CN110128415B - Indoline compound used as immunomodulator and preparation method thereof - Google Patents

Indoline compound used as immunomodulator and preparation method thereof Download PDF

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CN110128415B
CN110128415B CN201910475329.6A CN201910475329A CN110128415B CN 110128415 B CN110128415 B CN 110128415B CN 201910475329 A CN201910475329 A CN 201910475329A CN 110128415 B CN110128415 B CN 110128415B
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秦铭泽
宫平
赵燕芳
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Shenyang Pharmaceutical University
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    • C07D471/04—Ortho-condensed systems

Abstract

The invention belongs to the technical field of medicines, and relates to indoline compounds used as immunomodulators, stereoisomers and pharmaceutically acceptable salts thereof, a preparation method of the indoline compounds and the stereoisomers and pharmaceutically acceptable salts thereof, and a pharmaceutical composition containing the indoline compounds. The invention also relates to application of the compounds, stereoisomers and pharmaceutically acceptable salts thereof in preparing medicaments for treating diseases related to the PD-1/PD-L1 signal channel, such as cancers, infectious diseases and autoimmune diseases. The indoline compound and the stereoisomer and pharmaceutically acceptable salt thereof have the following structures, wherein substituents Cy, Q, X, Y and Z have the meanings given in the specification. The indoline compound and the stereoisomer, pharmaceutically acceptable salt or pharmaceutical composition thereof have obvious inhibition effect on PD-1/PD-L1 protein/protein interaction, and can be used for preparing medicines for treating diseases related to PD-1/PD-L1 protein/protein interaction, such as various diseases of cancer, virus infection and the like.

Description

Indoline compound used as immunomodulator and preparation method thereof
The technical field is as follows:
the invention belongs to the technical field of medicines, and relates to indoline compounds used as immunomodulators, stereoisomers and pharmaceutically acceptable salts thereof, a preparation method of the indoline compounds and the stereoisomers and pharmaceutically acceptable salts thereof, and a pharmaceutical composition containing the indoline compounds. The invention also relates to application of the compounds, stereoisomers and pharmaceutically acceptable salts thereof in preparing medicaments for treating diseases related to the PD-1/PD-L1 signal channel, such as cancers, infectious diseases and autoimmune diseases.
Background art:
immunotherapy is a hotspot field of tumor therapy in recent years, and is the first of ten scientific breakthroughs by Science in 2013. Programmed death receptor 1 (PD-1) is a T cell surface receptor that, when bound to programmed death ligand 1(PD-L1), generates a negative immune regulatory signal that inhibits T cell activation, proliferation, and release of cytokines such as interleukin 2(IL-2), interferon gamma (IFN-. gamma.) (Eur. J. Immunol.,2002,32(3), 634. sup. 643.). A large number of researches show that the tumor microenvironment in a body can induce the up-regulation of PD-1 expression in infiltrated T cells, and the tumor cells highly express PD-L1, so that the signal path mediated by PD-1/PD-L1 is continuously activated, the function of tumor specific CD8+ T cells is inhibited, and the tumor cells cannot be recognized or killed, namely, the tumor cells realize immune escape. Therefore, the targeted blocking of the PD-1/PD-L1 protein/protein interaction can restore the function of the T cell, and lead the T cell to re-recognize and kill the tumor cell.
Immunotherapy based on PD-1/PD-L1 is of great interest, and currently approved commercially available PD-1/PD-L1 monoclonal antibodies include Pembrolizumab by Moshadong, Nivolumab by Baume Shinobo, Avelumab by Merck, Durvalumab by Asricon, Atezolizumab by Roche, and the like. The monoclonal antibodies have shown significant efficacy in the treatment of a variety of tumor types, and approved indications include melanoma, non-small cell lung cancer, gastric cancer, urothelial cancer, and the like. With the development of clinical research, monoclonal antibody drugs are expected to realize breakthrough in more indications.
Although monoclonal antibody drugs have shown advantages in clinical treatment, there are also significant drawbacks such as difficulty in preparation and purification, and high production cost; is easy to be decomposed by protease and has short half-life period; can not be taken orally, and can only be taken by injection; the immunogenicity of monoclonal antibodies leads to severe toxic side effects. Compared with biological macromolecular drugs, the small molecular compound is chemically modified, so that the pharmacokinetic properties of the small molecular compound are controllable, and the small molecular compound has larger exploration and optimization space in the aspects of production process, administration mode and the like. Therefore, the development of small molecule inhibitors targeting the PD-1/PD-L1 protein/protein interaction is a viable option for the realization of immunotherapy.
At present, a small-molecule PD-1/PD-L1 inhibitor is developed in an early stage, a PD-L1 inhibitor AC-170 of Curis is in a clinical I stage, and a small-molecule inhibitor of Baishi Guibao and Incyte is also in a preclinical research stage. Therefore, the development of small molecule PD-1/PD-L1 inhibitors with novel chemical structures is urgently needed.
The inventor designs and synthesizes a series of novel indoline compounds. The activity research result shows that the compound can obviously inhibit the interaction of PD-1/PD-L1 protein/protein.
The invention content is as follows:
the invention relates to indoline compounds of general formula I, stereoisomers and pharmaceutically acceptable salts thereof,
Figure BDA0002080126520000011
wherein the content of the first and second substances,
cy is selected from 6-10 membered aryl or 5-12 membered heteroaryl, or
Figure BDA0002080126520000012
Said 5-12 membered heteroaryl contains 1-3 heteroatoms selected from N, O or S; said 6-to 10-membered aryl, 5-to 12-membered heteroaryl or
Figure BDA0002080126520000013
Optionally substituted by 1-3R1Substitution;
R1independently selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, cyano, hydroxy, carboxy, amino; said (C)1-C4) Alkyl, (C)1-C4) Alkoxy may optionally be substituted with 1-3R2Substitution;
R2independently selected from hydrogen, halogen, (C)1-C4) Alkyl, hydroxy, amino, carboxyl, or
Figure BDA0002080126520000014
Ra、RbIndependently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxy formyl radical(C1-C4) Alkyl, tetrahydropyran-4-yl; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl may optionally be substituted with 1-3R3Substitution;
or Ra、RbAnd the nitrogen atom to which they are attached form a 3-to 7-membered, preferably 5-to 6-membered, nitrogen-containing heterocycle; the nitrogen-containing heterocycle contains 1-3 heteroatoms selected from N, O or S; said nitrogen-containing heterocycle being optionally substituted with 1-3R4Substitution;
R3independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino and (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, (C)1-C4) An acyl group;
R4independently selected from hydrogen, hydroxy, carboxy, amino, carbamoyl, (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alcoxyl formyl group and hydroxyl group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) An alkyl group;
x is selected from N or CH;
y is selected from N or CR5；
R5Selected from hydrogen, halogen, (C)1-C4) Alkyl, or
Figure BDA0002080126520000021
Z is CR6；
R6Selected from hydrogen, (C)1-C4) Alkyl, or
Figure BDA0002080126520000022
Rc、RdIndependently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl may optionally be substituted with 1-3R7Substitution;
or Rc、RdAnd the nitrogen atom to which they are attached form a 3-to 7-membered, preferably 5-to 6-membered, nitrogen-containing heterocycle; the nitrogen-containing heterocycle contains 1-3 heteroatoms selected from N, O or S; said nitrogen-containing heterocycle being optionally substituted with 1-3R8Substituted, the ring carbon atoms may be oxo;
R7independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino and (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, (C)1-C4) An acyl group;
R8independently selected from hydrogen, hydroxy, carboxy, amino, carbamoyl, (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alcoxyl formyl group and hydroxyl group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) An alkyl group;
q is selected from O, S or NR9；
R9Selected from hydrogen or (C)1-C4) An alkyl group.
The invention preferably relates to indoline compounds of general formula I, stereoisomers and pharmaceutically acceptable salts thereof, wherein,
cy is selected from:
Figure BDA0002080126520000023
Figure BDA0002080126520000024
Figure BDA0002080126520000025
the Cy can be optionally substituted by 1-3R1Substitution;
R1independently selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, cyano, hydroxy, carboxy, amino; said (C)1-C4) Alkyl, (C)1-C4) Alkoxy may optionally be substituted with 1-3R2Substitution;
R2independently selected from hydrogen, halogen, (C)1-C4) Alkyl, hydroxy, amino, carboxyl, or
Figure BDA0002080126520000026
Figure BDA0002080126520000031
Selected from:
Figure BDA0002080126520000032
x is selected from N or CH;
y is selected from N or CR5；
R5Selected from hydrogen, halogen, (C)1-C4) Alkyl, or
Figure BDA0002080126520000033
Z is CR6；
R6Selected from hydrogen, (C)1-C4) Alkyl, or
Figure BDA0002080126520000034
Rc、RdIndependently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl may optionally be substituted with 1-3R7Substitution;
or Rc、RdAnd the nitrogen atom to which they are attached form a 3-to 7-membered, preferably 5-to 6-membered, nitrogen-containing heterocycle; the nitrogen-containing heterocycle contains 1-3 heteroatoms selected from N, O or S; said nitrogen-containing heterocycle being optionally substituted with 1-3R8Substituted, the ring carbon atoms may be oxo;
R7independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino and (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, (C)1-C4) An acyl group;
R8independently selected from hydrogen, hydroxy, carboxy, amino, carbamoyl, (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alcoxyl formyl group and hydroxyl group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) An alkyl group;
q is selected from O, S or NR9；
R9Selected from hydrogen or (C)1-C4) An alkyl group.
More preferably, the invention relates to indoline compounds of general formula I, stereoisomers and pharmaceutically acceptable salts thereof, wherein,
cy is selected from:
Figure BDA0002080126520000035
Figure BDA0002080126520000036
Figure BDA0002080126520000041
Figure BDA0002080126520000042
the Cy can be optionally substituted by 1-3R1Substitution;
R1independently selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, cyano, hydroxy, carboxy, amino; said (C)1-C4) Alkyl, (C)1-C4) Alkoxy may optionally be substituted with 1-3R2Substitution;
R2independently selected from hydrogen, halogen, (C)1-C4) Alkyl, hydroxy, amino, carboxyl, or
Figure BDA0002080126520000043
Figure BDA0002080126520000044
Selected from:
Figure BDA0002080126520000045
x is selected from N or CH;
y is selected from N or CR5；
R5Selected from hydrogen, (C)1-C4) An alkyl group;
z is CR6；
R6Selected from hydrogen or
Figure BDA0002080126520000046
Figure BDA0002080126520000047
Selected from:
Figure BDA0002080126520000048
Figure BDA0002080126520000051
q is S.
More particularly, the invention relates to indoline compounds of general formula I, stereoisomers and pharmaceutically acceptable salts thereof, wherein,
cy is
Figure BDA0002080126520000052
Figure BDA0002080126520000053
The Cy may optionally be substituted with 1-3R1Substitution;
R1independently selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, cyano, hydroxy, carboxy, amino; said (C)1-C4) Alkyl, (C)1-C4) Alkoxy may optionally be substituted with 1-3R2Substitution;
R2independently selected from hydrogen, halogen, (C)1-C4) Alkyl, hydroxy, amino, carboxyl, or
Figure BDA0002080126520000054
Figure BDA0002080126520000055
Selected from:
Figure BDA0002080126520000056
x is selected from N or CH;
y is selected from N or CR5；
R5Selected from hydrogen, (C)1-C4) An alkyl group;
z is CR6；
R6Selected from hydrogen or
Figure BDA0002080126520000057
Figure BDA0002080126520000058
Selected from:
Figure BDA0002080126520000059
Figure BDA0002080126520000061
q is S.
Simultaneously, the invention also more particularly preferably relates to indoline compounds of the general formula I, stereoisomers and pharmaceutically acceptable salts thereof, wherein,
cy is selected from:
Figure BDA0002080126520000062
Figure BDA0002080126520000063
the Cy can be optionally substituted by 1-3R1Substitution;
R1independently selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) An alkoxy group; said (C)1-C4) Alkyl, (C)1-C4) Alkoxy may optionally be substituted with 1-3R2Substitution;
R2independently selected from halogen or
Figure BDA0002080126520000064
Figure BDA0002080126520000065
Selected from:
Figure BDA0002080126520000066
x is selected from N or CH;
y is selected from N or CH;
z is CR6；
R6Selected from hydrogen or
Figure BDA0002080126520000067
Figure BDA0002080126520000068
Selected from:
Figure BDA0002080126520000069
Figure BDA0002080126520000071
q is S.
The indoline compounds of general formula i of the present invention and stereoisomers and pharmaceutically acceptable salts thereof are preferably selected from the following compounds, but these compounds are not meant to limit the present invention in any way:
Figure BDA0002080126520000072
Figure BDA0002080126520000081
Figure BDA0002080126520000091
Figure BDA0002080126520000101
Figure BDA0002080126520000111
Figure BDA0002080126520000121
Figure BDA0002080126520000131
Figure BDA0002080126520000141
in addition, the present invention also includes prodrugs of the compounds of the present invention. Prodrugs of the compounds of the present invention are derivatives of formula i which may themselves be less active or even inactive, but which, upon administration, are converted to the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis, or otherwise).
The indoline compound of the general formula I, the stereoisomer and the pharmaceutically acceptable salt thereof comprise salts formed by inorganic acid, organic acid and alkali metal ions; the inorganic acid is selected from: hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid; the organic acid is selected from: succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, or p-toluenesulfonic acid; the alkali metal ions are selected from lithium ions, sodium ions or potassium ions.
"halogen" in the present invention means fluorine, chlorine, bromine or iodine; "alkyl" refers to straight or branched chain alkyl; "heteroaryl" refers to a monocyclic or polycyclic ring system containing carbon and heteroatoms, and the ring system having aromatic groupsThe aromatic property, the species and the number of the hetero atoms are defined in the claims;
Figure BDA0002080126520000142
represents a substituent connection site.
The composition can contain the indoline compound shown in the formula I, the stereoisomer and the pharmaceutically acceptable salt thereof as active ingredients, and is mixed with a pharmaceutically acceptable carrier or excipient to prepare the composition. Such carriers or excipients include diluents, binders, wetting agents, disintegrants, lubricants, glidants and the like as are well known in the art. Diluents include, but are not limited to, starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, dibasic calcium phosphate, and the like; the humectant includes water, ethanol, isopropanol, etc.; binders include, but are not limited to, starch slurry, dextrin, syrup, honey, glucose solution, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyethylene glycol, and the like; disintegrants include, but are not limited to, dry starch, microcrystalline cellulose, low substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium carboxymethyl starch, sodium lauryl sulfate, and the like; lubricants and glidants include, but are not limited to, talc, silicon dioxide, polyethylene glycol, and the like.
The pharmaceutical composition of the present invention can be formulated into several dosage forms including, but not limited to, injections, tablets, capsules, and the like.
The indoline compound, the stereoisomer and the pharmaceutically acceptable salt thereof can be combined with other active ingredients for use, so that a better treatment effect is achieved.
The invention also provides an indoline compound of the general formula I, a stereoisomer and a pharmaceutically acceptable salt thereof, and application of the indoline compound in preparation of a medicine for preventing and/or treating diseases related to a PD-1/PD-L1 signal channel. The diseases related to the PD-1/PD-L1 signal channel are selected from cancers, infectious diseases and autoimmune diseases. The cancer is selected from liver cancer, lung cancer, skin cancer, blood tumor, glioma, digestive system tumor, breast cancer, lymphoma, nervous system tumor, and melanoma; the infectious diseases are selected from bacterial infection and viral infection; the autoimmune disease is selected from organ specific and systemic autoimmune diseases. Wherein the organ-specific autoimmune disease comprises chronic lymphocytic thyroiditis, hyperthyroidism, insulin-dependent diabetes mellitus, ulcerative colitis and acute idiopathic polyneuritis, and the systemic autoimmune disease comprises rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis and autoimmune hemolytic anemia.
The positive progress effects of the invention are as follows: the indoline compound has a novel chemical structure, has high inhibitory activity on PD-1/PD-L1 interaction in vitro research, and can be used for treating and preventing various diseases such as cancer and the like.
The examples and preparations provided below further illustrate and exemplify the compounds of the present invention and their methods of preparation. It should be understood that the scope of the following examples and preparations are not intended to limit the scope of the invention in any way.
The following synthetic schemes outline and describe the preparation of the derivatives of formula I of the present invention, all starting materials prepared by the procedures described in these schemes, by procedures well known to those of ordinary skill in the organic chemistry art, or are commercially available. The derivatives of the invention are prepared by the methods described in these schemes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All the variable factors applied in these procedures are as defined in the claims.
Route one:
Figure BDA0002080126520000151
(a) preparing an intermediate 2 by using 4-bromo-1H-indole and benzene, substituted benzene or heteroaromatic boric acid or borate as raw materials through a Suzuki-Miyaura coupling reaction;
(b) taking the intermediate 2 as a raw material, and preparing an indoline intermediate 3 under the action of a reducing agent such as sodium cyanoborohydride;
(c) taking the intermediate 3 and heterocyclic carboxylic acid containing formyl as raw materials, and carrying out amidation reaction under the condition of a condensing agent to obtain an intermediate 4 containing formyl;
(d) the intermediate 4 is used as a raw material, and is condensed with an amine compound and reduced under the action of sodium cyanoborohydride or sodium triacetoxyborohydride or further subjected to nucleophilic substitution reaction or carbonylation to prepare the target compound with the general formula I.
And a second route:
Figure BDA0002080126520000152
(e) taking the intermediate 3 and heterocyclic carboxylic acid containing halogen as raw materials, and carrying out amidation reaction under the condition of a condensing agent to obtain an intermediate 5;
(f) taking the intermediate 5 as a raw material, and carrying out coupling reaction with vinyl boronic acid pinacol ester or tributyl vinyl tin to obtain an intermediate 6;
(g) taking the intermediate 6 as a raw material, and preparing an intermediate 4 containing formyl under the action of an osmium reagent and an oxidizing agent;
(h) the intermediate 4 is used as a raw material, condensed with an amine compound and reduced under the action of sodium cyanoborohydride or sodium triacetoxyborohydride to prepare the target compound with the general formula I.
And a third route:
Figure BDA0002080126520000153
(i) 4-bromo-1H-indole is used as a raw material to prepare an indoline intermediate 7 under the action of a reducing agent such as sodium cyanoborohydride;
(j) preparing an intermediate 3 by using the intermediate 7 and benzene, substituted benzene or heteroaromatic boric acid or boric acid ester as raw materials through Suzuki-Miyaura coupling reaction;
(k) taking the intermediate 3 and heterocyclic carboxylic acid containing an acetal structure as raw materials, and carrying out amidation reaction under the condition of a condensing agent to obtain an intermediate 8;
(l) Taking the intermediate 8 as a raw material, and carrying out deprotection under an acidic condition to obtain an intermediate 4 containing formyl;
(m) taking the intermediate 4 as a raw material, condensing with an amine compound, reducing under the action of sodium cyanoborohydride or sodium triacetoxyborohydride or further carrying out nucleophilic substitution reaction or carbonylation to prepare the target compound shown in the general formula I.
And a fourth route:
Figure BDA0002080126520000161
(n) taking the intermediate 7 and heterocyclic carboxylic acid containing an acetal structure as raw materials, and carrying out amidation reaction under the condition of a condensing agent to obtain an intermediate 9;
(o) taking the intermediate 9 as a raw material, and performing deprotection under an acidic condition to obtain an intermediate 10 containing formyl;
(p) taking the intermediate 10 as a raw material, condensing with an amine compound, and reducing under the action of sodium cyanoborohydride or sodium triacetoxyborohydride to obtain an intermediate 11.
(q) preparing the target compound shown in the general formula I by using the intermediate 11 and benzene, substituted benzene or heteroaromatic boric acid or boric acid ester as raw materials through Suzuki-Miyaura coupling reaction or further nucleophilic substitution reaction or carbonylation.
And a fifth route:
Figure BDA0002080126520000162
(r) taking the intermediate 7 and heterocyclic carboxylic acid containing formyl as raw materials, and carrying out amidation reaction under the condition of a condensing agent to obtain an intermediate 10 containing formyl;
(s) preparing an intermediate 4 by using the intermediate 10 and benzene, substituted benzene or heteroaromatic boric acid or boric acid ester as raw materials through a Suzuki-Miyaura coupling reaction or further through a nucleophilic substitution reaction;
(t) taking the intermediate 4 as a raw material, condensing with an amine compound, and reducing under the action of sodium cyanoborohydride or sodium triacetoxyborohydride to obtain the target compound shown in the general formula I.
Route six:
Figure BDA0002080126520000163
(u) taking the intermediate 7 and the substituted heterocyclic carboxylic acid as raw materials, and performing amidation reaction under the condition of a condensing agent to obtain an intermediate 11;
(v) the intermediate 11 and benzene, substituted benzene or heteroaromatic boric acid or boric acid ester are used as raw materials, and the target compound with the general formula I is prepared through Suzuki-Miyaura coupling reaction or further through nucleophilic substitution reaction.
A seventh route:
Figure BDA0002080126520000164
(w) preparing an intermediate 8 by using the intermediate 9 and benzene, substituted benzene or heteroaromatic boric acid or boric acid ester as raw materials through a Suzuki-Miyaura coupling reaction or further through a nucleophilic substitution reaction.
(x) Taking the intermediate 8 as a raw material, and carrying out deprotection under an acidic condition to obtain an intermediate 4 containing formyl;
and (y) taking the intermediate 4 as a raw material, condensing with an amine compound, and reducing under the action of sodium cyanoborohydride or sodium triacetoxyborohydride or further performing carbonylation to obtain the target compound shown in the general formula I.
The definition of Cy, Q, X, Y and Z is defined in the claims. In intermediate 5, a is chloro, bromo or iodo.
The indoline compounds of the general formula I can be prepared according to the method described in the reaction scheme or similar methods.
The specific implementation mode is as follows:
in the following examples, methods of preparing some of the compounds are depicted. It is to be understood that the following methods, as well as other methods known to those of ordinary skill in the art, can be applied to the preparation of all of the compounds described herein. The examples are intended to illustrate, but not to limit, the scope of the invention.
Example 1: (2- (((2-hydroxyethyl) amino) methyl) thiazol-5-yl) (4-phenylindolin-1-yl) formyl
Figure BDA0002080126520000171
Step 1: 4-phenyl-1H-indoles
Figure BDA0002080126520000172
4-bromo-1H-indole (7g, 35.9mmol), phenylboronic acid (4.38g, 35.9mmol), tetrakis (triphenylphosphine) palladium (1.24g, 1.07mmol), and potassium carbonate (14.89g, 107.7mmol) were dissolved in a mixed solvent of dioxane and water (volume ratio 4:1, 200mL) at room temperature. Under the protection of nitrogen, the temperature is raised to 60 ℃ for reaction for 10 hours. Cooling to room temperature, suction-filtering with celite, extracting the filtrate with dichloromethane, washing the organic layer with saturated brine, concentrating under reduced pressure, and separating by column chromatography to obtain white solid 4.28g with yield 61.7%.1H NMR(600MHz,DMSO-d6)δ11.27(s,1H),7.67(d,J＝7.3Hz,2H),7.49(t,J＝7.7Hz,2H),7.42(t,J＝5.9Hz,2H),7.37(t,J＝7.4Hz,1H),7.18(t,J＝7.6Hz,1H),7.08(d,J＝7.1Hz,1H),6.55(s,1H)。
Step 2: 4-phenylindolines
Figure BDA0002080126520000173
4-phenyl-1H-indole (3g, 15.54mmol) was dissolved in glacial acetic acid (20mL) at room temperature, and sodium cyanoborohydride (2.93g, 46.61mmol) was slowly added and reacted at room temperature for 3 hours. Adjusting pH to 9-10 with 40% NaOH solution in ice bath, extracting with ethyl acetate, washing organic layer with saturated saline solution, concentrating under reduced pressure, and separating by column chromatography to obtain white solid 2.09g with yield 68.9%.1H NMR(600MHz,DMSO-d6)δ7.47-7.40(m,4H),7.36-7.29(m,1H),7.00(t,J＝7.7Hz,1H),6.59(d,J＝7.1Hz,1H),6.51(d,J＝7.7Hz,1H),5.59(s,1H),3.39(t,J＝8.4Hz,2H),2.97(t,J＝8.4Hz,2H)。
And step 3: (2-Bromothiazol-5-yl) (4-phenylindolin-1-yl) formyl
Figure BDA0002080126520000174
4-phenylindoline (1g, 5.13mmol), 2-bromothiazole-5-carboxylic acid (1.06g, 5.13mmol) and 2- (7-oxybenzotriazole) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (HATU, 2.93g, 7.7mmol) were added to dry DMF (20mL) and stirred well at room temperature, followed by addition of N, N-diisopropylethylamine (1.33g, 10.26mmol) and reaction at room temperature for 3 hours. The reaction solution was poured into ice water, stirred at room temperature for half an hour, filtered under suction to give 1.51g of an off-white solid with a yield of 76.7%.1H NMR(600MHz,DMSO-d6)δ8.27(s,1H),8.08(s,1H),7.51-7.45(m,4H),7.42-7.37(m,1H),7.35(t,J＝7.9Hz,1H),7.15(d,J＝7.6Hz,1H),4.41(t,J＝8.1Hz,2H),3.26(t,J＝8.1Hz,2H)。
And 4, step 4: (4-phenylindolin-1-yl) (2-vinylthiazol-5-yl) formyl
Figure BDA0002080126520000181
(2-Bromothiazol-5-yl) (4-phenylindolin-1-yl) formyl (0.5g, 1.3mmol), tributylvinyltin (0.46g, 1.43mmol), tetrakis (triphenylphosphine) palladium (0.15g, 0.13mmol) and cesium carbonate (0.76g, 2.34mmol) were dissolved in a mixed solvent of 1, 4-dioxane/water (volume ratio 3:1, 15mL) at room temperature, and reacted at 100 ℃ for 3.5 hours under nitrogen protection. The reaction solution was cooled to room temperature, and 1, 4-dioxane was distilled off. The reaction solution was extracted with ethyl acetate, the organic layer was washed with saturated brine, the organic layer was evaporated to dryness, and the yellow solid was obtained by column chromatography separation in a yield of 46.3%.1H NMR(600MHz,DMSO-d6)δ8.37(s,1H),8.09(s,1H),7.48(dd,J＝9.4,5.1Hz,4H),7.41(dt,J＝12.6,6.8Hz,1H),7.34(t,J＝7.8Hz,1H),7.14(d,J＝7.4Hz,1H),7.01(dd,J＝17.5,10.9Hz,1H),6.23(d,J＝17.5Hz,1H),5.73(d,J＝11.0Hz,1H),4.42(s,2H),3.25(t,J＝8.1Hz,2H)。
And 5: 5- (4-phenylindoline-1-formyl) thiazole-2-carbaldehyde
Figure BDA0002080126520000182
(4-Phenylindolin-1-yl) (2-vinylthiazol-5-yl) formyl (0.6g, 1.8mmol) and potassium osmate dihydrate (0.13g, 0.36mmol) were dissolved in a mixed solvent of 1, 4-dioxane/water (volume ratio 5:1, 12mL), stirred at room temperature for 5 minutes, added with sodium periodate (1.54g, 7.2mmol), and stirred at room temperature for reaction for 3 hours. The reaction solution was poured into water, stirred and filtered to obtain a pale yellow solid (0.52 g) with a yield of 86.6%.1H NMR(600MHz,DMSO-d6)δ8.73(s,1H),7.52-7.46(m,5H),7.43-7.33(m,3H),7.18(d,J＝7.5Hz,1H),4.40(t,J＝7.9Hz,2H),3.26(t,J＝8.1Hz,2H)。
Step 6: (2- (((2-hydroxyethyl) amino) methyl) thiazol-5-yl) (4-phenylindolin-1-yl) formyl (example 1)
Figure BDA0002080126520000183
5- (4-phenylindoline-1-formyl) thiazole-2-carbaldehyde (0.2g, 0.6mmol), ethanolamine (0.18g, 3mmol) and glacial acetic acid (0.054g, 0.9mmol) were added to a mixed solvent of dichloromethane/methanol (volume ratio 1:1, 7mL) at room temperature, reacted at room temperature for 3 hours, added with sodium cyanoborohydride (0.19g, 3mmol), and reacted at room temperature for 10 hours. Adding water into the reaction solution, distilling off the organic solvent, adding dichloromethane for extraction, washing the organic layer with saturated saline, distilling off the solvent, and performing column chromatography to obtain 0.062g of white solid with the yield of 27.2%.
ESI-MS m/z:380.1[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.26(s,1H),7.51-7.45(m,5H),7.39(ddd,J＝8.4,5.9,2.4Hz,1H),7.33(t,J＝7.9Hz,1H),7.13(d,J＝7.5Hz,1H),4.56(t,J＝5.3Hz,1H),4.38(t,J＝8.2Hz,2H),4.04(s,2H),3.50(q,J＝5.5Hz,2H),3.24(t,J＝8.1Hz,2H),2.69(t,J＝5.7Hz,2H)。
According to the synthesis method of the embodiment 1, the compound of the embodiment 2 is prepared by taking 5- (4-phenylindoline-1-formyl) thiazole-2-formaldehyde as a raw material, reacting with N- (2-aminoethyl) acetamide, and reducing by sodium cyanoborohydride.
Example 2: n- (2- (((5- (4-phenylindolin-1-formyl) thiazol-2-yl) methyl) amino) ethyl) acetamide
Figure BDA0002080126520000184
ESI-MS m/z:421.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.26(s,1H),7.83(s,1H),7.48(dd,J＝9.0,5.2Hz,4H),7.39(ddd,J＝8.2,5.9,2.3Hz,1H),7.33(t,J＝7.8Hz,1H),7.13(d,J＝7.6Hz,1H),4.39(t,J＝8.2Hz,2H),4.01(s,2H),3.24(t,J＝8.1Hz,2H),3.16(q,J＝6.2Hz,2H),2.66(t,J＝6.4Hz,2H),1.80(s,3H)。
Example 3: (5- (((2-hydroxyethyl) amino) methyl) thiophen-2-yl) (4-phenylindolin-1-yl) formyl
Figure BDA0002080126520000191
Step 1: 5- (4-phenylindoline-1-formyl) thiophene-2-carbaldehyde
Figure BDA0002080126520000192
4-phenylindoline (2g, 10.25mmol), 5-formylthiophene-2-carboxylic acid (2.08g, 13.33mmol), HATU (5.85g, 15.38mmol) were dissolved in DMF (30mL), stirred at room temperature for 20min, N-diisopropylethylamine (6.62g, 51.26mmol) was added, and reacted at room temperature for 3 hours. The reaction solution was poured into water, stirred for 10 minutes, and filtered under suction to obtain 2.51g of a tan solid with a yield of 73.4%. ESI-MS M/z 334.1[ M + H ]]+。
Step 2: (5- (((2-hydroxyethyl) amino) methyl) thiophen-2-yl) (4-phenylindolin-1-yl) formyl (example 3)
Figure BDA0002080126520000193
5- (4-phenylindoline-1-formyl) thiophene-2-carbaldehyde (0.1g, 0.3mmol), ethanolamine (0.092g, 1.5mmol) and glacial acetic acid (0.027g, 0.45mmol) were added to a mixed solvent of dichloromethane/methanol (volume ratio 1:1, 5mL) at room temperature to react for 5 hours at room temperature, sodium cyanoborohydride (0.095g, 1.5mmol) was added, and the reaction was continued at room temperature for 10 hours. Adding water to the reaction solution, evaporating to remove the organic solvent, adding dichloromethane for extraction, washing the organic layer with saturated saline, evaporating to remove the solvent, and performing column chromatography to obtain 0.035g of white solid with the yield of 30.7%.
ESI-MS m/z:379.1[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.05(d,J＝7.7Hz,1H),7.60(d,J＝3.6Hz,1H),7.53-7.45(m,4H),7.43-7.37(m,1H),7.32(t,J＝7.8Hz,1H),7.11(d,J＝7.5Hz,1H),7.05(d,J＝3.3Hz,1H),4.54(s,1H),4.40(t,J＝8.1Hz,2H),3.95(s,2H),3.49(d,J＝4.0Hz,2H),3.24(t,J＝8.0Hz,2H),2.64(t,J＝5.7Hz,2H)。
According to the synthesis method of the embodiment 3, 5- (4-phenylindoline-1-formyl) thiophene-2-formaldehyde is used as a raw material, and is reacted with different amine compounds, and then is reduced by sodium cyanoborohydride to prepare the compounds of the embodiments 4-7.
Example 4: n- (2- (((5- (4-phenylindolin-1-formyl) thiophen-2-yl) methyl) amino) ethyl) acetamide
Figure BDA0002080126520000194
ESI-MS m/z:420.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.04(d,J＝7.8Hz,1H),7.80(s,1H),7.59(d,J＝3.7Hz,1H),7.51-7.45(m,4H),7.41-7.36(m,1H),7.32(t,J＝7.8Hz,1H),7.10(d,J＝7.6Hz,1H),7.03(d,J＝3.5Hz,1H),4.39(t,J＝8.1Hz,2H),3.91(s,2H),3.23(t,J＝8.0Hz,2H),3.13(dd,J＝12.2,6.2Hz,2H),2.59(t,J＝6.4Hz,2H),1.79(s,3H)。
Example 5: n- (2- (((5- (4-phenylindolin-1-formyl) thiophen-2-yl) methyl) amino) ethyl) methanesulfonamide
Figure BDA0002080126520000195
ESI-MS m/z:456.1[M+H]+。
Example 6: ((5- (4-phenylindolin-1-formyl) thiophen-2-yl) methyl) -D-serine
Figure BDA0002080126520000201
ESI-MS m/z:423.1[M+H]+。
Example 7: ((5- (4-phenylindolin-1-formyl) thiophen-2-yl) methyl) -D-alanine
Figure BDA0002080126520000202
ESI-MS m/z:407.1[M+H]+。
Example 8: (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) (4-phenylindolin-1-yl) formyl
Figure BDA0002080126520000203
Step 1: 5-Formylthiazole-2-carboxylic acid ethyl ester
Figure BDA0002080126520000204
Ethyl thioaluminate (5g, 37.59mmol) and 2-bromomalondialdehyde (5.64g, 37.59mmol) were added to ethylene glycol dimethyl ether (120mL) at room temperature and the reaction was stirred for an additional 10 hours. Water was added to the reaction mixture, extraction was performed with dichloromethane, the organic layer was washed with saturated brine, the organic layer was washed with water, and the solvent was evaporated to dryness to obtain a tan solid (3.94 g) with a yield of 56.6%.1H NMR(600MHz,DMSO-d6)δ10.15(s,1H),8.87(s,1H),4.42(q,J＝7.1Hz,2H),1.35(t,J＝7.1Hz,3H)。
Step 2: 5-formylthiazole-2-carboxylic acid
Figure BDA0002080126520000205
Ethyl 5-formylthiazole-2-carboxylate (1g, 5.41mmol) was added to a mixed solvent of tetrahydrofuran/water (volume ratio 4:1, 5mL) at room temperature, and lithium hydroxide (0.26g, 10.81mmol) was added thereto, followed by stirring and reacting for 1 hour. Tetrahydrofuran was distilled off, extraction was performed with dichloromethane, the pH of the aqueous layer was adjusted to 5-6 with dilute hydrochloric acid, and the aqueous layer was evaporated to dryness to obtain 0.57g of pale yellow solid with a yield of 67.3%. ESI-MS M/z 158.0[ M + H ]]+。
And step 3: 2- (4-phenylindoline-1-formyl) thiazole-5-carbaldehyde
Figure BDA0002080126520000206
4-phenylindoline (1.5g, 7.69mmol), 5-formylthiazole-2-carboxylic acid (1.45g, 9.23mmol), HATU (4.39g, 11.53mmol) were dissolved in DMF (30mL) at room temperature, stirred for 20min, and N, N-diisopropylethylamine (4.96g, 38.44mmol) was added and reacted at room temperature for 2.5 hours. The reaction solution was poured into water, stirred for 10 minutes, and filtered under suction to obtain 2.12g of a tan solid with a yield of 82.7%.1H NMR(600MHz,DMSO-d6)δ10.15(s,1H),8.87(s,1H),8.25(d,J＝8.0Hz,1H),7.52-7.47(m,4H),7.40(dd,J＝12.9,7.2Hz,2H),7.21(d,J＝7.5Hz,1H),4.70(t,J＝8.1Hz,2H),3.29(t,J＝8.1Hz,2H)。
And 4, step 4: (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) (4-phenylindolin-1-yl) formyl (example 8)
Figure BDA0002080126520000207
2- (4-phenylindoline-1-formyl) thiazole-5-carbaldehyde (0.1g, 0.3mmol), ethanolamine (0.092g, 1.5mmol) and glacial acetic acid (0.027g, 0.45mmol) were added to a mixed solvent of dichloromethane/methanol (volume ratio 1:1, 5mL) at room temperature to react at room temperature for 7 hours, sodium cyanoborohydride (0.095g, 1.5mmol) was added, and the reaction was continued at room temperature for 12 hours. Adding water to the reaction solution, distilling off the organic solvent, adding dichloromethane for extraction, washing the organic layer with saturated saline, distilling off the solvent, and performing column chromatography to obtain 0.022g of white solid with the yield of 19.3%.
ESI-MS m/z:380.1[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.23(s,1H),7.91(s,1H),7.80(s,1H),7.49(q,J＝7.8Hz,4H),7.38(dt,J＝15.3,7.2Hz,2H),7.16(d,J＝7.6Hz,1H),4.68(t,J＝7.9Hz,2H),3.98(s,2H),3.26(t,J＝8.1Hz,2H),3.13(dd,J＝11.8,5.8Hz,2H),2.58(t,J＝6.3Hz,2H),1.79(s,3H)。
According to the synthesis method of the embodiment 8, the compounds of the embodiments 9 to 21 are prepared by reacting 2- (4-phenylindoline-1-formyl) thiazole-5-formaldehyde with different amine compounds and then reducing the obtained product by sodium cyanoborohydride.
Example 9: (5- (((2-hydroxyethyl) (methyl) amino) methyl) thiazol-2-yl) (4-phenylindolin-1-yl) formyl
Figure BDA0002080126520000211
ESI-MS m/z:394.2[M+H]+。
Example 10: n- (2- (((2- (4-phenylindolin-1-formyl) thiazol-5-yl) methyl) amino) ethyl) acetamide
Figure BDA0002080126520000212
ESI-MS m/z:421.2[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.23(s,1H),7.91(s,1H),7.80(s,1H),7.49(q,J＝7.8Hz,4H),7.38(dt,J＝15.3,7.2Hz,2H),7.16(d,J＝7.6Hz,1H),4.68(t,J＝7.6Hz,2H),3.98(s,2H),3.26(t,J＝8.1Hz,2H),3.13(dd,J＝11.8,5.8Hz,2H),2.58(t,J＝6.3Hz,2H),1.79(s,3H)。
Example 11: 2- (((2- (4-phenylindolin-1-formyl) thiazol-5-yl) methyl) amino) ethane-1-sulfonamide
Figure BDA0002080126520000213
ESI-MS m/z:443.1[M+H]+。
Example 12: n- (2- (((2- (4-phenylindolin-1-formyl) thiazol-5-yl) methyl) amino) ethyl) methanesulfonamide
Figure BDA0002080126520000214
ESI-MS m/z:457.1[M+H]+。
Example 13: ((2- (4-phenylindolin-1-formyl) thiazol-5-yl) methyl) -D-serine
Figure BDA0002080126520000215
ESI-MS m/z:424.1[M+H]+。
Example 14: ((2- (4-phenylindolin-1-formyl) thiazol-5-yl) methyl) -D-threonine
Figure BDA0002080126520000221
ESI-MS m/z:438.1[M+H]+。
Example 15: ((2- (4-phenylindolin-1-formyl) thiazol-5-yl) methyl) -D-alanine
Figure BDA0002080126520000222
ESI-MS m/z:408.1[M+H]+。
Example 16: ((2- (4-phenylindolin-1-formyl) thiazol-5-yl) methyl) -L-alanine
Figure BDA0002080126520000223
ESI-MS m/z:408.1[M+H]+。
Example 17: (S) -3-hydroxy-4- (((2- (4-phenylindolin-1-formyl) thiazol-5-yl) methyl) amino) butanoic acid
Figure BDA0002080126520000224
ESI-MS m/z:438.2[M+H]+。
Example 18: (S) - (5- ((2- (hydroxymethyl) pyrrolidin-1-yl) methyl) thiazol-2-yl) (4-phenylindolin-1-yl) formyl
Figure BDA0002080126520000225
ESI-MS m/z:420.2[M+H]+。
Example 19: ((2- (4-phenylindolin-1-formyl) thiazol-5-yl) methyl) -L-proline
Figure BDA0002080126520000226
ESI-MS m/z:434.2[M+H]+。
Example 20: (S) -1- ((2- (4-phenylindolin-1-formyl) thiazol-5-yl) methyl) piperidine-2-carboxylic acid
Figure BDA0002080126520000227
ESI-MS m/z:448.2[M+H]+。
Example 21: (4-phenylindolin-1-yl) (5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) thiazol-2-yl) formyl
Figure BDA0002080126520000231
ESI-MS m/z:420.2[M+H]+。
Example 22: 3- ((2- (4-phenylindolin-1-formyl) thiazol-5-yl) methyl) oxazolidin-2-one
Figure BDA0002080126520000232
(5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) (4-phenylindolin-1-yl) formyl (example 8, 0.1g, 0.26mmol) was dissolved in absolute ethanol (8mL) at room temperature, and a mixed solution of sodium ethoxide (1M, 0.53mL, 0.53mmol) and diethyl carbonate (0.31g, 2.64mmol) was slowly added dropwise, and the mixture was heated to reflux for 7 hours. Adding acetic acid into the system, evaporating to remove the solvent, adding dichloromethane, washing with water, evaporating to remove the organic phase, and performing column chromatography to obtain a white solid with the weight of 0.046g and the yield of 42.6%.
ESI-MS m/z:406.1[M+H]+。
Intermediate: 5-bromo-1, 3, 4-thiadiazole-2-carboxylic acid
Figure BDA0002080126520000233
Ethyl 5-bromo-1, 3, 4-thiadiazole-2-carboxylate (1g, 4.24mmol) and NaOH (1g, 25mmol) were added to a mixed solvent of methanol/water (volume ratio 4:1, 15mL) under ice-bath. The reaction mixture was stirred at room temperature for 2 hours. Dilute hydrochloric acid is added into the system to adjust the pH value to 6, the solvent is distilled off to obtain 0.79g of white solid, the yield is 89.7%, and the white solid can be directly used in the next step.
Similar to the synthesis of example 1, 4-phenylindoline was used as starting material and was amidated with 5-bromo-1, 3, 4-thiadiazole-2-carboxylic acid, coupled with tributylvinyltin, oxidized with sodium periodate, and reductively aminated with an amine compound via sodium cyanoborohydride to give the compounds of examples 23-27.
Example 23: (5- (((2-hydroxyethyl) amino) methyl) -1,3, 4-thiadiazol-2-yl) (4-phenylindolin-1-yl) formyl
Figure BDA0002080126520000234
ESI-MS m/z:381.1[M+H]+。
Example 24: n- (2- (((5- (4-phenylindolin-1-formyl) -1,3, 4-thiadiazol-2-yl) methyl) amino) ethyl) acetamide
Figure BDA0002080126520000235
ESI-MS m/z:422.2[M+H]+。
Example 25: n- (2- (((5- (4-phenylindolin-1-formyl) -1,3, 4-thiadiazol-2-yl) methyl) amino) ethyl) methanesulfonamide
Figure BDA0002080126520000236
ESI-MS m/z:458.1[M+H]+。
Example 26: ((5- (4-phenylindolin-1-formyl) -1,3, 4-thiadiazol-2-yl) methyl) -D-serine
Figure BDA0002080126520000241
ESI-MS m/z:425.1[M+H]+。
Example 27: ((5- (4-phenylindolin-1-formyl) -1,3, 4-thiadiazol-2-yl) methyl) -D-alanine
Figure BDA0002080126520000242
ESI-MS m/z:409.2[M+H]+。
Example 28: (4- (benzo [ d ] oxazol-5-yl) indolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl
Figure BDA0002080126520000243
Step 1: 5- (1, 3-Dioxolan-2-yl) thiazole-2-carboxylic acid ethyl ester
Figure BDA0002080126520000244
Ethyl 5-formylthiazole-2-carboxylate (3g, 16.22mmol), ethylene glycol (3.5g, 56.42mmol) and p-toluenesulfonic acid monohydrate (0.25g, 1.32mmol) were dissolved in toluene (20mL) at room temperature, and the reaction was carried out at 110 ℃ for 3 hours. The toluene was distilled off, the residue was dissolved in methylene chloride, the organic layer was washed with a saturated sodium bicarbonate solution and a saturated brine, respectively, and the solvent was distilled off to obtain 2.17g of a tan solid, the yield of which was 58.4%.1H NMR(600MHz,DMSO-d6)δ8.17(s,1H),6.24(s,1H),4.38(q,J＝7.1Hz,2H),4.09-4.03(m,2H),4.02-3.96(m,2H),1.34(dt,J＝11.7,4.5Hz,3H)。
Step 2: 5- (1, 3-dioxolan-2-yl) thiazole-2-carboxylic acid
Figure BDA0002080126520000245
Ethyl 5- (1, 3-dioxolan-2-yl) thiazole-2-carboxylate (2.17g, 9.47mmol) was dissolved in a mixed solvent of tetrahydrofuran/water (volume ratio 4:1, 20mL) at room temperature, lithium hydroxide (0.68g, 28.42mmol) was added, and the reaction was stirred for further 6 hours. The tetrahydrofuran was distilled off, the aqueous layer was extracted with dichloromethane, the pH of the aqueous layer was adjusted to 6 with dilute hydrochloric acid, n-butanol was extracted, the organic layers were combined and the solvent was distilled off to give 0.75g of an orange-brown solid with a yield of 39.4%. ESI-MS M/z 202.0[ M + H ]]+。
And step 3: (5- (1, 3-Dioxolan-2-yl) thiazol-2-yl) (4-bromoindolin-1-yl) formyl
Figure BDA0002080126520000246
At room temperature, mixing4-Bromoindoline (0.57g, 2.89mmol), 5- (1, 3-dioxolan-2-yl) thiazole-2-carboxylic acid (0.7g, 3.47mmol), HATU (1.65g, 4.34mmol) were dissolved in DMF (20mL), stirred for 20min, N-diisopropylethylamine (1.87g, 14.48mmol) was added, and the reaction was carried out at room temperature for 3 hours. The reaction solution was poured into water, stirred for 10 minutes, and filtered under suction to obtain 1.01g of an orange-brown solid with a yield of 91.8%.1H NMR(600MHz,DMSO-d6)δ8.22-8.14(m,2H),7.34(d,J＝8.0Hz,1H),7.22(t,J＝8.0Hz,1H),6.23(s,1H),4.73(t,J＝8.1Hz,2H),4.09-4.03(m,2H),4.03-3.98(m,2H),3.19(t,J＝8.3Hz,2H)。
And 4, step 4: 2- (4-bromoindoline-1-formyl) thiazole-5-formaldehyde
Figure BDA0002080126520000247
(5- (1, 3-Dioxolan-2-yl) thiazol-2-yl) (4-bromoindolin-1-yl) formyl (1.01g, 2.66mmol) and p-toluenesulfonic acid (0.91g, 5.29mmol) were dissolved in a mixed solvent of acetone/water (volume ratio 3: 2, 10mL) at room temperature and reacted at 70 ℃ for 2.5 hours. The reaction solution was poured into ice water and stirred for 10 minutes, filtered and dried to obtain a pale yellow solid 0.84g with a yield of 94.1%. ESI-MS M/z 337.0[ M + H ]]+。
And 5: (4-Bromoindolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl
Figure BDA0002080126520000251
2- (4-Bromoindoline-1-formyl) thiazole-5-carbaldehyde (0.84g, 2.5mmol), ethanolamine (0.76g, 12.5mmol) and glacial acetic acid (0.23g, 3.75mmol) were added to a mixed solvent of dichloromethane/water (volume ratio 1:1, 10mL) at room temperature, and stirring was continued for 5 hours. Sodium cyanoborohydride (0.79g, 12.5mmol) was added to the system, and the reaction was continued at room temperature for 12 hours. Adding water into the reaction solution, distilling off the organic solvent, adding dichloromethane for extraction, washing the organic layer with saturated saline, distilling off the solvent, and performing column chromatography to obtain a light yellow solid with the yield of 54.6 percent, wherein the light yellow solid is 0.52 g.1H NMR(600MHz,DMSO-d6)δ8.18(d,J＝8.1Hz,1H),7.92(s,1H),7.32(d,J＝8.0Hz,1H),7.21(t,J＝8.1Hz,1H),4.73(t,J＝8.2Hz,2H),4.51(t,J＝5.4Hz,1H),4.00(s,2H),3.46(q,J＝5.7Hz,2H),3.18(t,J＝8.4Hz,2H),2.60(t,J＝5.7Hz,2H)。
Step 6: (4- (benzo [ d ] oxazol-5-yl) indolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl (example 28)
Figure BDA0002080126520000252
At room temperature, (4-bromoindolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl (0.5g, 1.31mmol), 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] oxazole (0.48g, 1.97mmol), [1, 1' -bis (diphenylphosphino) ferrocene ] palladium dichloride (0.067g, 0.092mmol) and sodium carbonate (0.28g, 2.62mmol) were added to a mixed solvent of dioxane/water (volume ratio 3:1, 15mL) and reacted at 80 ℃ for 4 hours under nitrogen protection. Filtering, evaporating to remove solvent, and separating by column chromatography to obtain white solid 0.15g with yield 27.2%.
ESI-MS m/z:421.1[M+H]+；1H NMR(600MHz,DMSO-d6)δ8.82(s,1H),8.25(d,J＝7.0Hz,1H),7.94-7.90(m,2H),7.87(d,J＝8.4Hz,1H),7.56(dd,J＝8.4,1.5Hz,1H),7.38(t,J＝7.8Hz,1H),7.22(d,J＝7.4Hz,1H),4.69(t,J＝7.8Hz,2H),4.52(t,J＝5.3Hz,1H),4.00(s,2H),3.47(q,J＝5.6Hz,2H),3.29(t,J＝8.2Hz,2H),2.61(t,J＝5.7Hz,2H)。
The compounds of examples 29-43 were prepared by a Suzuki-Miyaura coupling reaction starting from (4-bromoindolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl and benzene, substituted benzene or heteroaromatic boronic acids or boronic acid esters analogous to the synthesis of example 28.
Example 29: (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (1-methyl-1H-indazol-4-yl) indolin-1-yl) formyl
Figure BDA0002080126520000253
ESI-MS m/z:434.2[M+H]+。
Example 30: (4- (1H-indol-4-yl) indolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl
Figure BDA0002080126520000254
ESI-MS m/z:419.2[M+H]+。
Example 31: (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (6-methoxypyridin-2-yl) indolin-1-yl) formyl
Figure BDA0002080126520000255
ESI-MS m/z:411.1[M+H]+。
Example 32: (4- (1H-pyrrolo [2,3-b ] pyridin-5-yl) indolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl
Figure BDA0002080126520000261
ESI-MS m/z:420.1[M+H]+。
Example 33: (4- (2, 3-dihydrobenzo [ b ] [1,4] dioxin-6-yl) indolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl
Figure BDA0002080126520000262
ESI-MS m/z:438.1[M+H]+。
Example 34: (4- (benzo [ d ] thiazol-5-yl) indolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl
Figure BDA0002080126520000263
ESI-MS m/z:437.1[M+H]+。
Example 35: (4- (benzo [ d ] oxazol-6-yl) indolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl
Figure BDA0002080126520000264
ESI-MS m/z:421.1[M+H]+。
Example 36: (4- (benzo [ d ] thiazol-6-yl) indolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl
Figure BDA0002080126520000265
ESI-MS m/z:437.1[M+H]+。
Example 37: (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (quinoxalin-6-yl) indolin-1-yl) formyl
Figure BDA0002080126520000266
ESI-MS m/z:432.1[M+H]+。
Example 38: (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (quinolin-3-yl) indolin-1-yl) formyl
Figure BDA0002080126520000267
ESI-MS m/z:431.2[M+H]+。
Example 39: (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (thien-2-yl) indolin-1-yl) formyl
Figure BDA0002080126520000271
ESI-MS m/z:386.1[M+H]+。
Example 40: (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (4- (trifluoromethoxy) phenyl) indolin-1-yl) formyl
Figure BDA0002080126520000272
ESI-MS m/z:464.1[M+H]+。
Example 41: (4- (2-fluoro-3-methoxyphenyl) indolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl
Figure BDA0002080126520000273
ESI-MS m/z:428.1[M+H]+。
Example 42: (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (3-methoxy-2-methylphenyl) indolin-1-yl) formyl
Figure BDA0002080126520000274
ESI-MS m/z:424.2[M+H]+。
Example 43: (4- (3, 4-Dimethoxyphenyl) indolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl
Figure BDA0002080126520000275
ESI-MS m/z:440.2[M+H]+。
Example 44: n- (2- (((2- (4- (benzo [ d ] oxazol-5-yl) indolin-1-formyl) thiazol-5-yl) methyl) amino) ethyl) acetamide
Figure BDA0002080126520000276
Step 1: 4-bromoindolines
Figure BDA0002080126520000277
4-bromo-1H-indole (17g, 87.19mmol) was dissolved in glacial acetic acid (15mL) at room temperature and stirred for 10 min. Sodium cyanoborohydride (16.32g, 258.92mmol) was slowly added to the reaction solution. After the addition, the reaction was continued at room temperature with stirring for 1 hour. Adding sodium hydroxide solution into the system until the pH value is 8-9, extracting with dichloromethane, washing the organic layer with saturated saline, evaporating the organic layer, and carrying out column chromatography to obtain 9.88g of yellow oily matter with the yield of 57.5%. ESI-MS M/z 198.0[ M + H ]]+。
Step 2: 5- (indolin-4-yl) benzo [ d ] oxazoles
Figure BDA0002080126520000278
4-Bromoindoline (1g, 5.08mmol), 5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzo [ d ] is reacted at room temperature]Oxazole (1.87g, 7.61mmol) and [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.26g, 0.36mmol) and sodium carbonate (1.08g, 10.15mmol) were added to a mixed solvent of dioxane/water (volume ratio 3:1, 15mL) and reacted at 80 ℃ for 5 hours under nitrogen protection. Filtering, evaporating to remove solvent, and separating by column chromatography to obtain white solid 0.71g with yield 59.1%. ESI-MS M/z 237.1[ M + H ]]+。
And step 3: (5- (1, 3-Dioxolan-2-yl) thiazol-2-yl) (4- (benzo [ d ] oxazol-5-yl) indolin-1-yl) formyl
Figure BDA0002080126520000281
Reacting 5- (indolin-4-yl) benzo [ d ] with a catalyst at room temperature]Oxazole (0.7g, 2.96mmol), 5- (1, 3-dioxolan-2-yl) thiazole-2-carboxylic acid (0.72g, 3.56mmol), HATU (1.69g, 4.45mmol) were dissolved in DMF (20mL)After stirring for 20min, N-diisopropylethylamine (1.92g, 14.82mmol) was added and reacted at room temperature for 2.5 hours. The reaction solution was poured into water, stirred for 10 minutes, and filtered under suction to obtain 1.06g of pale yellow solid with a yield of 85.7%. ESI-MS M/z 420.1[ M + H ]]+。
And 4, step 4: 2- (4- (benzo [ d ] oxazol-5-yl) indoline-1-formyl) thiazole-5-carbaldehyde
Figure BDA0002080126520000282
Reacting (5- (1, 3-dioxolan-2-yl) thiazol-2-yl) (4- (benzo [ d ]) at room temperature]Oxazol-5-yl) indolin-1-yl) formyl (1g, 2.39mmol), p-toluenesulfonic acid (0.82g, 4.77mmol) was dissolved in acetone/water (volume ratio 3: 2, 10mL) was added to the reaction mixture, and the mixture was reacted at 70 ℃ for 3 hours. The reaction solution was poured into ice water and stirred for 10 minutes, filtered and dried to obtain a pale yellow solid 0.8g with a yield of 89.7%. ESI-MS M/z 376.1[ M + H ]]+。
And 5: n- (2- (((2- (4- (benzo [ d ] oxazol-5-yl) indolin-1-formyl) thiazol-5-yl) methyl) amino) ethyl) acetamide (example 44)
Figure BDA0002080126520000283
2- (4- (benzo [ d ] oxazol-5-yl) indoline-1-formyl) thiazole-5-carbaldehyde (0.1g, 0.27mmol), N- (2-aminoethyl) acetamide (0.14g, 1.33mmol) and glacial acetic acid (0.024g, 0.4mmol) were added to a mixed solvent of dichloromethane/methanol (volume ratio 1:1, 5mL) at room temperature to react at room temperature for 5 hours, sodium cyanoborohydride (0.084g, 1.33mmol) was added, and the reaction was continued at room temperature for 13 hours. Adding water to the reaction solution, distilling off the organic solvent, adding dichloromethane for extraction, washing the organic layer with saturated saline, distilling off the solvent, and performing column chromatography to obtain a white solid of 0.04g with the yield of 32.7%.
ESI-MS m/z:462.2[M+H]+。
According to the synthesis method of the embodiment 44, the compound of the embodiment 45-50 is prepared by reacting 2- (4- (benzo [ d ] oxazol-5-yl) indoline-1-formyl) thiazole-5-formaldehyde with different amine compounds and then reducing the obtained product by sodium cyanoborohydride.
Example 45: 2- (((2- (4- (benzo [ d ] oxazol-5-yl) indolin-1-formyl) thiazol-5-yl) methyl) amino) ethane-1-sulfonamide
Figure BDA0002080126520000284
ESI-MS m/z:484.1[M+H]+。
Example 46: n- (2- (((2- (4- (benzo [ d ] oxazol-5-yl) indolin-1-formyl) thiazol-5-yl) methyl) amino) ethyl) methanesulfonamide
Figure BDA0002080126520000285
ESI-MS m/z:498.1[M+H]+。
Example 47: ((2- (4- (benzo [ D ] oxazol-5-yl) indolin-1-formyl) thiazol-5-yl) methyl) -D-serine
Figure BDA0002080126520000291
ESI-MS m/z:465.1[M+H]+。
Example 48: ((2- (4- (benzo [ D ] oxazol-5-yl) indolin-1-formyl) thiazol-5-yl) methyl) -D-alanine
Figure BDA0002080126520000292
ESI-MS m/z:449.1[M+H]+。
Example 49: ((2- (4- (benzo [ d ] oxazol-5-yl) indolin-1-formyl) thiazol-5-yl) methyl) -L-alanine
Figure BDA0002080126520000293
ESI-MS m/z:449.1[M+H]+。
Example 50: (4- (benzo [ d ] oxazol-5-yl) indolin-1-yl) (5- (((tetrahydro-2H-pyran-4-yl) amino) methyl) thiazol-2-yl) formyl
Figure BDA0002080126520000294
ESI-MS m/z:461.2[M+H]+。
The compound of example 51 was prepared in analogy to the preparation of example 22, starting from (4- (benzo [ d ] oxazol-5-yl) indolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl (example 28).
Example 51: 3- ((2- (4- (benzo [ d ] oxazol-5-yl) indolin-1-formyl) thiazol-5-yl) methyl) oxazolidin-2-one
Figure BDA0002080126520000295
ESI-MS m/z:447.1[M+H]+。
Example 52: (R) - (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (3- (3- (3-hydroxypyrrolidin-1-yl) propoxy) -2-methylphenyl) indolin-1-yl) formyl
Figure BDA0002080126520000296
Step 1: 1-bromo-3- (3-bromopropoxy) -2-methylbenzene
Figure BDA0002080126520000297
1, 3-dibromopropane (75.24g, 376.4mmol), 3-bromo-2-methylphenol (7g, 37.64mmol) and potassium carbonate (14.02g, 101.63mmol) were added to acetone (300mL) at room temperature, and the reaction was stirred at room temperature for 7 days. Filtering, distilling under reduced pressure to remove filtrate, and performing column chromatography10.28g of colorless liquid was obtained, with a yield of 89.3%. ESI-MSm/z 307.0[ M + H ]]+。
Step 2: 2- (3- (3-Bromopropoxy) -2-methylphenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan
Figure BDA0002080126520000301
1-bromo-3- (3-bromopropoxy) -2-methylbenzene (5g, 16.34mmol), pinacol diboron (6.23g, 24.52mmol) and [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.84g, 1.14mmol) and potassium acetate (4.81g, 49.03mmol) were added to 1, 4-dioxane (60 mL). The reaction was carried out at 80 ℃ for 20 hours under nitrogen protection. Filtering, evaporating to remove the solvent, and separating by column chromatography to obtain 3.91g of white solid with the yield of 67.6%. ESI-MS M/z 355.1[ M + H ]]+。
And step 3: (4- (3- (3-Bromopropoxy) -2-methylphenyl) indolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl
Figure BDA0002080126520000302
(4-Bromoindolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl (0.5g, 1.31mmol), 2- (3- (3-bromopropoxy) -2-methylphenyl) -4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan (0.7g, 1.97mmol) and [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (0.067g, 0.092mmol) and sodium carbonate (0.28g, 2.62mmol) were added to a mixed solvent of dioxane/water (volume ratio 3:1, 15mL) and reacted at 80 ℃ for 7 hours under nitrogen protection. Filtering, evaporating to remove solvent, and separating by column chromatography to obtain white solid 0.22g with yield of 31.3%. ESI-MS M/z 530.1[ M + H ]]+。
And 4, step 4: (R) - (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) (4- (3- (3- (3-hydroxypyrrolidin-1-yl) propoxy) -2-methylphenyl) indolin-1-yl) formyl (example 52)
Figure BDA0002080126520000303
(4- (3- (3-bromopropoxy) -2-methylphenyl) indolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl (0.1g, 0.19mmol), (R) -3-hydroxypyrrolidine hydrochloride (0.34g, 2.74mmol), and N, N-diisopropylethylamine (0.44g, 3.4mmol) were dissolved in methanol (7mL) at room temperature, and the reaction was heated to 70 ℃ for reaction for 15 hours. The solvent was distilled off, methylene chloride and saturated brine were added to the system to wash, the organic layer was distilled off, and column chromatography was carried out to obtain 0.027g of a pale yellow solid with a yield of 26.7%.
ESI-MS m/z:537.3[M+H]+。
The compounds of example 53 and example 54 were prepared according to the synthesis of example 52 starting from (4- (3- (3-bromopropoxy) -2-methylphenyl) indolin-1-yl) (5- (((2-hydroxyethyl) amino) methyl) thiazol-2-yl) formyl by nucleophilic substitution reaction with different amine compounds.
Example 53: 2- (3-hydroxy-1- (3- (3- (1- (5- (((2-hydroxyethyl) amino) methyl) thiazole-2-formyl) indolin-4-yl) -2-methylphenoxy) propyl) pyrrolidin-3-yl) acetic acid
Figure BDA0002080126520000304
ESI-MS m/z:595.3[M+H]+。
Example 54: (3- (3- (1- (5- (((2-hydroxyethyl) amino) methyl) thiazole-2-formyl) indolin-4-yl) -2-methylphenoxy) propyl) -D-serine
Figure BDA0002080126520000305
ESI-MS m/z:555.2[M+H]+。
Study of the biological Activity of the Compound of the present invention
Homogeneous Time-Resolved Fluorescence (HTRF) assays were used to examine the ability of the compounds of the invention to inhibit the PD-1/PD-L1 interaction. The Detection kit is purchased from CisBio and comprises Anti-Tag1-Cyptate, Anti-Tag2-XL665/d2, Tag1-PD-L1, Tag2-PD-1, Dilution Buffer, Detection Buffer and other reagents required by experiments.
The experimental steps are as follows: PD-1 recombinant protein and PD-L1 recombinant protein were diluted to 500nM and 50nM, respectively, with Dilution Buffer. 4mM DMSO-solubilized small molecule compound was diluted 20-fold to 200uM with Dilution Buffer. Four-fold gradient Dilution with Dilution Buffer containing 5% DMSO. Concurrent Dilution of 600uM with Dilution Buffer the DMSO-solubilized PD-1/PD-L1 inhibitor was 20-fold to 30uM diluted in a four-fold gradient with Dilution Buffer containing 5% DMSO. To 384 wells, 2uL of diluted test compound, 4uL of diluted PD-1, and 4uL of diluted PDL-1 were added in that order. Mixing, and standing at room temperature for 15 min. Diluting anti-Tag1-Eu with Detection buffer3+(1:25) and anti-Tag2-XL665(1: 100). The diluted detection reagent was then mixed in equal volume, and 10. mu.L of antibody mixture was added to each reaction well. And (5) sealing the membrane and incubating for 2h at room temperature. Fluorescence signals (320nm stimulation, 665nm, 615nm emission) were detected with an envision (perkinelmer) instrument. 8-12 concentrations were measured per compound.
The results of the compounds' activity in inhibiting the PD-1/PD-L1 interaction are shown in Table 1.
TABLE 1 Activity Range or IC for the inhibition of the PD-1/PD-L1 interaction by the Compounds of the invention50The value is obtained. The ranges are as follows: a-1 nM-100 nM; b-100.01 nM-1 μ M; c ═ 1.01 μ M to 20 μ M.
Figure BDA0002080126520000311
HTRF test results indicate that the example compounds significantly inhibited PD-1/PD-L1 interaction at the molecular level.

Claims (13)

1. Indoline compounds of general formula I, stereoisomers and pharmaceutically acceptable salts thereof,
Figure FDA0003506577590000011
wherein the content of the first and second substances,
cy is selected from phenyl or 5-12 membered heteroaryl, or is
Figure FDA0003506577590000012
Said 5-12 membered heteroaryl contains 1-3 heteroatoms selected from N, O or S; said phenyl, 5-12 membered heteroaryl or
Figure FDA0003506577590000013
Optionally substituted by 1-3R1Substitution;
R1independently selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, cyano, hydroxy, carboxy, amino; said (C)1-C4) Alkyl, (C)1-C4) Alkoxy may optionally be substituted with 1-3R2Substitution;
R2independently selected from hydrogen, halogen, (C)1-C4) Alkyl, hydroxy, amino, carboxyl, or
Figure FDA0003506577590000014
Ra、RbIndependently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamido (C1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl may optionally be substituted with 1-3R3Substitution;
or Ra、RbAnd the nitrogen atom to which they are attached form a 3-to 7-membered nitrogen-containing heterocyclic ring; the nitrogen-containing heterocycle contains 1-3 heteroatoms selected from N, O or S; said nitrogen-containing heterocycle being optionally substituted with 1-3R4Substitution;
R3independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino and (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, (C)1-C4) An acyl group;
R4independently selected from hydrogen, hydroxy, carboxy, amino, carbamoyl, (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alcoxyl formyl group and hydroxyl group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) An alkyl group;
x is selected from N or CH;
y is selected from N or CR5；
R5Selected from hydrogen, (C)1-C4) An alkyl group;
z is CR6；
R6Selected from hydrogen or
Figure FDA0003506577590000015
Rc、RdIndependently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoylRadical (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl may optionally be substituted with 1-3R7Substitution;
or Rc、RdAnd the nitrogen atom to which they are attached form a 3-to 7-membered nitrogen-containing heterocyclic ring; the nitrogen-containing heterocycle contains 1-3 heteroatoms selected from N, O or S; said nitrogen-containing heterocycle being optionally substituted with 1-3R8Substituted, the ring carbon atoms may be oxo;
R7independently selected from hydrogen, halogen, hydroxyl, carboxyl, amino and (C)1-C4) Alkyl, hydroxy (C)1-C4) Alkyl, (C)1-C4) Alkoxy (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, (C)1-C4) An acyl group;
R8independently selected from hydrogen, hydroxy, carboxy, amino, carbamoyl, (C)1-C4) Alkyl, (C)1-C4) Alkoxy group, (C)1-C4) Alcoxyl formyl group and hydroxyl group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) An alkyl group;
q is selected from S.
2. Indoline compounds of general formula i according to claim 1, their stereoisomers and pharmaceutically acceptable salts thereof,
Ra、Rbindependently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl may optionally be substituted with 1-3R3Substitution;
or Ra、RbAnd the nitrogen atom to which they are attached form a 5-6 membered nitrogen containing heterocyclic ring containing 1-3 heteroatoms selected from N, O or S; said nitrogen-containing heterocycle being optionally substituted with 1-3R4And (4) substitution.
3. Indoline compounds of general formula i according to claim 1, their stereoisomers and pharmaceutically acceptable salts thereof,
Rc、Rdindependently selected from hydrogen, (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methylSulfonamide (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl; said (C)1-C4) Alkyl, (C)3-C8) Cycloalkyl, hydroxy (C)1-C4) Alkyl, amino (C)1-C4) Alkyl, carbamoyl (C)1-C4) Alkyl, aminosulfonyl (C)1-C4) Alkyl, methanesulfonamide group (C)1-C4) Alkyl, carboxyl (C)1-C4) Alkyl, (C)1-C4) Alkoxycarbonyl (C)1-C4) Alkyl, tetrahydropyran-4-yl may optionally be substituted with 1-3R7Substitution;
or Rc、RdAnd the nitrogen atom to which they are attached form a 5-6 membered nitrogen containing heterocyclic ring; the nitrogen-containing heterocycle contains 1-3 heteroatoms selected from N, O or S; said nitrogen-containing heterocycle being optionally substituted with 1-3R8The carbon atoms on the ring may be substituted by oxo.
4. Indoline compounds of general formula i according to claim 1, their stereoisomers and pharmaceutically acceptable salts thereof,
cy is selected from:
Figure FDA0003506577590000021
Figure FDA0003506577590000022
Figure FDA0003506577590000023
the Cy can be optionally substituted by 1-3R1Substitution;
R1independently selected from hydrogen, halogen, (C)1-C4) Alkyl, (C)1-C4) Alkoxy, cyano, hydroxy, carboxy, amino; said (C)1-C4) Alkyl, (C)1-C4) Alkoxy may optionally be substituted with 1-3R2Substitution;
R2independently selected from hydrogen, halogen, (C)1-C4) Alkyl, hydroxy, amino, carboxyl, or
Figure FDA0003506577590000024
5. Indolines of the general formula I and stereoisomers and pharmaceutically acceptable salts thereof according to any of claims 1-4, wherein,
Figure FDA0003506577590000025
selected from:
Figure FDA0003506577590000026
Figure FDA0003506577590000031
6. indolines of the general formula I and stereoisomers and pharmaceutically acceptable salts thereof according to any of claims 1-4, wherein,
Figure FDA0003506577590000032
selected from:
Figure FDA0003506577590000033
7. indoline compounds of general formula I according to claim 5, their stereoisomers and pharmaceutically acceptable salts thereof,
Figure FDA0003506577590000034
selected from:
Figure FDA0003506577590000035
8. indoline compounds and stereoisomers and pharmaceutically acceptable salts thereof as described below:
Figure FDA0003506577590000041
Figure FDA0003506577590000051
Figure FDA0003506577590000061
Figure FDA0003506577590000071
Figure FDA0003506577590000081
Figure FDA0003506577590000091
Figure FDA0003506577590000101
9. a pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 8 and stereoisomers thereof, and a pharmaceutically acceptable salt, carrier or excipient.
10. Use of a compound according to any one of claims 1 to 8, and stereoisomers and pharmaceutically acceptable salts thereof, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament for the prevention and/or treatment of diseases associated with the PD-1/PD-L1 signalling pathway.
11. The use according to claim 10, wherein the disease associated with the PD-1/PD-L1 signaling pathway is selected from the group consisting of cancer, infectious disease, autoimmune disease.
12. The use according to claim 11, wherein the cancer is selected from the group consisting of liver cancer, lung cancer, skin cancer, hematological tumors, glioma, digestive system tumors, breast cancer, lymphoma, nervous system tumors, melanoma; the infectious diseases are selected from bacterial infection and viral infection; the autoimmune disease is selected from organ specific and systemic autoimmune diseases.
13. The use according to claim 12, wherein the organ-specific autoimmune disease is selected from chronic lymphocytic thyroiditis, hyperthyroidism, insulin dependent diabetes mellitus, ulcerative colitis, acute idiopathic polyneuritis, and the systemic autoimmune disease is selected from rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, autoimmune hemolytic anemia.
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