ASK1 inhibitor and application thereof
阅读说明：本技术 Ask1抑制剂及其应用 (ASK1 inhibitor and application thereof ) 是由 王听中 刘斌 于 2018-07-10 设计创作，主要内容包括：本发明涉及通式(I)所示的化合物、其药学上可接受的盐、酯或其立体异构体。本发明还涉及该化合物的制备方法、包含该化合物的药物制剂及药物组合物。本发明的化合物能够有效抑制ASK1的氨基酸磷酸化,抑制ASK1的激活；因此能够治疗和/或预防ASK1介导的疾病及相关疾病。<Image he="381" wi="700" file="DDA0001725922130000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention relates to a compound shown in a general formula (I), and pharmaceutically acceptable salt, ester or stereoisomer thereof. The invention also relates to a preparation method of the compound, a pharmaceutical preparation containing the compound and a pharmaceutical composition. The compound can effectively inhibit the amino acid phosphorylation of ASK1 and inhibit the activation of ASK 1; therefore, can treat and/or prevent ASK1 mediated diseases and related diseases.)
1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof,
wherein the content of the first and second substances,
ring A is selected from 5-8 membered heterocyclyl, 5-8 membered heteroaryl, wherein each group is substituted with 0-3P, each P is independently selected from C1-6Alkyl radical, C1-6Alkoxy, cyano, halogen, nitro, amino, hydroxy, carboxy;
X1selected from CH, C-R or N, R is selected from hydroxyl, amino, carboxyl, nitro, halogen and C1-6Alkyl radical, C1-6An alkoxy group;
X2，X3，X4，X5，X6，X7，X8independently selected from C-R4Or N, R4Selected from hydrogen, hydroxy, amino, carboxyl, nitro, halogen, and optionally substituted by hydrogen, halogen, hydroxy, oxo, -CF3、-O-CF3、-N(R5)(R6)-、-C(O)-R5、-C(O)-O-R6、-C(O)-N(R5)(R6)-、-CN、-O-R5Substituted C1-6Alkyl radical, C2-6Alkenyl radical, C1-6Alkoxy radical, C3-8A cycloalkyl group;
or X4、X7、X8Is selected from C-R4，X4And X7Or X7And X8R taken together and linked4Form a cycloalkyl, heterocyclyl, aryl or heteroaryl group;
R1selected from hydrogen, hydroxyl, amino, carboxyl, nitro, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, amino C1-6Alkyl, hydroxy C1-6Alkyl, carboxyl C1-6An alkyl group;
R2selected from hydrogen, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl, halo C1-6Alkyl, amino C1-6Alkyl, hydroxy C1-6Alkyl, carboxyl C1-6An alkyl group; or R2And X2Or X6Together with the attached nitrogen, form a heterocyclic group;
R3is selected fromA 5-10 membered heteroaryl or 5-10 membered heterocyclyl, wherein the ring-forming heteroatom in the 5-10 membered heteroaryl or 5-10 membered heterocyclyl contains at least one N, and wherein one N is attached to ring B; said 5-10 membered heteroaryl or 5-10 membered heterocyclyl is substituted with 0-3Q; q is selected from C1-6Alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano, nitro, haloC1-6Alkoxy radical, C1-6Alkylamino, oxo, -O-R5、-O-C(O)-R5、-O-C(O)-N(R5)(R6)、-S-R5、-N(R5)(R6)、-S(＝O)-R5、-S(＝O)2R5、-S(＝O)2-N(R5)(R6)、-S(＝O)2-OR5、-N(R5)-C(O)-R6、-N(R5)-C(O)-O-R6、-N(R5)-C(O)-N(R5)(R6)、-C(O)-R5、-C(O)-O-R5、-C(O)-N(R5)-R6or-N (R)5)-S(＝O)2-R6Wherein said C is1-6Alkyl, 3-8 membered cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one or more halogen, hydroxy, amino, cyano, nitro, carboxy, oxo or-O-R5Substitution;
R5and R6Each independently selected from hydrogen and C1-6Alkyl, 3-8 membered cycloalkyl, or when R is5And R6When attached to the same N atom, R5And R6Together with the N atom to which they are attached form a 3-12 membered heterocyclic ring.
2. The compound of claim 1, a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein the compound has the structure of formula (II),
ring A is selected from 5-6 membered heterocyclyl, 5-6 membered heteroaryl, wherein each group is substituted with 0-3PSubstituted, each P is independently selected from C1-6Alkyl radical, C1-6Alkoxy, cyano, halogen, nitro, amino, hydroxy, carboxy;
X1selected from CH, C-R or N, R is selected from hydroxyl, amino, carboxyl, nitro, halogen and C1-6Alkyl radical, C1-6An alkoxy group;
X2，X3，X4independently selected from C-R4Or N, R4Selected from hydrogen, hydroxyl, amino, carboxyl, nitro, halogen, C1-6Alkyl radical, C2-6Alkenyl radical, C1-6Alkoxy, halo C1-6Alkyl, hydroxy C1-6An alkyl group;
R1selected from hydrogen, hydroxyl, amino, carboxyl, nitro, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, amino C1-6Alkyl, hydroxy C1-6Alkyl, carboxyl C1-6An alkyl group;
R2selected from hydrogen, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl, halo C1-6Alkyl, amino C1-6Alkyl, hydroxy C1-6Alkyl, carboxyl C1-6An alkyl group;
rc is selected from hydrogen, hydroxy, amino, carboxyl, nitro, halogen, and optionally substituted by halogen, hydroxy, oxo, -CF3、-O-CF3、–N(R5)(R6)-、-C(O)-R5、-C(O)-O-R6、-C(O)-N(R5)(R6)-、-CN、-O-R5Substituted C1-6Alkyl radical, C2-6Alkenyl radical, C1-6Alkoxy radical, C3-8A cycloalkyl group;
R3selected from 5-8 membered heteroaryl or 5-8 membered heterocyclyl, said ring-forming heteroatoms in 5-8 membered heteroaryl or 5-8 membered heterocyclyl containing at least one N, and wherein one N is attached to ring B; the 5-8 membered heteroaryl or 5-8 membered heterocyclyl may be substituted with 0-3Q; q is selected from C1-6Alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, haloElements, cyano, nitro, halogeno C1-6Alkoxy radical, C1-6Alkylamino, oxo, -O-R5、-O-C(O)-R5、-O-C(O)-N(R5)(R6)、-S-R5、-N(R5)(R6)、-S(＝O)-R5、-S(＝O)2R5、-S(＝O)2-N(R5)(R6)、-S(＝O)2-OR5、-N(R5)-C(O)-R6、-N(R5)-C(O)-O-R6、-N(R5)-C(O)-N(R5)(R6)、-C(O)-R5、-C(O)-O-R5、-C(O)-N(R5)-R6or-N (R)5)-S(＝O)2-R6Wherein said C is1-6Alkyl, 3-8 membered cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one or more halogen, hydroxy, amino, cyano, nitro, carboxy, oxo or-O-R5Substitution;
R5and R6Each independently selected from hydrogen and C1-6Alkyl, 3-6 membered cycloalkyl, or when R is5And R6When attached to the same N atom, R5And R6Together with the N atom to which they are attached form a 3-8 membered heterocyclic ring.
3. The compound, pharmaceutically acceptable salt, ester or stereoisomer thereof of claim 2, wherein,
ring A is selected from the group consisting of a 5-6 membered heterocyclyl containing 1-3N, O or S, a 5-6 membered heteroaryl containing 1-3N, O or S, said heterocyclyl or heteroaryl substituted with 0-2P, each P is independently selected from the group consisting of halogen, C1-6Alkyl radical, C1-6An alkoxy group;
X1selected from CH or N; x2Is selected from N; x3Is selected from CH; x4Is selected from C-R4Or N, R4Selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkyl group;
R3selected from 5-8 membered heteroaryl group containing 1-4N, O or S, 5-8 membered heterocyclyl group containing 1-4N, O or S, ring-forming heteroatoms in said 5-8 membered heteroaryl or 5-8 membered heterocyclyl group being medium toAt least one N is contained, and one of the N is connected with the ring B; said heteroaryl or heterocyclyl may be substituted with 0-3Q; q is selected from C1-6Alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkylalkyl, 5-8 membered aryl, 5-8 membered arylalkyl, 5-8 membered heteroaryl, 5-8 membered heteroarylalkyl, 5-8 membered heterocyclyl, 5-8 membered heterocyclylalkyl wherein said C is1-6Alkyl, 3-8 membered cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl or 5-8 membered heterocyclyl is optionally substituted with one or more halogen, hydroxy, amino, cyano, nitro, carboxy, oxo or-O-R5And (4) substitution.
4. The compound, pharmaceutically acceptable salt, ester or stereoisomer thereof of claim 3, wherein,
R3selected from the group consisting of a 5-8 membered monocyclic heteroaryl group having 1-4N, O or S, a 5-8 membered monocyclic heterocyclyl group having 1-4N, O or S, wherein at least one N is present in the ring-forming heteroatoms in said 5-8 membered heteroaryl or 5-8 membered heterocyclyl group, and wherein one N is attached to ring B; said heteroaryl or heterocyclyl may be substituted with 0-3Q; q is selected from C1-6Alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkylalkyl, 5-8 membered aryl, 5-8 membered arylalkyl, 5-8 membered heteroaryl, 5-8 membered heteroarylalkyl, 5-8 membered heterocyclyl, 5-8 membered heterocyclylalkyl;
ring a forms the following group with the rings connected in parallel:
5. The compound, pharmaceutically acceptable salt, ester or stereoisomer thereof of claim 4, wherein,
R1selected from hydrogen, hydroxyl, amino, carboxyl, nitro, halogen, C1-6Alkyl radical, C1-6An alkoxy group;
R2selected from hydrogen, C1-6Alkyl radical, C1-6An alkoxy group;
X4is selected from C-R4Or N, R4Selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkyl group;
R3is selected from
rc is selected from hydrogen, halogen, C1-6Alkyl radical, C1-6An alkoxy group.
6. The compound of claim 5, a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein the compound has the structure of formula (III),
wherein the content of the first and second substances,
X1selected from CH or N;
p is selected from absent, halogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, cyclopentyl, methoxy, ethoxy, propoxy, butoxy;
X4is selected from C-R4Or N, R4Selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkyl group;
R1selected from hydrogen, hydroxyl, amino, carboxyl, nitro, halogen, C1-6Alkyl radical, C1-6An alkoxy group;
R2selected from hydrogen, C1-6Alkyl radical, C1-6An alkoxy group;
rc is selected from hydrogen, halogen, C1-6Alkyl radical, C1-6An alkoxy group;
q is selected from absent, C1-6Alkyl radical, C1-6Alkoxy, 3-6 membered monocyclic cycloalkyl;
7. The compound of any one of claims 1-6, a pharmaceutically acceptable salt, ester, or stereoisomer thereof, selected from:
8. a method for synthesizing a compound of formula (II), wherein the method comprises:
wherein, Y1Selected from fluorine atom, chlorine atom, bromine atom or iodine atom; y is2Selected from fluorine atom, chlorine atom, bromine atom, iodine atom or hydroxyl; y is3Selected from fluorine atom, chlorine atom, bromine atom, iodine atom or carboxyl C1-6An alkyl group; ring A, X1、X2、X3、X4、R1、R2、R3Rc is as described in claims 1-7.
9. A pharmaceutical composition comprising a compound of any one of claims 1-7, a pharmaceutically acceptable salt, ester, or stereoisomer thereof, and optionally one or more second therapeutically active agents; preferably, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and/or diluents.
10. A pharmaceutical formulation comprising a compound according to any one of claims 1 to 7, a pharmaceutically acceptable salt, ester or stereoisomer thereof and one or more pharmaceutically acceptable carriers and/or diluents; the pharmaceutical preparation is any clinically or pharmaceutically acceptable dosage form, preferably an oral preparation or an injection; more preferably, the pharmaceutical formulation further comprises one or more second therapeutically active agents.
11. Use of a compound of any one of claims 1-7, a pharmaceutically acceptable salt, ester or stereoisomer thereof, or a pharmaceutical composition of claim 10, or a pharmaceutical formulation of claim 10, in the manufacture of a medicament for the treatment and/or prevention of ASK 1-mediated diseases and related disorders.
12. The use according to claim 11, wherein the ASK1 mediated diseases and related diseases are selected from the group consisting of non-alcoholic fatty liver disease, autoimmune disorders, diabetes and its complications, heart-kidney disease, fibrotic diseases, respiratory diseases, pulmonary hypertension, multiple sclerosis, metabolic diseases, atherosclerosis, bile acid disorders, primary sclerosing cholangitis, cholesterol stones, fatty liver, liver cirrhosis, hepatitis, liver failure, cholestasis, cholelithiasis, myocardial infarction, stroke, thrombosis, tumors, and neurodegenerative diseases; preferably, the diabetes and its complications include diabetic nephropathy; the respiratory diseases include: chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, acute lung injury; the tumor diseases comprise hyperproliferation diseases such as gastric cancer, liver cancer, polyposis, colon cancer, breast cancer, pancreatic cancer, esophageal cancer and the like.
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an ASK1 inhibitor, pharmaceutically acceptable salts, esters and stereoisomers thereof, a pharmaceutical preparation containing the compounds, and application of the compounds, the pharmaceutically acceptable salts, esters and stereoisomers thereof in preparation of medicines for treating and/or preventing related diseases such as alcoholic/non-alcoholic fatty liver, autoimmune diseases, diabetes and complications thereof, malignant tumors and the like mediated by ASK 1.
Background
Mitogen-activated protein kinases (MAPKs) exist as sequentially activated MAPKKKs, MAPKKs, MAPKs. Environmental signals affect MAPKKK, which in turn phosphorylates MAPKK, phosphorylates specific MAPK, which then mediates cellular responses, including cell growth, differentiation, apoptosis and inflammation, by phosphorylating cellular substrates.
Apoptosis signal-regulating kinase 1(ASK1) is a member of the MAPKKK family, and is an oligomer-like compound linked to the C-helical region, the N-helical region is linked to thioredoxin (Trx), and Trx inhibits activation of ASK 1. Under the stimulation conditions of oxidative stress, endoplasmic reticulum pressure, intramolecular calcium concentration, GPCR signal and the like, thioredoxin of ASK1 is dissociated, and the self amino acid (human: Thr838, mouse: Thr845) of ASK1 is subjected to autophosphorylation, so that MAPKK (such as MAPKK3/MAPKK6, MAPKK4/MAPKK7) is phosphorylated; p38 and JNK downstream were subsequently phosphorylated and activated. Activation of this pathway is closely related to tumor growth, metabolic diseases and neurological diseases.
The ASK1 inhibitor has the action mechanism of inhibiting the phosphorylation of ASK1 and blocking the activation of downstream channels, thereby achieving the treatment effect on alcoholic/non-alcoholic fatty liver, tumor diseases, metabolic diseases and neurodegenerative diseases.
The ASK1 inhibitor which is researched internationally is only GS-4997 of Gilead in clinical stage, PhaseIII (stage III) is being developed, PhaseII (stage II) research on diabetic nephropathy, pulmonary hypertension and nonalcoholic steatohepatitis is completed, and the effectiveness and safety of the target are proved through the verification of PhaseII.
In order to better meet the market demand, the development of a novel ASK1 inhibitor which is more efficient, low in toxicity and better in stability is still desired.
Disclosure of Invention
The invention aims to provide an ASK1 inhibitor with a novel molecular structure, which can inhibit ASK1 phosphorylation, block downstream channels controlled by ASK1, relieve or cure related diseases, has good drug effect, and provides possibility for the application of the ASK1 inhibitor in drugs for treating and/or preventing related diseases such as alcoholic/non-alcoholic fatty liver, autoimmune diseases, diabetes and complications thereof, malignant tumors and the like mediated by ASK 1.
Other objects of the present invention are to provide a method for synthesizing the ASK1 inhibitor, a synthetic intermediate, and use of the ASK1 inhibitor.
The present inventors have made intensive studies to achieve the above object and as a result, have found that a compound represented by the following general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, and a stereoisomer thereof are effective in inhibiting ASK1, thereby completing the present invention.
The specific technical scheme is as follows: the invention also provides a compound shown in the general formula (I), and pharmaceutically acceptable salt, ester or stereoisomer thereof:
wherein the content of the first and second substances,
ring A is selected from 5-8 membered heterocyclyl, 5-8 membered heteroaryl, wherein each group is substituted with 0-3P, each P is independently selected from C1-6Alkyl radical, C1-6Alkoxy, cyano, halogen, nitro, amino, hydroxy, carboxy;
X1selected from CH, C-R or N, R is selected from hydroxyl, amino, carboxyl, nitro, halogen and C1-6Alkyl radical, C1-6An alkoxy group;
X2，X3，X4，X5，X6，X7，X8independently selected from C-R4Or N, R4Selected from hydrogen, hydroxy, amino, carboxyl, nitro, halogen, and optionally substituted by hydrogen, halogen, hydroxy, oxo, -CF3、-O-CF3、-N(R5)(R6)-、-C(O)-R5、-C(O)-O-R6、-C(O)-N(R5)(R6)-、-CN、-O-R5Substituted C1-6Alkyl radical, C2-6Alkenyl radical, C1-6Alkoxy radical, C3-8A cycloalkyl group;
or X4、X7、X8Is selected from C-R4，X4And X7Or X7And X8R taken together and linked4Form cycloalkyl, heterocyclyl, arylheteroaryl;
R1selected from hydrogen, hydroxyl, amino, carboxyl, nitro, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, amino C1-6Alkyl, hydroxy C1-6Alkyl, carboxyl C1-6An alkyl group;
R2selected from hydrogen, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl, halo C1-6Alkyl, amino C1-6Alkyl, hydroxy C1-6Alkyl, carboxyl C1-6An alkyl group; or R2And X2Or X6Together with the attached nitrogen, form a heterocyclic group;
R3selected from 5-10 membered heteroaryl or 5-10 membered heterocyclyl, wherein at least one of the ring-forming heteroatoms in said 5-10 membered heteroaryl or 5-10 membered heterocyclyl contains one N, and wherein one N is attached to ring B; said 5-10 membered heteroaryl or 5-10 membered heterocyclyl is substituted with 0-3Q; q is selected from C1-6Alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano, nitro, haloC1-6Alkoxy radical, C1-6Alkylamino, oxo, -O-R5、-O-C(O)-R5、-O-C(O)-N(R5)(R6)、-S-R5、-N(R5)(R6)、-S(＝O)-R5、-S(＝O)2R5、-S(＝O)2-N(R5)(R6)、-S(＝O)2-OR5、-N(R5)-C(O)-R6、-N(R5)-C(O)-O-R6、-N(R5)-C(O)-N(R5)(R6)、-C(O)-R5、-C(O)-O-R5、-C(O)-N(R5)-R6or-N (R)5)-S(＝O)2-R6Wherein said C is1-6Alkyl, 3-8 membered cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one or more halogen, hydroxy, amino, cyano, nitro, carboxy, oxo or-O-R5Substitution;
R5and R6Each independently selected from hydrogen and C1-6Alkyl, 3-8 membered cycloalkyl, or when R is5And R6When attached to the same nitrogen atom, R5And R6Together with the nitrogen atom to which they are attached form a 3-12 membered heterocyclic ring.
Some embodiments of the present invention relate to the aforementioned compound, a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein the compound has the structure of formula (II),
ring A is selected from 5-6 membered heterocyclyl, 5-6 membered heteroaryl, wherein each group is substituted with 0-3P, each P is independently selected from C1-6Alkyl radical, C1-6Alkoxy, cyano, halogen, nitro, amino, hydroxy, carboxy;
X1selected from CH, C-R or N, R is selected from hydroxyl, amino, carboxyl, nitro, halogen and C1-6Alkyl radical, C1-6An alkoxy group;
X2，X3，X4independently selected from C-R4Or N, R4Selected from hydrogen, hydroxyl, amino, carboxyl, nitro, halogen, C1-6Alkyl radical, C2-6Alkenyl radical, C1-6Alkoxy, halo C1-6Alkyl, hydroxy C1-6An alkyl group;
R1selected from hydrogen, hydroxy, amino,Carboxy, nitro, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6Alkyl, halo C1-6Alkoxy, amino C1-6Alkyl, hydroxy C1-6Alkyl, carboxyl C1-6An alkyl group;
R2selected from hydrogen, C1-6Alkyl radical, C1-6Alkoxy radical, C2-6Alkenyl, halo C1-6Alkyl, amino C1-6Alkyl, hydroxy C1-6Alkyl, carboxyl C1-6An alkyl group;
rc is selected from hydrogen, hydroxy, amino, carboxyl, nitro, halogen, and optionally substituted by halogen, hydroxy, oxo, -CF3、-O-CF3、–N(R5)(R6)-、-C(O)-R5、-C(O)-O-R6、-C(O)-N(R5)(R6)-、-CN、-O-R5Substituted C1-6Alkyl radical, C2-6Alkenyl radical, C1-6Alkoxy radical, C3-8A cycloalkyl group;
R3selected from 5-8 membered heteroaryl or 5-8 membered heterocyclyl, said ring-forming heteroatoms in 5-8 membered heteroaryl or 5-8 membered heterocyclyl containing at least one N, and wherein one N is attached to ring B; the 5-8 membered heteroaryl or 5-8 membered heterocyclyl may be substituted with 0-3Q; q is selected from C1-6Alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen, cyano, nitro, haloC1-6Alkoxy radical, C1-6Alkylamino, oxo, -O-R5、-O-C(O)-R5、-O-C(O)-N(R5)(R6)、-S-R5、-N(R5)(R6)、-S(＝O)-R5、-S(＝O)2R5、-S(＝O)2-N(R5)(R6)、-S(＝O)2-OR5、-N(R5)-C(O)-R6、-N(R5)-C(O)-O-R6、-N(R5)-C(O)-N(R5)(R6)、-C(O)-R5、-C(O)-O-R5、-C(O)-N(R5)-R6or-N (R)5)-S(＝O)2-R6Wherein said C is1-6Alkyl, 3-8 membered ringAlkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one or more halogen, hydroxy, amino, cyano, nitro, carboxy, oxo or-O-R5Substitution;
R5and R6Each independently selected from hydrogen and C1-6Alkyl, 3-6 membered cycloalkyl, or when R is5And R6When attached to the same N atom, R5And R6Together with the N atom to which they are attached form a 3-8 membered heterocyclic ring.
Some embodiments of the present invention relate to the aforementioned compounds, pharmaceutically acceptable salts, esters, or stereoisomers thereof, wherein,
ring A is selected from the group consisting of a 5-6 membered heterocyclyl containing 1-3N, O or S, a 5-6 membered heteroaryl containing 1-3N, O or S, said heterocyclyl or heteroaryl substituted with 0-2P, each P is independently selected from the group consisting of halogen, C1-6Alkyl radical, C1-6An alkoxy group;
X1selected from CH or N; x2Is selected from N; x3Is selected from CH; x4Is selected from C-R4Or N, R4Selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkyl group;
R3a 5-8 membered heteroaryl group selected from 1-4N, O or S, a 5-8 membered heterocyclyl group including 1-4N, O or S, wherein at least one N is present in the ring-forming heteroatoms in the 5-8 membered heteroaryl or 5-8 membered heterocyclyl group, and wherein one N is attached to ring B; said heteroaryl or heterocyclyl may be substituted with 0-3Q; q is selected from C1-6Alkyl, 3-8 membered cycloalkyl, 3-8 membered cycloalkylalkyl, 5-8 membered aryl, 5-8 membered arylalkyl, 5-8 membered heteroaryl, 5-8 membered heteroarylalkyl, 5-8 membered heterocyclyl, 5-8 membered heterocyclylalkyl wherein said C is1-6Alkyl, 3-8 membered cycloalkyl, 5-8 membered aryl, 5-8 membered heteroaryl or 5-8 membered heterocyclyl is optionally substituted with one or more halogen, hydroxy, amino, cyano, nitro, carboxy, oxo or-O-R5And (4) substitution.
Some embodiments of the present invention relate to the aforementioned compounds, pharmaceutically acceptable salts, esters, or stereoisomers thereof, wherein,
R3selected from 1-4N, O or S, a 5-8 membered monocyclic heterocyclyl containing 1-4N, O or S, wherein at least one of the ring-forming heteroatoms in the 5-8 membered heteroaryl or 5-8 membered heterocyclyl contains one N, and wherein one N is attached to ring B; said heteroaryl or heterocyclyl may be substituted with 0-3Q; q is selected from C1-6Alkyl, 3-6 membered cycloalkyl, 3-8 membered cycloalkylalkyl, 5-8 membered aryl, 5-8 membered arylalkyl, 5-8 membered heteroaryl, 5-8 membered heteroarylalkyl, 5-8 membered heterocyclyl, 5-8 membered heterocyclylalkyl;
ring a forms the following group with the rings connected in parallel:
Some embodiments of the present invention relate to the aforementioned compounds, pharmaceutically acceptable salts, esters, or stereoisomers thereof, wherein,
R1selected from hydrogen, hydroxyl, amino, carboxyl, nitro, halogen, C1-6Alkyl radical, C1-6An alkoxy group;
R2selected from hydrogen, C1-6Alkyl radical, C1-6An alkoxy group;
X4is selected from C-R4Or N, R4Selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkyl group;
R3is selected from
rc selectionFrom hydrogen, halogen, C1-6Alkyl radical, C1-6An alkoxy group.
Some embodiments of the present invention relate to the aforementioned compound, a pharmaceutically acceptable salt, ester, or stereoisomer thereof, wherein the compound has the structure of formula (III),
X1selected from CH or N;
p is selected from absent, halogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, cyclopentyl, methoxy, ethoxy, propoxy, butoxy;
X4is selected from C-R4Or N, R4Selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy, halo C1-6An alkyl group;
R1selected from hydrogen, hydroxyl, amino, carboxyl, nitro, halogen, C1-6Alkyl radical, C1-6An alkoxy group;
R2selected from hydrogen, C1-6Alkyl radical, C1-6An alkoxy group;
rc is selected from hydrogen, halogen, C1-6Alkyl radical, C1-6An alkoxy group;
q is selected from hydrogen and C1-6Alkyl radical, C1-6Alkoxy, 3-6 membered monocyclic cycloalkyl;
Some embodiments of the present invention relate to the aforementioned compounds, pharmaceutically acceptable salts, esters, or stereoisomers thereof, wherein,
X1selected from CH or N;
p is selected from absent, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, cyclopentyl, methoxy, ethoxy, propoxy, butoxy;
X4is selected from C-R4Or N, R4Selected from the group consisting of hydrogen, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, cyclopentyl, methoxy, ethoxy, propoxy, butoxy;
R1selected from the group consisting of hydrogen, hydroxy, amino, carboxy, nitro, fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, cyclopentyl, methoxy, ethoxy, propoxy, butoxy;
R2selected from hydrogen, C1-6Alkyl radical, C1-6An alkoxy group;
rc is selected from hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, methoxy, ethoxy, propoxy, butoxy;
q is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, isopropyl, butyl, methoxy, ethoxy, propoxy, butoxy, cyclobutyl, cyclopentyl, cyclohexyl;
The above embodiments and the features of the embodiments can be arbitrarily combined, and the technical solutions obtained are described herein and belong to the technical solution of the present invention.
In some embodiments of the present invention, the structures of the compounds of the foregoing general formulae (I), (II), (iii), their pharmaceutically acceptable salts, esters, or stereoisomers thereof are shown in table 1:
the term "pharmaceutically acceptable salts" as used herein refers to pharmaceutically acceptable acid and base addition salts and solvates.
The "ester" as referred to herein means a pharmaceutically acceptable ester, particularly an ester which is hydrolyzed in vivo and includes an ester which is easily decomposed in the human body to leave the parent compound (the compound represented by the general formulae (I), (II), (III)) or a salt thereof.
"stereoisomers" of the compounds of the general formulae (I), (II), (III) according to the invention mean enantiomers which occur when asymmetric carbon atoms are present in the compounds of the formulae (I), (II), (III); when the compound has a carbon-carbon double bond or a cyclic structure, cis-trans isomers can be generated; tautomers can arise when a compound is present as a ketone or oxime, and in some embodiments of the invention, stereoisomers include, but are not limited to: enantiomers, diastereomers, racemates, cis-trans isomers, tautomers, geometrical isomers, epimers and mixtures thereof.
The invention also provides a preparation method of the compound represented by the general formula (II), pharmaceutically acceptable salts, esters and stereoisomers of the compound and the pharmaceutically acceptable salts.
In particular, the preparation method includes, but is not limited to, the following process schemes (wherein each abbreviation is represented as defined below:
DPPA: azoic acid diphenyl ester
Y1Selected from fluorine atom, chlorine atom, bromine atom or iodine atom; y is2Selected from fluorine atom, chlorine atom, bromine atom, iodine atom or hydroxyl; y is3Selected from fluorine atom, chlorine atom, bromine atom, iodine atom or carboxyl C1-6An alkyl group; ring A, X1、X2、X3、X4、R1、R2、R3Rc is as described above.
Specific exemplary steps are as follows:
1. preparation of intermediate 1
Dissolving the raw material 1 (purchased or prepared) and the raw material 2 (purchased or prepared) in an organic solvent, adding a catalyst and an alkaline compound, heating (100 ℃ C. and 150 ℃ C.), filtering, concentrating, and carrying out column chromatography to obtain an intermediate 1. The basic compound is selected from sodium hydroxide, lithium hydroxide, cesium carbonate, potassium carbonate, sodium carbonate, preferably cesium carbonate; the organic solvent is selected from pyridine, N-methyl pyrrolidone, tetrahydrofuran, tert-butanol, dichloromethane, dichloroethane, ethyl acetate, 1, 4-dioxane, tetrahydrofuran, etc., preferably 1, 4-dioxane.
2. Preparation of intermediate 2
The method comprises the following steps: dissolving the intermediate 1 in an organic solvent, adding ammonia water, heating (100 ℃ C.) and 150 ℃ C, reacting for 5-10 hours, and separating to obtain an intermediate 2. The organic solvent is selected from pyridine, N-methyl pyrrolidone, tetrahydrofuran, tert-butanol, dichloromethane, dichloroethane, ethyl acetate, 1, 4-dioxane, tetrahydrofuran, etc., preferably N-methyl pyrrolidone.
The second method comprises the following steps: dissolving the intermediate 1 in an organic solvent, adding an alkaline compound, reacting, adjusting the pH value to 3-4 by using an acidic reagent, concentrating, preparing in reverse phase, dissolving the prepared compound in the organic solvent, adding an azide reagent and the alkaline solvent, heating, filtering, concentrating, performing column chromatography, dissolving the compound obtained by the column chromatography in the organic solvent, adding the acidic reagent, reacting, and concentrating to obtain an intermediate 2. The organic solvent is selected from pyridine, N-methylpyrrolidone, tetrahydrofuran, tert-butyl alcohol, dichloromethane, dichloroethane, ethyl acetate, 1, 4-dioxane, tetrahydrofuran, etc., preferably tetrahydrofuran, tert-butyl alcohol, dichloromethane; the alkaline solvent is preferably triethylamine, and the acidic reagent is preferably hydrochloric acid or trifluoroacetic acid; the azide reagent is preferably DPPA.
3. Preparation of Compounds of formula (II)
Dissolving the intermediate 2 and the raw material 3 (purchased or prepared) in an organic solvent, adding 1-ethyl- (3-dimethylaminopropyl) carbodiimide hydrochloride (or oxalyl chloride and triethylamine), reacting at 20-30 ℃ for 15-20 hours, and performing column chromatography to obtain the compound of the formula (II). The organic solvent is selected from pyridine, N-methylpyrrolidone, tetrahydrofuran, tert-butanol, dichloromethane, dichloroethane, ethyl acetate, 1, 4-dioxane, tetrahydrofuran, etc., preferably pyridine and dichloromethane.
The present invention also provides a pharmaceutical composition comprising the aforementioned compound, a pharmaceutically acceptable salt, ester or stereoisomer thereof, and optionally one or more second therapeutically active agents. The second therapeutically active agent includes, but is not limited to, FXR agonists, ACC inhibitors, BTK inhibitors.
In some embodiments of the invention, the pharmaceutical composition further comprises one or more pharmaceutically acceptable carriers and/or diluents.
The invention also provides a pharmaceutical preparation, which contains the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof, and one or more pharmaceutical carriers and/or diluents; the pharmaceutical preparation is any clinically or pharmaceutically acceptable dosage form.
In some embodiments of the invention, the pharmaceutical formulations described above may be administered to a patient or subject in need of such treatment by oral, parenteral, rectal, or pulmonary administration, and the like. For oral administration, the pharmaceutical composition can be prepared into oral preparations, for example, conventional oral solid preparations such as tablets, capsules, pills, granules and the like; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, the pharmaceutical preparations can also be prepared into injections, including injections, sterile powders for injection, and concentrated solutions for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding suitable additives according to the properties of the medicine. For rectal administration, the pharmaceutical composition may be formulated as a suppository or the like. For pulmonary administration, the pharmaceutical composition may be formulated as an inhalant or a spray.
The pharmaceutically acceptable carrier and/or diluent useful in the pharmaceutical composition or pharmaceutical formulation of the present invention may be any conventional carrier and/or diluent in the art of pharmaceutical formulation, and the selection of a particular carrier and/or diluent will depend on the mode of administration or the type and state of the disease used to treat a particular patient. The preparation of suitable pharmaceutical compositions for a particular mode of administration is well within the knowledge of those skilled in the pharmaceutical art. For example, the pharmaceutically acceptable carrier and/or diluent may include solvents, diluents, dispersing agents, suspending agents, surfactants, isotonic agents, thickening agents, emulsifiers, binders, lubricants, stabilizers, hydrating agents, emulsification accelerators, buffers, absorbents, colorants, ion exchangers, release agents, coating agents, flavors, antioxidants, and the like, which are conventional in the pharmaceutical art. If necessary, a flavor, a preservative, a sweetener and the like may be further added to the pharmaceutical composition.
In one embodiment of the present invention, the aforementioned pharmaceutical formulation may further comprise one or more second therapeutically active agents. The second therapeutically active agent includes, but is not limited to, FXR agonists, ACC inhibitors, BTK inhibitors.
The invention also provides the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof, and application of the pharmaceutical composition and the pharmaceutical preparation in preparing medicines for treating and/or preventing ASK 1-mediated diseases and related diseases.
In some embodiments of the invention, the ASK 1-mediated disease and related diseases are selected from the group consisting of nonalcoholic fatty liver, autoimmune disorders, diabetes and its complications, heart-kidney disease, fibrotic diseases, respiratory diseases, pulmonary hypertension, multiple sclerosis, metabolic diseases, atherosclerosis, bile acid disorders, primary sclerosing cholangitis, cholesterol stones, fatty liver, liver cirrhosis, hepatitis, liver failure, cholestasis, cholelithiasis, myocardial infarction, stroke, thrombosis, tumors, and neurodegenerative diseases; preferably, the diabetes and its complications include diabetic nephropathy; the respiratory diseases include: chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, acute lung injury; the tumor diseases comprise hyperproliferation diseases such as gastric cancer, liver cancer, polyposis, colon cancer, breast cancer, pancreatic cancer, esophageal cancer and the like.
The invention also provides the application of the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof, the pharmaceutical preparation or the pharmaceutical composition in treating and/or preventing diseases. The invention also provides the application of the compound, the pharmaceutically acceptable salt, the ester or the stereoisomer thereof, the pharmaceutical preparation or the pharmaceutical composition in treating and/or preventing ASK1 mediated diseases and related diseases; the ASK 1-mediated disease and related disorders are selected from the group consisting of non-alcoholic fatty liver disease, autoimmune disorders, diabetes and its complications, heart-kidney disease, fibrotic disease, respiratory disease, pulmonary hypertension, multiple sclerosis, metabolic disease, atherosclerosis, bile acid disorders, primary sclerosing cholangitis, cholesterol stones, fatty liver, liver cirrhosis, hepatitis, liver failure, cholestasis, cholelithiasis, myocardial infarction, stroke, thrombosis, tumors, and neurodegenerative diseases; preferably, the diabetes and its complications include diabetic nephropathy; the respiratory diseases include: chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, acute lung injury; the tumor diseases comprise hyperproliferation diseases such as gastric cancer, liver cancer, polyposis, colon cancer, breast cancer, pancreatic cancer, esophageal cancer and the like.
The present invention also provides a method of treating a disease comprising administering to a patient in need thereof a therapeutically effective amount of the aforementioned compound, a pharmaceutically acceptable salt, ester or stereoisomer thereof, a pharmaceutical formulation of the aforementioned, or a pharmaceutical composition of the aforementioned, wherein the disease is an ASK1 mediated disease and related diseases; the ASK 1-mediated disease and related disorders are selected from the group consisting of non-alcoholic fatty liver disease, autoimmune disorders, diabetes and its complications, heart-kidney disease, fibrotic disease, respiratory disease, pulmonary hypertension, multiple sclerosis, metabolic disease, atherosclerosis, bile acid disorders, primary sclerosing cholangitis, cholesterol stones, fatty liver, liver cirrhosis, hepatitis, liver failure, cholestasis, cholelithiasis, myocardial infarction, stroke, thrombosis, tumors, and neurodegenerative diseases; preferably, the diabetes and its complications include diabetic nephropathy; the respiratory diseases include: chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, acute lung injury; the tumor diseases comprise hyperproliferation diseases such as gastric cancer, liver cancer, polyposis, colon cancer, breast cancer, pancreatic cancer, esophageal cancer and the like.
"halogen" as referred to herein means fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.
The ' oxo ' in the invention means that any C atom in the substituent structure can be oxidized into ' -C (O) -; if containing heteroatoms, the heteroatoms may form oxides, e.g.Can be oxidized into
"halo" as used herein means that any one of the substituents may be substituted by one or more of the same or different halogens. "halogen" is as defined above.
"C" according to the invention1-6Alkyl "means a straight chain or branched alkyl group derived by removing one hydrogen from a hydrocarbon moiety having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2-methylpropyl, and the like.
"C" according to the invention1-6Alkoxy "means" C "as defined hereinbefore1-6Alkyl "radicals attached to the parent body via an oxygen atom, i.e." C1-6alkyl-O- "groups such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, n-pentoxy, neopentoxy, n-hexoxy and the like.
And "C1-6Alkoxy "analogously," aminoC1-6Alkyl "means H2N-C1-6alkyl-radical-C thereof1-6One hydrogen on the alkyl group is substituted by an amino group; "hydroxy group C1-6Alkyl "refers to HO-C1-6alkyl-radical-C thereof1-6One hydrogen on the alkyl group is substituted by a hydroxyl group; "carboxy group C1-6Alkyl "refers to HO (O) C-C1-6alkyl-radical-C thereof1-6One hydrogen on the alkyl group is replaced by a carboxyl group; "C1-6Alkylamino "means C1-6alkyl-NH-; "C1-6"Alkylamido" means C1-6alkyl-C (O) -NH-; "C1-6Alkylaminoacyl "means C1-6alkyl-NH-C (O) -; "C1-6Alkylsulfonyl "means C1-6alkyl-S (O)2-；“C1-6Alkylsulfonamido "means C1-6alkyl-S (O)2-NH-；“C1-6Alkylsulfonyloxy "means C1-6alkyl-S (O)2-O-；“C1-6Alkylcarbonyloxy "means C1-6alkyl-C (O) -O-; "C1-6Alkoxy radical C1-6Alkyl "means C1-6alkyl-O-C1-6Alkyl-, "carboxy C1-6Alkoxy "means HO (O) C-C1-6alkyl-O-.
The term "halo C" as used herein1-6Alkyl group "," halogeno C1-6Alkoxy "means C of the group1-6The hydrogen in the alkyl group is substituted with one or more halogens; the "halogen" is as defined above.
The "cycloalkyl", "aryl", "heterocyclyl" and "heteroaryl" in the present invention include a monocyclic ring system and a fused ring system (bicyclic ring system or polycyclic ring system), wherein monocyclic ring means that the ring is present in the form of only one ring, and the fused ring means a polycyclic ring structure formed by connecting two or more rings in parallel, spiro or bridged manner. The fused ring refers to a fused ring structure formed by two or more ring structures sharing two adjacent ring atoms with each other (i.e., sharing one bond). The bridged ring refers to a fused ring structure formed by two or more cyclic structures sharing two non-adjacent ring atoms with each other. The spiro ring refers to a fused ring structure formed by two or more cyclic structures sharing one ring atom with each other. The cycloalkyl group, aryl group, heterocyclic group and heteroaryl group defined by the number of atoms in the present invention include, unless otherwise specified, monocyclic and fused ring structures which can be formed.
The term "cycloalkyl" as used herein refers to a monocyclic cycloalkyl, bicyclic cycloalkyl system or polycyclic cycloalkyl system. These groups may be saturated or unsaturated, but are not aromatic. For example, a 3-12 membered cycloalkyl group, a 3-10 membered cycloalkyl group, a 5-10 membered cycloalkyl group, etc.; more specifically, the monocyclic cycloalkyl group may be a 3-6 membered cycloalkyl group, a 3-8 membered cycloalkyl group, a 5-6 membered cycloalkyl group, a 3-5 membered cycloalkyl group, and the like, and examples include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1, 4-cyclohexadienyl, cycloheptenyl, 1, 4-cycloheptadienyl, cyclooctenyl, 1, 5-cyclooctadienyl, and the like. The fused cycloalkyl group may be a 6-12 membered fused cycloalkyl group, a 7-10 membered fused cycloalkyl group, representative examples of which include, but are not limited to, bicyclo [3.1.1]Heptane, bicyclo [2.2.1]Heptane, bicyclo [2.2.2]Octane, bicyclo [3.2.2]Nonane, bicyclo [3.3.1]Nonanes and bicyclo [4.2.1]Nonane. Spirocyclic cycloalkyl groups, which may be 6-12-membered spirocyclic groups, 7-11-membered spirocyclic groups, and the like, examples thereof include, but are not limited to:
the "3-to 8-membered cycloalkyl" as used herein includes, unless otherwise specified, monocyclic and fused ring structures which can be formed.
The term "heterocyclic group" as used herein means a non-aromatic cyclic group in which at least one ring carbon atom is replaced by a heteroatom selected from the group consisting of O, S, N, preferably 1 to 3 heteroatoms, and 1 to 4 heteroatoms, and includes carbon, nitrogen and sulfur atoms which may be substituted by oxo.
"heterocyclyl" means a monocyclic heterocyclyl, fused heterocyclyl system, including saturated, partially saturated heterocyclyl groups, but excluding aromatic rings, e.g., 3-12 membered heterocyclyl, 5-10 membered heterocyclyl, and the like; more specifically, the heteromonocyclic group may be a 3-to 10-membered heterocyclic group, a 3-to 8-membered saturated heterocyclic group, a 5-to 8-membered heterocyclic group, a 3-to 6-membered heterocyclic group, a 4-to 7-membered heterocyclic group, a 5-to 6-membered oxygen-containing heterocyclic group, a 5-to 6-membered nitrogen-containing heterocyclic group, a 5-to 6-membered saturated heterocyclic group or the like. Examples of saturated mono-heterocyclic groups include, but are not limited to, aziridinyl, oxacyclopropane, thietane, azetidinyl, oxetanyl, thietane, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydrothienyl, imidazolidinyl, pyrazolidinyl, 1, 2-oxazolidinyl, 1, 3-oxazolidinyl, 1, 2-thiazolidinyl, 1, 3-thiazolidinyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl, piperidinyl, piperazinyl, morpholinyl, 1, 4-dioxanyl, 1, 4-oxathianyl; examples of partially saturated heteromonocyclic groups include, but are not limited to, 4, 5-dihydroisoxazolyl, 4, 5-dihydrooxazolyl, 2, 3-dihydrooxazolyl, 3, 4-dihydro-2H-pyrrolyl, 2, 3-dihydro-1H-pyrrolyl, 2, 5-dihydro-1H-imidazolyl, 4, 5-dihydro-1H-pyrazolyl, 4, 5-dihydro-3H-pyrazolyl, 4, 5-dihydrothiazolyl, 2H-pyranyl, 4H-pyranyl, 2H-thiopyranyl, 4H-thiopyranyl, 2,3,4, 5-tetrahydropyridinyl, 2, 5-dihydropyranyl, 2H-pyranyl, 4H-thiopyranyl, 2,3,4, 5-tetrahydropyridinyl, and the like, 1, 2-isooxazinyl, 1, 4-isooxazinyl, or 6H-1, 3-oxazinyl, and the like.
Fused heterocycles include heterocyclo, spiroheterocyclyl, bridged heterocyclo, and may be saturated, partially saturated, or unsaturated, but are not aromatic.
The heterocyclic group may be a 6-to 12-membered fused ring group, a 7-to 11-membered fused ring group, a 6-to 10-membered fused ring group, a 6-to 12-membered saturated fused ring group, a 7-to 11-membered saturated fused ring group, examples of which include, but are not limited to: 3-azabicyclo [3.1.0] hexanyl, 3, 6-diazabicyclo [3.2.0] heptane, 3, 8-diazabicyclo [4.2.0] octanyl, 3, 7-diazabicyclo [4.2.0] octanyl, octahydropyrrolo [3,4-c ] pyrrole, octahydropyrrolo [3,4-b ] [1,4] oxazinyl, octahydro-1H-pyrrolo [3,4-c ] pyridine, 2, 3-dihydrobenzofuran-2-yl, 2, 3-dihydrobenzofuranyl-3-yl, indolin-1-yl, indolin-2-yl, indolin 3-yl, 2, 3-dihydrobenzothien-2-yl, octahydro-1H-indolyl, substituted benzyl-3-2-yl, octahydro-1H-indolyl, Octahydrobenzofuranyl.
The spiro heterocyclic group may be a 6-12 membered spiro heterocyclic group, a 7-11 membered saturated spiro heterocyclic group, a 6-12 membered saturated spiro cyclic group, examples of which include, but are not limited to:
examples of said bridged heterocyclic group which may be a 6-12 membered bridged heterocyclic group, a 7-11 membered bridged heterocyclic group, a 6-12 membered saturated bridged heterocyclic group, a 7-11 membered saturated bridged heterocyclic group include, but are not limited to:
the 3-to 12-membered heterocyclic group, 5-to 10-membered heterocyclic group, 5-to 8-membered heterocyclic group, 5-to 6-membered heterocyclic group, 3-to 8-membered heterocyclic group, and 4-to 6-membered heterocyclic group described in the present invention include, unless otherwise specified, monocyclic and condensed ring structures which can be formed.
The aryl group refers to an aromatic cyclic group, and comprises a monocyclic system, a bicyclic system or a polycyclic system, can be 6-12-membered aryl and 6-10-membered aryl, and comprises 6-8-membered monocyclic aryl, such as phenyl and the like; included are "8-12 membered fused ring aryl radicals" such as naphthalene and the like.
The term "heteroaryl" as used herein refers to an aromatic cyclic group wherein at least one ring carbon atom is replaced by a heteroatom selected from O, S, N, preferably 1-3 heteroatoms, 1-4 heteroatoms, including both carbon and sulfur atoms by oxo, e.g. carbon atom by C (O), S(O)、S(O)2And (4) replacing. Heteroaryl includes monoheteroaryl and fused heteroaryl groups, and may be 5-12 membered heteroaryl, 5-10 membered heteroaryl, 5-8 membered heteroaryl, 5-6 membered heteroaryl, representative examples of monoheteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl and triazinyl. The fused heteroaryl group means a fused ring structure having aromaticity, which is formed by connecting two or more cyclic structures sharing two adjacent atoms (i.e., sharing one bond) with each other to form at least one heteroatom. The fused heteroaryl group may be an 8-12 membered heteroaryl group, an 8-10 membered heteroaryl group, a 9-10 membered heteroaryl group, representative examples include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzooxadiazolyl, benzothiazolyl, cinnolinyl, 5, 6-dihydroquinolin-2-yl, 5, 6-dihydroisoquinolin-1-yl, indazolyl, indolyl, isoquinolyl, naphthyridinyl, purinyl, quinolyl, 5,6,7, 8-tetrahydroquinolin-2-yl, 5,6,7, 8-tetrahydroquinolyl, 5,6,7, 8-tetrahydroquinolin-4-yl, 5,6,7, 8-tetrahydroisoquinolin-1-yl, 4,5,6, 7-tetrahydro [ c ] do][1,2,5]Oxadiazoles and 6, 7-dihydro [ c ]][1,2,5]Oxadiazol-4 (5H) onyl.
The 5-to 12-membered heteroaryl group, the 5-to 10-membered heteroaryl group, and the 5-to 8-membered heteroaryl group in the present invention include, unless otherwise specified, monocyclic and fused ring structures which can be formed.
In the general formula (III) of the present invention
A "therapeutically effective amount" as referred to herein, refers to an amount of a compound, pharmaceutical formulation, pharmaceutical composition as described above which, when administered to a patient, is capable of at least alleviating the symptoms of the condition in the patient. The actual amount comprising a "therapeutically effective amount" will vary depending on a variety of circumstances, including but not limited to the particular condition being treated, the severity of the condition, the physical and health of the patient, and the route of administration. The appropriate amount can be readily determined by the skilled medical practitioner using methods known in the medical arts.
The compound shown in the general formulas (I), (II) and (III) and the pharmaceutically acceptable salt, ester or stereoisomer thereof can effectively inhibit the amino acid phosphorylation of ASK1 and inhibit the activation of ASK 1; therefore, can treat and/or prevent ASK1 mediated diseases and related diseases.
The compound of the invention has the following advantages:
(1) the compounds of formula (I), (II) and (III), pharmaceutically acceptable salts, esters and stereoisomers thereof have excellent ASK1 inhibitory activity, and can be safely used for treating and/or preventing related diseases such as alcoholic/non-alcoholic fatty liver, autoimmune diseases, diabetes and complications thereof, malignant tumors and the like mediated by ASK 1;
(2) the compounds of the formula (I), (II) and (III), the pharmaceutically acceptable salts, the esters and the stereoisomers thereof show good biological stability, have more lasting effect and high bioavailability;
(3) the compounds of formula (I), (II) and (III), pharmaceutically acceptable salts, esters and stereoisomers thereof show lower toxicity, good drug resistance and high safety.
Detailed Description
The technical solutions of the present invention will be described below with reference to specific embodiments, and the described embodiments are only a part of embodiments of the present invention, but not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The definitions represented by the abbreviations in the following experiments are as follows:
NIS is N-iodosuccinimide; pd (PPh)3)2Cl2Bis (triphenylphosphine) palladium chloride.
- 上一篇：一种医用注射器针头装配设备
- 下一篇：一种吡咯喹啉醌的纯化方法