AROMATIC ACETYLENE OR AROMATIC ETHYLENE COMPOUND, INTERMEDIATE, PREPARATION METHOD, PHARMACEUTICAL COMPOSITION AND USE THEREOF

• US 20190308957A1
• Filed: 07/04/2017
• Published: 10/10/2019
• Est. Priority Date: 07/05/2016
• Status: Active Grant

• Current Assignee: Guangzhou Maxinovel Pharmaceuticals Co., Ltd.
• Original Assignee: Guangzhou Maxinovel Pharmaceuticals Co., Ltd.
• Inventors: WANG, Yuguang, XU, Zusheng, WU, Tianzhi, HE, Min, ZHANG, Nong
• Granted Patent: US 11,078,192 B2
• Time in Patent Office: Days
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07B 2200/07 Optical isomers
• CPC Class Codes: C07C 215/10 with one amino group and at least two hydroxy groups bound to the carbon skeleton
• CPC Class Codes: C07C 217/58 with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
• CPC Class Codes: C07C 22/04 containing six-membered aromatic rings
• CPC Class Codes: C07C 22/08 containing fluorine
• CPC Class Codes: C07C 229/22 the carbon skeleton being further substituted by oxygen atoms
• CPC Class Codes: C07C 229/24 having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
• CPC Class Codes: C07C 229/64 the carbon skeleton being further substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 233/18 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 235/84 with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/30 having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 25/24 Halogenated aromatic hydrocarbons with unsaturated side chains
• CPC Class Codes: C07C 255/56 containing cyano groups and doubly-bound oxygen atoms bound to the carbon skeleton
• CPC Class Codes: C07C 43/225 containing halogen
• CPC Class Codes: C07C 47/548 having unsaturation outside the six-membered aromatic rings
• CPC Class Codes: C07C 47/55 containing halogen
• CPC Class Codes: C07C 47/575 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 69/94 of polycyclic hydroxy carboxylic acids, the hydroxy groups and the carboxyl groups of which are bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07D 207/08 with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 211/60 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 213/38 : having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
• CPC Class Codes: C07D 213/48 : Aldehydo radicals
• CPC Class Codes: C07D 231/10 : having two or three double bonds between ring members or between ring members and non-ring members
• CPC Class Codes: C07D 231/12 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 319/18 : Ethylenedioxybenzenes, not substituted on the hetero ring
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/10 : linked by a carbon chain containing aromatic rings

Abstract

Disclosed are an aromatic acetylene or aromatic ethylene compound, an intermediate, a preparation method, a pharmaceutical composition and a use thereof. The aromatic acetylene or aromatic ethylene compound has a significant inhibitory effect on PD-1 and PD-L1, and can effectively relieve or treat cancers and other related diseases.

Claims

1. An aromatic acetylene or aromatic ethylene compound represented by formula I, a pharmaceutically acceptable salt, a tautomer, a mesomer, a racemate, a stereoisomer, a metabolite, a metabolic precursor or a prodrug thereof:

2. The aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 1, wherein,

L is alkynyl or —

C(R⁴)═

C(R⁵)—

;

each of R² is independently hydrogen, deuterium, substituted or unsubstituted hydroxy, substituted or unsubstituted amino, halogen, substituted or unsubstituted alkyl, or, substituted or unsubstituted alkoxy;

in

3. The aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 1, wherein,

when the substituent in the substituted alkyl, the substituted alkoxy, the substituted cycloalkyl, the substituted carbocycle or the substituted heterocycle is halogen, the halogen is fluorine, chlorine, bromine or iodine;

or, when the substituent in the substituted hydroxy, the substituted amino, the substituted alkyl, the substituted alkoxy, the substituted cycloalkyl, the substituted carbocycle or the substituted heterocycle is C₁-C₄ alkyl, the C₁-C₄ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl;

or, when the substituent in the substituted alkyl, the substituted alkoxy, the substituted cycloalkyl, the substituted carbocycle or the substituted heterocycle is

4. The aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 1, wherein,

when the substituent in the substituted alkyl, the substituted alkoxy, the substituted cycloalkyl, the substituted carbocycle or the substituted heterocycle is

5. The aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 1, wherein,

in the definition of ring A or ring B, the aromatic ring is C₆-C₁₄ aromatic ring;

or, in the definition of ring A or ring B, the heteroaromatic ring is C₂-C₁₀ heteroaromatic ring having 1-4 heteroatoms selected from nitrogen, oxygen and sulfur;

or, the halogen is fluorine, chlorine, bromine or iodine;

or, the alkyl is C₁-C₄ alkyl; and

/or, the alkoxy is C₁-C₄ alkoxy; and

/or, the cycloalkyl is C₃-C₆ cycloalkyl; and

/or, the hydroxyalkyl is C₁-C₄ hydroxyalkyl; and

/or, the aminoalkyl is C₁-C₄ aminoalkyl; and

/or, the carbocycle is cyclopentane, cyclohexane or cycloheptane;

or, the heterocycle is preferably pyrrole ring or piperidine ring.

6. The aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 1, wherein,

in the definition of ring A or ring B, the aromatic ring is C₆-C₁₀ aromatic ring;

or, in the definition of ring A or ring B, the heteroaromatic ring is C₂-C₈ heteroaromatic ring having 1-3 heteroatoms selected from nitrogen and oxygen;

or, the alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl

or, the alkoxy is methoxy, ethoxy, n-propoxy, isopropoxy or tert-butoxy;

or, the cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

or, the hydroxyalkyl is

7. The aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 1, wherein,

in the definition of ring A or ring B, the aromatic ring is benzene ring;

or, in the definition of ring A or ring B, the heteroaromatic ring is

8. The aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 1, wherein,

in formula I, each of R¹ is independently hydrogen, deuterium, halogen, substituted or unsubstituted hydroxy, substituted or unsubstituted alkyl, or, substituted or unsubstituted alkoxy, the substituent in the substituted alkyl is substituted by one or more than one

9. The aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 1, wherein,

in formula I, each of R¹ is independently

10. The aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 1, wherein,

11. The aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 1, wherein, formula I is the compound represented by formula II-0, II-1, II-2, II-1-1, II-1-2, II-1-1A, II-1-2A, II-1-1B or II-1-2B;

12. The aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 1, wherein, the aromatic acetylene or aromatic ethylene compound represented by formula I is selected from

13. A process for preparing the aromatic acetylene or aromatic ethylene compound represented by formula I as defined in claim 1, wherein, when formula I is the compound represented by formula II-0, a process for preparing the compound represented by formula II-0 includes process 1 or process 2:

process 1 comprising conducting a reductive amination reaction of the compound represented by formula I-a with the compound represented by formula I-b as shown below in the presence of a reducing agent in a solvent to give the compound represented by formula II-0;

14. A compound represented by formula I-a or formula I-a1:

15. The compound represented by formula I-a or formula I-a1 as defined in claim 14, which is selected from

16. A process for preventing, alleviating or treating a cancer, an infection, an autoimmune disease or related disease in a subject in need thereof, comprising:

administering an effective amount of use of the aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 1 to the subject.

17. The process as defined in claim 16, wherein, the cancer is selected from the group consisting of lung cancer, esophageal cancer, gastric cancer, colon cancer, liver cancer, nasopharyngeal cancer, brain tumor, breast cancer, cervical cancer, blood cancer and bone cancer.

18. A use of the aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 1 in manufacturing a PD-1 inhibitor and/or a PD-L1 inhibitor.

19. A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 1, and a pharmaceutically acceptable carrier and/or diluent.

20. A process for preventing, alleviating or treating a cancer, an infection, an autoimmune disease or related disease in a subject in need thereof, comprising:

administering an effective amount of use of the aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 12 to the subject.

21. A pharmaceutical composition comprising a therapeutically and/or prophylactically effective amount of the aromatic acetylene or aromatic ethylene compound represented by formula I, the pharmaceutically acceptable salt, the tautomer, the mesomer, the racemate, the stereoisomer, the metabolite, the metabolic precursor or the prodrug thereof as defined in claim 12, and a pharmaceutically acceptable carrier and/or diluent.