceutical composition and application thereof.
Background
Apoptosis signal regulating kinase 1 (ASK 1) belongs to the family of cytomitogen activated protein kinases (MAPKs), and the MAPK signaling pathway is one of important signaling systems in organisms and is involved in physiological processes such as cell proliferation, differentiation, apoptosis, inflammatory reaction and the like. The MAPK family includes three major subfamilies of extracellular signal-regulated kinases (ERKs), p38MAPK, and JNK. The MAPK family comprises tertiary kinases, first activated by intracellular and extracellular stimuli of cytokinin-activating protein kinase (MAP 3K), activated MAP3K phosphorylating activated MAP2K, which in turn activates MAPK. ASK1 belongs to MAP3K5, at P 38 Upstream of the MAPK and JNK signaling pathways.
ASK1 is activated under the stimulation of a range of stress responses such as oxidative stress, endoplasmic reticulum stress, and calcium influx. Activated ASK1 activates P by phosphorylating MKK3/6 and MKK4/7 38 MAPK and JNK pathways. ASK1 plays an important role in regulating cell physiological processes such as apoptosis, cytokine response, cell differentiation, and innate immune response. Studies have shown that ASK1 has a clear correlation with many diseases, such as: neurodegenerative diseases, cardiovascular system diseases, inflammatory diseases, metabolic diseases, autoimmune diseases, etc.
Relevant literature reports indicate that ASK1 small molecule inhibitors exhibit therapeutic potential against a variety of diseases. For example, GS-444217 has remarkable effects in various experimental models of kidney fibrosis and inflammation animal, and K811, K812 have SOD1 in ALS (amyotrophic lateral sclerosis) G93A Extension of mouse survival in transgenic mouse models, K811 inIn vitro and in vivo experiments, GS-4997 was subjected to clinical experiments of pulmonary hypertension, diabetic nephropathy and nonalcoholic steatohepatitis (NASH) to inhibit gastric cancer cell growth. However, the structure type of ASK1 small molecule inhibitor is single at present, and only GS-4997 is subjected to clinical experiments of related diseases. However, GS-4997 did not reach clinical endpoints in both phase III clinical trials on nonalcoholic steatohepatitis (NASH).
Disclosure of Invention
The invention aims to: the first object of the invention is to provide an ASK1 inhibitor and a derivative thereof, the second object is to provide a preparation method of the ASK1 inhibitor and a derivative thereof, the third object is to provide a pharmaceutical composition containing the ASK1 inhibitor and/or a derivative thereof, and the fourth object is to provide an application of the ASK1 inhibitor and a derivative thereof in preparing ASK1 inhibitor medicines.
The technical scheme is as follows: ASK1 inhibitors and derivatives thereof of the present invention have the structure of formula I, said derivatives being isomers, diastereomers, enantiomers, tautomers, solvates, salts of solvates, pharmaceutically acceptable salts or mixtures thereof of said compounds:
Figure BDA0002751617330000021
wherein:
M 1 、M 2 or M 3 Is N or C (R) 3 )；
Ring a or ring B is an aromatic or heteroaromatic ring;
R 1 、R 2 or R is 3 Is the same or different hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 6 、-(CH 2 ) n SR 6 、-(CH 2 ) n C(O)R 6 、-(CH 2 ) n C(O)OR 6 、-(CH 2 ) n S(O) m R 6 、-(CH 2 ) n NR 7 R 8 、-(CH 2 ) n C(O)NR 7 R 8 、-(CH 2 ) n C(O)NHR 7 、-(CH 2 ) n NR 7 C(O)R 6 Or- (CH) 2 ) n NR 7 S(O) m R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is substituted with alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 9 R 10 、-(CH 2 ) n C(O)NR 9 R 10 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 、-(CH 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
R 6 is a hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is substituted with alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 9 R 10 、-(CH 2 ) n C(O)NR 9 R 10 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 、-(CH 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
R 7 or R is 8 Is a hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is substituted with alkyl, halo, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 9 R 10 、-(CH 2 ) n C(O)NR 9 R 10 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 、-(CH 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
R 9 or R is 10 Is a hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is substituted with one or more substituents of alkyl, halogen, hydroxy, amino, nitro, cyano, ester, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
x or n is an integer from 0 to 5;
m is an integer of 0 to 2.
Preferably, the ASK1 inhibitor and its derivative have the structure:
ring B is
Figure BDA0002751617330000031
Or->
Figure BDA0002751617330000032
Further, the ASK1 inhibitor and its derivatives have the structure of formula II:
Figure BDA0002751617330000033
wherein:
M 3 is N or C (R) 3 ) Preferably CH;
ring a is an aromatic or heteroaromatic ring, preferably a 5 membered heteroaromatic ring;
R 1 being identical or different hydrogen atoms, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy, halogen, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, 5-7 membered aryl, 5-7 membered heteroaryl, - (CH) 2 ) n OR 6 、-(CH 2 ) n SR 6 、-(CH 2 ) n C(O)R 6 、-(CH 2 ) n C(O)OR 6 、-(CH 2 ) n S(O) m R 6 、-(CH 2 ) n NR 7 R 8 、-(CH 2 ) n C(O)NR 7 R 8 、-(CH 2 ) n C(O)NHR 7 、-(CH 2 ) n NR 7 C(O)R 6 Or- (CH) 2 ) n NR 7 S(O) m R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the alkyl, alkoxy, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is C 1-8 Alkyl, C 1-8 Haloalkyl, halogen, hydroxy, C 1-8 Alkoxy, C 1-8 Haloalkoxy, C 1-8 Hydroxyalkyl, C 3-8 Cycloalkyl, 3-8 heterocyclyl, 5-7 membered aryl, 5-7 membered heteroaryl, preferably substituted by one or more substituents, preferably 6 membered aryl, 5 membered heteroaryl, C 1-8 Alkyl, C 1-8 Alkoxy, 3-8 membered heterocyclyl substituted with one or more substituents;
R 2 being identical or different hydrogen atoms, C 1-8 Alkyl, C 1-8 Haloalkyl, C 1-8 Alkoxy, C 1-8 Haloalkoxy group,C 3-8 Cycloalkyl, 3-8 membered heterocyclyl, C 1-8 Hydroxyalkyl, 5-7 membered aryl, 5-7 membered heteroaryl, - (CH) 2 ) n OR 6 、-(CH 2 ) n SR 6 、-(CH 2 ) n C(O)R 6 、-(CH 2 ) n C(O)OR 6 、-(CH 2 ) n S(O) m R 6 、-(CH 2 ) n NR 7 R 8 、-(CH 2 ) n C(O)NR 7 R 8 、-(CH 2 ) n C(O)NHR 7 、-(CH 2 ) n NR 7 C(O)R 6 Or- (CH) 2 ) n NR 7 S(O) m R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is substituted with one or more substituents selected from alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, preferably with C 1-8 Hydroxyalkyl, C 1-8 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclyl;
R 3 is the same or different hydrogen atom, alkyl, haloalkyl, alkoxy, haloalkoxy, halogen, amino, nitro, hydroxy, cyano, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 6 、-(CH 2 ) n SR 6 、-(CH 2 ) n C(O)R 6 、-(CH 2 ) n C(O)OR 6 、-(CH 2 ) n S(O) m R 6 、-(CH 2 ) n NR 7 R 8 、-(CH 2 ) n C(O)NR 7 R 8 、-(CH 2 ) n C(O)NHR 7 、-(CH 2 ) n NR 7 C(O)R 6 Or- (CH) 2 ) n NR 7 S(O) m R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is substituted with alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxyAlkoxy, haloalkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 9 R 10 、-(CH 2 ) n C(O)NR 9 R 10 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 Or- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
R 6 is a hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is substituted with alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 9 R 10 、-(CH 2 ) n C(O)NR 9 R 10 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 、-(CH 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
R 7 or R is 8 Is a hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is substituted with alkyl, halo, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroarylRadical, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 9 R 10 、-(CH 2 ) n C(O)NR 9 R 10 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 、-(CH 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
R 9 or R is 10 Is a hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is substituted with one or more substituents of alkyl, halogen, hydroxy, amino, nitro, cyano, ester, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl;
x or n is an integer from 0 to 5;
m is an integer of 0 to 2.
Further, the ASK1 inhibitor and its derivatives have the structure of formula III:
Figure BDA0002751617330000051
wherein:
R 1 being identical or different hydrogen atoms, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, halogen, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, 5-6 membered aryl, 5-6 membered heteroaryl, - (CH) 2 ) n OR 6 、-(CH 2 ) n C(O)R 6 、-(CH 2 ) n S(O) m R 6 、-(CH 2 ) n C(O)NR 7 R 8 、-(CH 2 ) n NR 7 C(O)R 6 Or- (CH) 2 ) n NR 7 S(O) m R 6 The method comprises the steps of carrying out a first treatment on the surface of the Wherein the alkoxy, heterocyclyl, aryl or heteroaryl is C 1-6 Alkyl, C 1-6 Haloalkyl, halogen, hydroxy, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 heterocyclyl, 6 membered aryl, 5 membered heteroaryl, preferably substituted by one or more substituents C 1-6 Alkoxy, C 1-6 One or more substituents in the alkyl group, the 6-membered aryl group, the substituted 5-membered heteroaryl group and the 3-6-membered heterocyclic group;
R 4 is hydrogen atom, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl or 3-6 membered heterocyclic groups, preferably hydrogen or C 1-6 An alkyl group;
R 6 is a hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, alkoxy, haloalkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is substituted with alkyl, haloalkyl, halogen, amino, nitro, cyano, hydroxy, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 9 R 10 、-(CH 2 ) n C(O)NR 9 R 10 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 Or- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
R 7 or R is 8 Is a hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the alkyl groupCycloalkyl, heterocyclyl, aryl or heteroaryl groups are substituted with alkyl, halogen, hydroxy, amino, nitro, cyano, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, - (CH) 2 ) n OR 9 、-(CH 2 ) n SR 9 、-(CH 2 ) n C(O)R 9 、-(CH 2 ) n C(O)OR 9 、-(CH 2 ) n S(O) m R 9 、-(CH 2 ) n NR 9 R 10 、-(CH 2 ) n C(O)NR 9 R 10 、-(CH 2 ) n C(O)NHR 10 、-(CH 2 ) n NR 10 C(O)R 9 Or- (CH) 2 ) n NR 10 S(O) m R 9 Is substituted by one or more substituents;
R 9 or R is 10 Is a hydrogen atom, alkyl, haloalkyl, hydroxyl, amino, ester, cycloalkyl, heterocyclyl, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is substituted with one or more substituents of alkyl, halo, hydroxy, amino, nitro, cyano, ester, alkoxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
x or n is an integer from 0 to 5;
m is an integer of 0 to 2.
Still further, the ASK1 inhibitor has the structure of formula IV:
Figure BDA0002751617330000061
wherein:
R 1 is the same or different hydrogen atom, halogen, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 1-3 Cycloalkyl, 6 membered heterocyclyl or 5 membered heteroaryl;
R 4 is hydrogen atom, C 1-3 Alkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl or 3-A 6 membered heterocyclyl group, preferably isopropyl;
R 5 is hydrogen atom, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl or 6 membered heterocyclyl, preferably methyl, methoxymethyl, 1-ethoxyethyl or tetrahydro-2H-pyran-4-yl;
x is an integer from 1 to 5.
Still further, the ASK1 inhibitor has the structure of formula V:
Figure BDA0002751617330000062
wherein:
R 1 is hydrogen atom, halogen, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Alkoxy, C 1-3 Haloalkoxy, C 3-6 Cycloalkyl, 6 membered heterocyclyl or 5 membered heteroaryl, preferably methyl, methoxy or 1-morpholinyl;
R 4 is hydrogen atom, C 1-3 Alkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclyl, preferably isopropyl;
R 5 selected from hydrogen atoms, C 1-3 Alkyl, halogenated C 1-3 Alkyl, C 1-3 Alkoxy, halo C 1-3 Alkoxy, C 3-6 Cycloalkyl or 6 membered heterocyclyl, preferably isopropyl;
x is an integer from 1 to 5.
Still further, in the structure of the above ASK1 inhibitor, R 1 Is C 1-8 Alkyl, C 1-8 Alkoxy, 5-to 7-membered heteroaryl or halogen, preferably 5-to 6-membered heteroaryl, halogen, C 1-3 Alkyl or C 1-3 Alkoxy, more preferably substituted 5 membered heteroaryl, methyl, methoxy or morpholinyl, wherein said R 6 Is C 1-6 An alkyl group; r is R 2 Is C 1-8 Alkyl, C 1-8 Alkoxy, 5-7 membered heteroaryl, C 1-8 Hydroxyalkyl or halogen, preferably C 1-3 Alkyl, C 1-3 Alkoxy or C 1-4 Hydroxyalkyl, more preferably isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or morpholinyl; r is R 3 Is a hydrogen atom.
Still further, in the structure of the above ASK1 inhibitor, M 1 、M 2 Or M 3 is-C (R) 3 ) Wherein said R is 3 Is hydrogen atom, C 1-8 Alkyl or C 3-8 Cycloalkyl groups are preferably hydrogen atoms.
Still further, in the structure of the above ASK1 inhibitor, R 4 Is hydrogen atom, C 1-8 Hydroxyalkyl, C 1-8 Alkyl, halogenated C 1-8 Alkyl or C 3-8 Cycloalkyl, preferably isopropyl; r is R 5 Is hydrogen atom, 3-8 membered heterocyclic group, C 1-8 Alkyl or C 3-8 Cycloalkyl is preferably cyclopropyl.
The ASK1 inhibitor is specifically any one of the following compounds:
3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-1),
3- (3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methylphenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-2),
3- (5- (4-cyclopropyl-1H-imidazol-1-yl) -2-methoxyphenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-3),
3- (3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxyphenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-4),
4- (2- (4-cyclopropyl-1H-imidazol-1-yl) -4- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) phenyl) morpholine (I-5),
4- (3- (4-cyclopropyl-1H-imidazol-1-yl) -5- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) phenyl) morpholine (I-6),
5- (4-cyclohexyl-4H-1, 2, 4-triazol-3-yl) -3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -1H-indazole (I-7),
5- (4-cyclopentyl-4H-1, 2, 4-triazol-3-yl) -3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -1H-indazole (I-8),
3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -5- (4-cyclopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-9),
(R) -2- (3- (3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -1H-indazol-5-yl) -4H-1,2, 4-triazol-4-yl) propan-1-ol (I-10),
5- (4-cyclobutyl-4H-1, 2, 4-triazol-3-yl) -3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -1H-indazole (I-11),
5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -3- (3- (methylsulfonyl) phenyl) -1H-indazole (I-12),
3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) benzamide (I-13),
n-cyclopropyl-3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) benzamide (I-14),
3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) -N- (1-methyl-1H-pyrazol-4-yl) benzamide (I-15),
3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) -N- (2-methoxyethyl) benzamide (I-16),
2-cyclopropyl-N- (5- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) -2-methylphenyl) acetamide (I-17),
4- (tert-butyl) -N- (3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) phenyl) benzamide (I-18),
n- (3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) phenyl) -4- (trifluoromethyl) benzamide (I-19),
5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -3- (3- (pyridin-3-yl) phenyl) -1H-indazole (I-20),
5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -3- (3- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) phenyl) -1H-indazole (I-21),
3- (3- (1- (1-ethoxyethyl) -1H-pyrazol-4-yl) phenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-22),
5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -3- (3- (1-methyl-1H-pyrazol-5-yl) phenyl) -1H-indazole (I-23),
5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -3- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) -1H-indazole (I-24),
5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -3- (3- (1- (methoxymethyl) -1H-pyrazol-4-yl) phenyl) -1H-indazole (I-25),
3- (5- (1- (1-ethoxyethyl) -1H-pyrazol-4-yl) pyridin-3-yl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-26),
5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -3- (5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1H-indazole (I-27),
n- (3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) phenyl) ethanesulfonamide (I-28),
3- (3- (3-cyclopropyl-1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-29),
3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) benzenesulfonamide (I-30),
n- (3- (5- (1H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) phenyl) -4- (tert-butyl) benzamide (I-31),
n- (3- (5- (1H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) phenyl) -4- (trifluoromethyl) benzamide (I-32),
3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -5- (4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-33),
5- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) -2-methylbenzenesulfonamide (I-34),
3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -5- (1H-pyrazol-4-yl) -1H-indazole (I-35),
(S) -2- ((3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) phenoxy) methyl) morpholine (I-36),
4- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) thiophene-2-carboxamide (I-37).
The preparation method of the ASK1 inhibitor and the derivatives thereof comprises the following steps:
the compound 1 and the compound 2 are subjected to a coupling reaction to obtain a compound I;
Figure BDA0002751617330000091
wherein, ring A, ring B, M 1 、M 2 、M 3 、R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R 8 、R 9 、R 10 The definitions of x, m and n are the same as described above;
adding the corresponding acid or alkali solution into the compound I solution prepared by the method, and removing the solvent under reduced pressure after complete salification to obtain the pharmaceutically acceptable salt of the ASK1 inhibitor.
The application also discloses a pharmaceutical composition, which comprises the ASK1 inhibitor and/or a derivative thereof and a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable salt of the ASK1 inhibitor is a salt formed by the ASK1 inhibitor and an acid or alkali, and the acid is an inorganic acid or an organic acid, specifically hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid or mandelic acid; the alkali is inorganic alkali or organic alkali, and specifically is inorganic alkali containing alkaline metal cations, alkaline earth metal cations or ammonium cation salts.
The ASK1 inhibitor and the derivatives thereof can be added with pharmaceutically acceptable carriers to prepare common medicinal preparations such as tablets, capsules, syrup, suspending agents or injection, and the preparations can be added with common medicinal auxiliary materials such as perfume, sweetener, liquid/solid filler, diluent and the like.
The ASK1 inhibitor and the derivatives thereof can be prepared into ASK1 inhibitor medicines, and can be used for treating and/or preventing neurodegenerative diseases, cardiovascular diseases, inflammatory diseases, metabolic diseases and other diseases.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages:
(1) The compounds, derivatives and pharmaceutical compositions thereof can effectively inhibit ASK1 protein kinase activity and IC 50 All reach nanomolar concentration level, optimally less than15nM; the application is wide, and the medicine can be prepared into medicines for treating and/or preventing and treating neurodegenerative diseases, cardiovascular diseases, inflammatory diseases, metabolic diseases and other diseases; the medicine can exert the medicine effect at the molecular level and the cellular level, has more excellent treatment effect, and can optimally reach the nanomolar concentration level;
(2) The preparation method of the compound is simple and convenient and is easy to operate.
Drawings
FIG. 1 is a diagram of Compound I-22 1 H-NMR spectrum;
FIG. 2 is a mass spectrum of Compound I-22;
FIG. 3 is a bar graph of the effect of compounds on the mRNA expression levels of the Colla1 gene from HSC cells;
FIG. 4 is a bar graph of the effect of compound I-22 on intestinal epithelial cell viability;
FIG. 5 is a cell image of the effect of compound I-22 on intestinal epithelial cell survival, wherein A is a blank, B is a TNF- α stimulated group, C is a GS-4997 group administered after TNF- α stimulation, and D is an I-22 group administered after TNF- α stimulation.
Detailed Description
The technical scheme of the invention is further described below with reference to the embodiment and the attached drawings.
Reagent and material: thin Layer Chromatography (TLC) adopts a thin layer chromatography silica gel plate (smoke stage Jiang You silica gel development Co., ltd.), self-made silica gel thin layer plate adopts GF254 silica gel (Qingdao ocean chemical plant), and silica gel column chromatography generally adopts 200-300 mesh silica gel (Qingdao ocean chemical plant). M-bromoaniline, methyl 1H-indazole-5-carboxylate, m-bromobenzoic acid, 1, 3-dibromobenzene, 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine, cyclopropylnitrile, m-bromobenzenesulfonamide, t-butyl (S) -2- (hydroxymethyl) morpholine-4-carboxylate, m-bromophenol, pd (pph) 3 ) 4 、Pd(dppf)Cl 2 The organic synthesis raw materials and the catalyst are purchased from Shanghai Pi obtained from medical science and technology Co., shanghai Annaiji chemical Co., ltd. HTRF kinase assay kit was purchased from Cisbio, ASK1 (MAP 3K 5) protein was purchased from Carna, AP1-HEK293 cell kit was purchased from BPS Bioscience, HT-29 cellsAre purchased from American Type Culture Collection (Manassas, va., USA).
Instrument: 1 H-NMR was performed using BRUKER AVANCE-300 type and BRUKER AVANCE-400 type nuclear magnetic resonance apparatus (BRUKER Co., switzerland) with deuterated dimethyl sulfoxide (DMSO-d) 6 ) And deuterated chloroform (CDCl) 3 ) The internal standard is Tetramethylsilane (TMS), and the displacement value (delta) is in ppm; mass spectrometry MS employed Advion Mass expression CMS mass spectrometer; HPLC was performed using an Agilent 1260 Infinicity liquid chromatography system.
Example 1: synthesis of 3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (Compound I-1)
Figure BDA0002751617330000111
1. Synthesis of 4-cyclopropyl-1- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-imidazole (Compound 1-1)
Figure BDA0002751617330000112
(1) Synthesis of 2- ((3 bromophenyl) amino) -1-cyclopropyl-1-ethanone (Compound 3)
M-bromoaniline (3.0 g,17.5 mmol) was dissolved in DMF and K was added 2 CO 3 (2.9 g,21 mmol) and KI (2.9 g,17.5 mmol) were stirred at room temperature for 30min, and 2-bromo-1-cyclopropylethyl-1-one (4.25 g,26.2 mmol) was added thereto and reacted at 60℃for 3h. After TLC detection, the reaction solution was diluted with water, extracted with EA, dried with EA and spun-dried on silica gel column chromatography to give the target product (3 g, 68%). ESI-MS m/z 254.0[ M+H ]] + .
(2) Synthesis of 1- (3-bromophenyl) -4-cyclopropyl-1H-imidazole-2-thiol (Compound 4)
2- ((3-bromophenyl) amino) -1-cyclopropyl-1-ethanone (3.0 g,11.9 mmol) using CH 3 COOH was dissolved, KSCN (2.3 g,23.7 mmol) was added thereto, and the mixture was reacted at 110℃for 4 hours. TLC detection of the end of the reaction, the CH was removed by spinning 3 After COOH, diluting with water, adjusting pH to neutrality with 2M NaOHThe reaction mixture was extracted with EA, dried and spun-dried with EA, and subjected to silica gel column chromatography to obtain the desired product (2.0 g, 58%). ESI-MS m/z 295.0[ M+H ]] + .
(3) Synthesis of 1- (3-bromophenyl) -4-cyclopropyl-1H-imidazole (Compound 5)
1- (3-bromophenyl) -4-cyclopropyl-1H-imidazole-2-thiol (2.0 g,6.8 mmol) was purified using 10mLCH 3 COOH was dissolved and added with 2mL of water, 30% h 2 O 2 (2.5 mL,20.4 mmol) was reacted at 55℃for 2h. TLC detection of the end of the reaction, the CH was removed by spinning 3 After COOH was diluted with water, pH was adjusted to neutral with 2M NaOH, extracted with EA, dried on EA and spun-dried on silica gel column chromatography to give the desired product (1.2 g, 68%). ESI-MS m/z 263.0[ M+H ]] + .
(4) Synthesis of 4-cyclopropyl-1- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-imidazole (Compound 1-1)
1- (3-bromophenyl) -4-cyclopropyl-1H-imidazole (1.2 g,4.58 mmol), pinacol diboronate (1.75 g,6.9 mmol), potassium acetate (670 mg,6.9 mmol) and Pd (dppf) Cl were taken 2 (330 mg,0.46 mmol) was dissolved in anhydrous Dioxane and reacted at 100℃for 4 hours after purging with nitrogen. After TLC detection reaction is finished, the reaction liquid is diluted with water after suction filtration, EA is extracted, EA is dried and spun-dried, and a target product (1.0 g, 71%) is obtained by silica gel column chromatography. ESI-MS m/z 311.2[ M+H ]] + .
2. Synthesis of 3-iodo-5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (Compound 2-1)
Figure BDA0002751617330000121
(1) Synthesis of 1H-indazole-5-carbohydrazide (Compound 6)
1H-indazole-5-carboxylic acid methyl ester (5 g,28.4 mmol) was dissolved in ethanol, and 2mL of hydrazine hydrate was added thereto to react at 80℃for 5 hours in a pressure-resistant tube; after the completion of TLC, ethanol and hydrazine hydrate were removed by rotation to give the desired product as a white solid (5.0 g, 98%). ESI-MS m/z 177.1[ M+H ]] + .
(2) Synthesis of (E) -N' - (1H-indazole-5-carboxylic acid) -N, N-dimethylformamide (Compound 7)
1H-indazole-5-carbohydrazide (5 g,28.4 mmol) dissolved with DMF-DMA, 10Reflux reaction is carried out for 4 hours at the temperature of 4 ℃; DMF-DMA was removed by spin-on, the residue was taken up in EA and then sanded and chromatographed on silica gel to give the desired product (3 g, 46%). ESI-MS m/z 232.1[ M+H ]] + .
(3) Synthesis of 5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (Compound 8)
(1H-indazole-5-carboxylic acid) -N, N-dimethylformamide (3 g,13.0 mmol) was performed using CH 3 CN/CH 3 COOH 5:1 dissolved, isopropylamine (5.6 mL,65 mmol) added, and reflux reacted at 90℃for 4h; TLC detection of the end of the reaction, the CH was removed by spinning 3 CN and CH 3 COOH, the residue was diluted with water and pH adjusted to weak base with 2M NaOH, EA extracted dried and column chromatographed on silica gel to give the desired product (1.5 g, 51%). ESI-MS m/z 228.1[ M+H ]] + .
(4) Synthesis of 3-iodo-5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (Compound 2-1)
5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (1.5 g,6.6 mmol) was dissolved in DMF and added I 2 (3.36 g,13.2 mmol), KOH (739 mg,13.2 mmol) and reacted at room temperature for 3h. After the TLC detection reaction, the reaction solution was quenched with saturated sodium sulfite aqueous solution, extracted with EA, and the EA layer was washed with saturated brine, dried with EA and spun-dried with EA, followed by silica gel column chromatography to give the objective product (1.5 g, 64%). ESI-MS m/z 354.0[ M+H ]] + .
3. Synthesis of 3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (Compound I-1)
Taking 4-cyclopropyl-1- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-imidazole (100 mg,0.325 mmol), 3-iodo-5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (110 mg,0.325 mmol), tetrakis triphenylphosphine palladium (37.6 mg,0.0325 mmol) and Na 2 CO 3 (69 mg,0.65 mmol) with Dioxane/H 2 O5 is dissolved in 1, and the reaction is carried out for 1h at 100 ℃. After TLC detection, insoluble substances are removed by suction filtration, an EA filter cake is washed, the filtrate is diluted by water and extracted by EA, the EA is dried and spun-dried, and the target product (30 mg, 23%) is obtained by silica gel column chromatography and separation of a silica gel thin layer and a large plate. 1 H NMR(300MHz,CDCl 3 )δ12.51(s,1H),8.40(s,1H),8.27(s,1H),7.96(s,2H),7.89(d,J＝7.8Hz,1H),7.74(d,J＝8.5Hz,1H),7.56-7.47(m,2H),7.34(d,J＝8.0Hz,1H),7.09(s,1H),4.53(m,1H),1.94(m,1H),1.51(d,J＝6.7Hz,6H),1.00-0.80(m,4H).ESI-MS m/z:410.2[M+H] + .
By operating in a similar manner to example 1, the following compounds were prepared:
Figure BDA0002751617330000131
Figure BDA0002751617330000141
Figure BDA0002751617330000151
example 2: synthesis of N-cyclopropyl-3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) benzamide (I-14)
Figure BDA0002751617330000152
1. Synthesis of N-cyclopropyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzamide (Compound 1-2)
Figure BDA0002751617330000161
(1) Synthesis of 3-bromo-N-cyclopropylbenzamide (Compound 9)
3-Bromobenzoic acid (500 mg,2.5 mmol), HATU (1.43 mmol,3.75 mmol) and DIEA (806 mg,6.25 mmol) were taken, dissolved in DMF and stirred at room temperature for 15min before cyclopropylamine (171 mg,3 mmol) was added and reacted at room temperature for 3h; after TLC detection, the reaction solution was diluted with water, dried by EA extraction, and subjected to silica gel column chromatography to give the objective product (400 mg, 67%). ESI-MS m/z 240.0[ M+H ]] + .
(2) Synthesis of N-cyclopropyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzamide (Compound 1-2)
3-bromo-N-cyclopropylbenzamide (400 mg,1.67 mmol), pinacol diboronate (636 mg,2.5 mmol), potassium acetate (245 mg,2.5 mmol) and Pd (dppf) Cl were taken 2 (122.4 mg,0.167 mmol), dissolved in anhydrous Dioxane, and reacted at 100℃for 4h after nitrogen purging; after TLC detection reaction is finished, the reaction liquid is diluted with water after suction filtration, EA is extracted, EA is dried and spun-dried, and a target product (300 mg, 63%) is obtained through silica gel column chromatography. 288.2[ M+H ] ESI-MS m/z] + .
2. Synthesis of N-cyclopropyl-3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) benzamide (I-14)
N-cyclopropyl-3- (4, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) benzamide (100 mg,0.35 mmol), 3-iodo-5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (124 mg,0.35 mmol), pd (dppf) Cl was taken 2 (25.7 mg,0.035 mmol) and Na 2 CO 3 (74 mg,0.70 mmol) with Dioxane/H 2 O5 is dissolved in 1, and the reaction is carried out for 1h at 95 ℃ by microwave; after TLC detection, insoluble substances are removed by suction filtration, an EA filter cake is washed, the filtrate is diluted by water and extracted by EA, the EA is dried and spun-dried, and the target product (40 mg, 30%) is obtained by silica gel column chromatography and separation of a silica gel thin layer and a large plate. 1 H NMR(300MHz,DMSO-d 6 )δ13.61(s,1H),8.87(s,1H),8.61(d,J＝4.3Hz,1H),8.42(s,1H),8.26(s,1H),8.16(d,J＝7.9Hz,1H),7.86(d,J＝7.9Hz,1H),7.79(d,J＝8.7Hz,1H),7.68-7.57(m,2H),4.49(m,1H),2.88(m,1H),1.45(d,J＝6.7Hz,6H),0.77-0.65(m,2H),0.61-0.50(m,2H).ESI-MS m/z:387.2[M+H] + .
By operating in a similar manner to example 2, the following compounds were prepared:
Figure BDA0002751617330000171
Figure BDA0002751617330000181
example 3: synthesis of 3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) benzamide (Compound I-20)
Figure BDA0002751617330000182
1. Synthesis of 3- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyridine (Compound 1-3)
Figure BDA0002751617330000183
(1) Synthesis of 3- (3-bromophenyl) pyridine (Compound 10)
1, 3-Dibromobenzene (343 mg,1.46 mmol), 3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyridine (300 mg,1.46 mmol), pd (pph) 3 ) 4 (168 mg,0.146 mmol) and K 2 CO 3 (404 mg,2.92 mmol) with Dioxane/H 2 O5 is dissolved in 1, and the reaction is carried out at 80 ℃ overnight; after TLC detection reaction is finished, insoluble matters are removed through suction filtration, a filter cake is washed by EA, a filtrate is diluted by water, the reaction liquid is extracted by EA after being diluted by water, the EA is dried and spun-dried, and a target product (300 mg, 89%) is obtained through silica gel column chromatography. ESI-MS m/z 234.0[ M+H ]] + .
(2) Synthesis of 3- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyridine (Compound 1-3)
3- (3-bromophenyl) pyridine (300 mg,1.29 mmol), pinacol biborate (393 mg,1.55 mmol), potassium acetate (255 mg,2.58 mmol) and Pd (dppf) Cl were taken 2 (95 mg,0.129 mmol), dissolved with anhydrous Dioxane, and reacted at 100℃for 4h after nitrogen purging; after TLC detection reaction is finished, the reaction liquid is diluted with water after suction filtration, EA is extracted, EA is dried and spun-dried, and a target product (300 mg, 83%) is obtained through silica gel column chromatography. ESI-MS m/z 282.2[ M+H ]] + .
2. Synthesis of 3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) benzamide (Compound I-20)
3- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) pyridine (100 mg,0.36 mmol), 3-iodo-5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (127 mg,0.36 mmol), pd (pph) 3 ) 4 (42 mg,0.036 mmol) and K 2 CO 3 (100mg0.72 mmol) with Dioxane/H 2 O5 is dissolved in 1, and the reaction is carried out for 1h at 100 ℃. After TLC detection, insoluble substances are removed by suction filtration, an EA filter cake is washed, filtrate is diluted by water and then extracted by EA, EA is dried and spun-dried, silica gel column chromatography is carried out, and a target product (40 mg, 28%) is obtained by separating a silica gel thin layer plate. 1 H NMR(300MHz,CDCl 3 )δ8.84(s,1H),8.55(s,1H),8.32(s,1H),8.20(s,1H),8.09(s,1H),7.89(s,2H),7.62(d,J＝8.6Hz,1H),7.57-7.43(m,3H),7.33(s,1H),4.54-4.27(m,1H),1.42(d,J＝6.5Hz,6H).ESI-MS m/z:381.2[M+H] + .
By operating in a similar manner to example 3, the following compounds were prepared:
Figure BDA0002751617330000191
Figure BDA0002751617330000201
example 4: synthesis of 3- (3- (3-cyclopropyl-1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (Compound I-29)
Figure BDA0002751617330000202
1. Synthesis of 3-cyclopropyl-1- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-1,2, 4-triazole (Compound 1-4)
Figure BDA0002751617330000203
(1) Synthesis of Cyclopropanecarboximide Ethyl ester (Compound 11)
Cyclopropylnitrile (500 mg,7.5 mmol) was taken and dissolved in 8M HCl/dioxane, absolute ethanol (345 mg,7.5 mmol) was added at 0deg.C, reacted for 2h at 0deg.C, then reacted for 12h at room temperature. The ethanol and the hydrochloride salt of the target product of Dioxane were directly removed (678 mg, 80%). ESI-MS m/z:114.1[M+H] + .
(2) Synthesis of 1- (3-bromophenyl) -3-cyclopropyl-1H-1, 2, 4-triazole (Compound 12)
Cyclopropanecarboximide ethyl ester hydrochloride (500 mg,3.34 mmol) and m-bromophenylhydrazine (62 mg,3.34 mmol) are taken and dissolved in absolute ethanol, triethylamine (675mg, 6.68 mmol) is added, the reaction is carried out for 30min at room temperature, ethanol is removed by rotation, the residue is dissolved in trimethyl orthoformate, ammonium formate (426 mg,6.68 mmol) is added and the reaction is carried out for 15h at 80 ℃; after TLC detection reaction is finished, the reaction liquid is diluted by water after the solvent is removed, EA is extracted, EA is dried and dried by spin-drying, and a target product (500 mg, 57%) is obtained through silica gel column chromatography. ESI-MS m/z 264.0[ M+H ]] + .
(3) Synthesis of 3-cyclopropyl-1- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-1,2, 4-triazole (1-4)
1- (3-bromophenyl) -3-cyclopropyl-1H-1, 2, 4-triazole (500 mg,1.9 mmol), pinacol biborate (580 mg,2.28 mmol), potassium acetate (372 mg,3.8 mmol) and Pd (dppf) Cl were taken 2 (139 mg,0.19 mmol), dissolved in anhydrous Dioxane, and reacted at 100℃for 4 hours after purging with nitrogen; after TLC detection reaction is finished, the reaction liquid is diluted with water after suction filtration, EA is extracted, EA is dried and spun-dried, and a target product (400 mg, 68%) is obtained by silica gel column chromatography. ESI-MS m/z 312.2[ M+H ]] + .
2. Synthesis of 3- (3- (3-cyclopropyl-1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (Compound I-29)
3-cyclopropyl-1- (3- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) -1H-1,2, 4-triazole (100 mg,0.32 mmol), 3-iodo-5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (113 mg,0.32 mmol), pd (pph) 3 ) 4 (37 mg,0.032 mmol) and Na 2 CO 3 (68 mg,0.64 mmol) with Dioxane/H 2 O5 is dissolved in 1, and the reaction is carried out for 2 hours at 100 ℃; after TLC detection, insoluble substances are removed by suction filtration, an EA filter cake is washed, the filtrate is diluted by water and extracted by EA, the EA is dried and spun-dried, and the target product (40 mg, 31%) is obtained by silica gel column chromatography and large plate separation. 1 H NMR(300MHz,CDCl 3 )δ8.40(d,J＝23.6Hz,2H),8.13(s,2H),7.81(s,1H),7.58(s,1H),7.46(s,2H),7.19(d,J＝3.3Hz,1H),4.45-4.57(m,1H),2.05-2.11(m,1H),1.44(d,J＝6.3Hz,6H),1.14-1.22(m,2H),0.92-1.02(m,2H).ESI-MS m/z:411.2[M+H] + .
Example 5: inhibition of ASK1 protein kinase by compounds
Compounds were tested for ASK1 kinase inhibitory activity using the Homogeneous Time Resolved Fluorescence (HTRF) method and compared to the positive compound GS-4997.
(1) Adding diluted compounds into 384-well plates, and respectively adding DMSO diluted by Assay Buffer into positive control wells and negative control wells;
(2) Compound wells and positive control wells were added with STK-Substrate 3-biotin/ATP and ASK1 (MAP 3K 5), and negative control wells were added with STK-Substrate 3-biotin/ATP and Assay Buffer;
(3) After incubation for 2.0h at room temperature, STK S3 anti-body-Eu is added;
(4) Incubating for 1.0h at room temperature, measuring fluorescent signal values of all plate holes by using an enzyme-labeled instrument, calculating inhibition rate according to the fluorescent signal values, and performing Integrated Circuit (IC) 50 The values were calculated by Prism (GraphPad Software) fitting the curve and the results are shown in table 1.
Inhibition of ASK1 kinase by compounds of table 1
Numbering of compounds IC 50 (nM) Numbering of compounds IC 50 (nM)
I-1 12.6 I-21 50
I-4 48.5 I-22 29.9
I-5 31.8 I-25 26.9
GS-4997 14 I-28 19.8
I-9 50 I-29 37
I-10 16.5 I-33 18.84
As shown in Table 1, all test compounds inhibited ASK1 kinase and IC 50 Values all reached nanomolar scale; wherein, the compound I-1 has the most obvious inhibition effect on ASK1 kinase and IC 50 Less than 15nM, comparable to the positive control.
Example 6: inhibition of AP1-HEK293 cells by Compounds
The effect of compounds on the signal pathway downstream of ASK1 was evaluated at the cellular level using AP1 Reporter-HEK293 recombinant cells.
The experimental steps are as follows:
(1) AP1-HEK293 cells were seeded into 96-well plates and 100. Mu.L of Thaw Medium 1 was added;
(2) Cell in CO 2 Incubating overnight in an incubator;
(3) Pouring the culture medium out of the pore plate slowly, diluting the compound to be tested by using the Assay medium, adding the compound to be tested into the cell hole, adding the Assay medium diluent with the same concentration of DMSO into the cell hole to serve as a control, adding the Assay medium diluent with the same concentration of DMSO into the cell-free hole to remove background fluorescent signals, and incubating for 1h;
(4) Adding PMA Assay medium diluent into a cell hole, adding 0.1% DMSO Assay medium diluent into the cell hole as a control, and adding 0.1% DMSO Assay medium diluent into a cell-free hole to remove a background fluorescent signal;
(5) By ONE-Step according to operating specifications TM The luciferase detection system performs luciferase detection: adding ONE-Step TM Luciferase reagent was added to the wells, shaken at room temperature for 15min, and fluorescence signal was measured using a luminometer;
(6) Data analysis: background fluorescence values were subtracted. The inhibition of each compound was calculated and the results are shown in table 2.
Inhibition of AP1-HEK293 cells by the Compounds of Table 2
Numbering of compounds IC 50 (nM) Numbering of compounds IC 50 (nM)
I-2 8729 I-22 4462
I-4 11294 GS-4997 7501
I-8 5502 I-24 8333
I-9 7045 I-25 9808
I-21 12064 I-29 8877
As shown in Table 2, all test compounds inhibited AP1-HEK293 cells, IC 50 Values all reached micromolar scale; wherein, the IC of the compounds I-2, I-24 and I-29 50 IC of compounds I-8, I-9 and I-22, with values comparable to positive controls 50 The value is superior to positive control, the inhibition effect of I-22 on AP1-HEK293 cells is most obvious, and the IC 50 The value is less than 5 mu M, which initially shows that the compounds have good drug properties.
Example 7: inhibition of Hepatic Stellate Cells (HSCs) by compounds
The effect of the compounds on LX-2 cell Colla1 mRNA expression was examined by qPCR, and the therapeutic potential of the compounds on liver fibrosis at the cellular level was assessed.
The experimental steps are as follows: (1) preparing a medicament; (2) cell resuscitation; (3) cell culture and passage; (4) adding medicine; (5) total RNA extraction; (6) RNA concentration measurement; (7) cDNA synthesis (two-step method); (8) Real-time PCR reaction.
And (3) data processing: the threshold value of the Real Time PCR result is automatically set by Real Time PCR detector system, and the specificity of the primer and whether the primer meets the experimental requirement or not are judged through an amplification curve and a dissolution curve; determining whether the dilution factor of the cDNA is reasonable according to the Ct value; the relative amounts of the Colla1 gene were calculated as follows, and the results are shown in Table 3 and FIG. 3.
Δct (TGF group Colla1 gene) =avg.ct (TGF group Colla1 gene) -avg.ct (TGF group GAPDH gene); Δct (control Colla1 gene) =avg.ct (control Colla1 gene) -avg.ct (control GAPDH gene); ΔΔct = average of Δct (TGF group/drug treatment group Colla1 gene) - Δct (control group Colla1 gene); the relative content of the Colla1 gene was calculated as: rq=2 -ΔΔCt 。
Inhibition of HSC cells by the compounds of Table 3 (3. Mu.M single concentration inhibition)
Group Average RQ 1 Abs Inhibition 2 (％) Rel Inhibition 3 (％)
Control 1.00 / /
TGF-β 3.16 0.00 0.00
I-1 1.94 38.60 56.47
I-5 2.21 29.96 43.83
I-20 2.31 27.06 39.58
I-22 1.82 42.50 62.17
Note that: 1: the mRNA expression level of the Colla1 gene; 2: absolute inhibition rate; 3: relative inhibition rate.
As shown in Table 3, the above compounds all had inhibitory effect on HSC cells, wherein the inhibition of compound I-22 on HSC cells was most remarkable, the absolute inhibition was more than 40%, and the relative inhibition was more than 60%. As shown in fig. 3, the experimental results are expressed as mean ± standard deviation (mean ± SD), n=2, compared to the Control group, ### P<0.001; comparison with TGF-beta group ** P<0.05， * P<0.05, the compounds have significant differences in the Colla1 gene mRNA expression level and Control combination, TGF-beta group. Taken together, the above compounds exhibit inhibitory activity against hepatic stellate cells at the cellular level, which initially indicates that the above compounds can be prepared as medicaments having potential therapeutic effects on hepatic fibrosis。
Example 8: effect of Compounds on intestinal epithelial cells (HT-29)
The effect of example compound I-22 on TNF- α stimulated intestinal epithelial cell survival was examined by the CCK-8 method and the therapeutic potential of the compound at the cellular level for inflammatory bowel disease was assessed.
The experimental steps are as follows:
(1) HT-29 cells were seeded in 96 well plates, 10000 cells per well;
(2) After 24h incubation, GS-4997 (10. Mu.M) and Compound I-22 (10. Mu.M) were added to the dosing wells, and incubation was performed for 24h with the dosing wells and TNF- α model Kong Jiaru TNF- α (10 ng/ml);
(3) Incubating for 24h, and incubating for 2h at 37 ℃ after adding 10 mu M of CCK-8 solution into each hole;
(4) The absorbance of the solution was measured at 450nm with a microplate detector and the cell viability was a percentage relative to the control group.
As shown in fig. 4, the experimental results are expressed as mean ± standard error (mean ± SEM), n=6, compared to the Control group, ### P<0.001, illustrating that the model modeling is successful; in comparison with the DSS group, ** P<0.01, demonstrating that compounds I-22, GS-4997 have significant differences in epithelial cell viability versus DSS group; as shown in FIG. 5, for the reduced survival of human colonic epithelial cells (HT-29) following TNF- α stimulation (FIG. 5B), compound I-22 (FIG. 5D) exhibited a comparable reversal effect as GS-4997 (FIG. 5C), indicating that the above compounds could be prepared as drugs with potential therapeutic effects on inflammatory diseases.

Claims (5)

1. An ASK1 inhibitor, wherein the ASK1 inhibitor has the structure of formula IV:
Figure FDA0004078736880000011
wherein:
R 1 is a hydrogen atom;
R 4 is C 1-3 An alkyl group;
R 5 is C 1-3 An alkyl group;
x is 5.
2. An ASK1 inhibitor, wherein the ASK1 inhibitor has the structure of formula V:
Figure FDA0004078736880000012
wherein:
R 1 is hydrogen atom, C 1-3 Alkyl, C 1-3 An alkoxy group;
R 4 is hydrogen atom, C 1-3 Alkyl, C 1-4 Hydroxyalkyl, C 3-6 Cycloalkyl;
R 5 selected from C 3-6 Cycloalkyl;
x is 2 and 5.
3. An ASK1 inhibitor, characterized in that the ASK1 inhibitor is any one of the following compounds:
3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-1),
3- (3- (4-cyclopropyl-1H-imidazol-1-yl) -4-methylphenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-2),
3- (3- (4-cyclopropyl-1H-imidazol-1-yl) -5-methoxyphenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-4),
4- (2- (4-cyclopropyl-1H-imidazol-1-yl) -4- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) phenyl) morpholine (I-5),
5- (4-cyclopentyl-4H-1, 2, 4-triazol-3-yl) -3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -1H-indazole (I-8),
3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -5- (4-cyclopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-9),
(R) -2- (3- (3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -1H-indazol-5-yl) -4H-1,2, 4-triazol-4-yl) propan-1-ol (I-10),
5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -3- (3- (pyridin-3-yl) phenyl) -1H-indazole (I-20),
5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -3- (3- (1- (tetrahydro-2H-pyran-4-yl) -1H-pyrazol-4-yl) phenyl) -1H-indazole (I-21),
3- (3- (1- (1-ethoxyethyl) -1H-pyrazol-4-yl) phenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-22),
5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -3- (3- (1-methyl-1H-pyrazol-4-yl) phenyl) -1H-indazole (I-24),
5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -3- (3- (1- (methoxymethyl) -1H-pyrazol-4-yl) phenyl) -1H-indazole (I-25),
n- (3- (5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazol-3-yl) phenyl) ethanesulfonamide (I-28), 3- (3- (3-cyclopropyl-1H-1, 2, 4-triazol-1-yl) phenyl) -5- (4-isopropyl-4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-29),
3- (3- (4-cyclopropyl-1H-imidazol-1-yl) phenyl) -5- (4H-1, 2, 4-triazol-3-yl) -1H-indazole (I-33).
4. A pharmaceutical composition comprising an ASK1 inhibitor according to any one of claims 1 to 3 and a pharmaceutically acceptable carrier.
5. Use of an ASK1 inhibitor according to any one of claims 1 to 3 in the manufacture of a medicament for the treatment of liver fibrosis, inflammatory bowel disease.
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