JAK kinase inhibitor, preparation method for same, and applications thereof in field of medicine
Related are a JAK kinase inhibitor, a preparation method for same, and applications thereof in the field of medicine, related to the field of medicinal chemistry. Provided is a novel small molecule JAK inhibitor, which has the structure as represented by formula (II). The compound provides improved efficacy and safeness in preventing or treating a JAK-related indication.
1. A compound of formula (II), tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof,
wherein,
T is —CN;
R 0 is hydrogen or C 1-3 alkyl;
R 1 is
R 2 is —C(O)R 4 , —C(O)NR 5 R 6 , or —S(O) 2 R 4 ;
R 3 is —H or —C 1-4 alkyl, wherein the —C 1-4 alkyl is optionally substituted by the following groups: —OH, —C 1-3 alkyl, —O—C 1-4 alkyl, —NH 2 , halogen, phenyl or cyano;
R 4 is —C 1-5 alkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, wherein the —C 1-5 alkyl is optionally substituted by the following groups: —OH, —C 1-3 alkyl, —C 5-6 cycloalkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —O—C 1-4 alkyl, —NH 2 , halogen, CF 3 , phenyl or cyano;
wherein the phenyl of R 4 is optionally substituted by R e ;
R 5 is hydrogen or —C 1-3 alkyl;
R 6 is —C 1-4 alkyl, —C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, phenyl,
—CHF 2 or —CH 2 CF 2 CF 3 , wherein the —C 1-4 alkyl is optionally substituted by the following groups: —OH, —C 1-3 alkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —O—C 1-4 alkyl, —NH 2 , halogen, CF 3 , phenyl or cyano; wherein phenyl is optionally substituted by R e or R g , or R e and R g ;
R e and R g are each independently halogen, —C 1-4 alkyl, alkoxy, 3- to 6-membered cycloalkyl, —NR c R d , —(CH 2 ) n —OH, —(CH 2 ) n —CF 3 , or —(CH 2 ) n —CN, wherein the —C 1-4 alkyl, alkoxy or cycloalkyl is optionally monosubstituted or disubstituted by the following groups: halogen, —OH, —NH 2 , —C 1-3 alkyl, —O—C 1-4 alkyl, CF 3 , phenyl or cyano;
R f is —C 1-4 alkyl or 3- to 6-membered cycloalkyl, wherein the —C 1-4 alkyl or cycloalkyl is optionally substituted by the following substituents: halogen, —OH, —NH 2 , —C 1-3 alkyl, —O—C 1-4 alkyl, CF 3 , phenyl or cyano;
R c and R d are each independently hydrogen, —C 1-3 alkyl, —C 1-4 alkylene-OH, —C 1-4 alkylene-CF 3 , —C 2-4 alkylene-OCH 3 , 3- to 6-membered cycloalkyl or 4- to 6-membered heterocyclyl; and
n is 0, 1, 2, 3 or 4.
2. The compound or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof according to claim 1 , wherein
R 4 is —C 1-5 alkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, or phenyl, wherein the —C 1-5 alkyl is optionally substituted by the following groups: —OH, —C 1-3 alkyl, —O—C 1-4 alkyl, —NH 2 , halogen, CF 3 , phenyl or cyano;
wherein the phenyl of R 4 is optionally substituted by R e ;
R 6 is —C 1-4 alkyl, —C 3-6 cycloalkyl, 4- to 6-membered heterocyclyl, or phenyl, wherein the phenyl is optionally substituted by R e or R g , or R e and R g ; wherein the —C 1-4 alkyl is optionally substituted by the following groups: —OH, —C 1-3 alkyl, 4- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl, —O—C 1-4 alkyl, —NH 2 , halogen, CF 3 , phenyl or cyano; and
R f is —C 1-4 alkyl or 3- to 6-membered cycloalkyl, wherein the —C 1-4 alkyl or cycloalkyl is optionally substituted by the following substituents: halogen, —OH, or —C 1-3 alkyl.
3. The compound or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof according to claim 1 , wherein
R 6 is —(CH 2 ) n —CH 2 CF 3 , —(CH 2 ) n —CF 2 CF 3 , —(CH 2 ) n —CH 2 CN, 4- to 6-membered heterocyclyl or phenyl, wherein the phenyl is optionally substituted by R e or R g , or R e and R g ;
R f is —C 1-4 alkyl, wherein the —C 1-4 alkyl is optionally substituted by halogen or —OH; and
Rc and Rd are each independently hydrogen, —C1-3 alkyl, —C1-4 alkylene-OH or —C2-4 alkylene-OCH3; n is 0, 1, 2 or 3.
4. The compound or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof according to claim 3 , wherein
R 3 is H, —CH 3 , or —CH 2 CH 3 ;
R 4 is methyl, ethyl, propyl, —(CH 2 ) n —CH 2 CN, —(CH 2 ) n —CH 2 CF 3 , —CH(OH)—(CH 2 ) n —CH 3 ,
R 5 is H;
R 6 is —(CH 2 ) n —CH 2 CF 3 , —(CH 2 ) n —CF 2 CF 3 , —(CH 2 ) n —CH 2 CN,
R e and R g are each independently —F, —Cl, methyl, ethyl, propyl, —CH(CH 3 )—(CH 2 ) n CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )CH(CH 3 ) 2 , —CH 2 C(CH 3 ) 3 , —C(CH 3 ) 2 —(CH 2 ) n CH 3 , —O—(CH 2 ) n CH 3 , —O—(CH 2 ) n CH 2 —O—CH 3 , —(CH 2 ) n OCH 3 , —O—(CH 2 ) n —CH 2 —C(CH 3 ) 2 —OH, —O—(CH 2 ) n —CH 2 —C(CH 3 ) 2 —NH 2 , C 3-6 cycloalkyl, —(CH 2 ) n —OH, —(CH 2 ) n —CF 3 , —(CH 2 ) n —CHF 2 , or —(CH 2 ) n —CN;
R f is methyl, ethyl or propyl;
R c and R d are each independently —H, methyl, ethyl or propyl; and
n is 0 or 1.
5. The compound or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof according to claim 1 , wherein the compound is:
6. The compound or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof according to claim 1 , wherein the pharmaceutically acceptable salts are acid addition salts, alkali addition salts, inner salts or betaines.
7. A pharmaceutical composition, comprising a therapeutically effective amount of the compound or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof according to claim 1 , and optionally one or more pharmaceutically acceptable carriers and excipients, wherein the pharmaceutical composition also comprises additional one or more agents, anticarcinogens or anti-inflammatory agents that regulate immune systems of mammals.
8. A method for preparing the compound of formula (II) or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof according to claim 1 , wherein the compound of formula (II) is prepared by:
or
wherein, Pg 1 is an aliphatic amine protecting group, and A1 is
R 2 —X is an active form of R 2 , and X is selected from the group consisting of bromine, chloride, phenoxyl and p-nitrophenoxy, or R 2 —X is isocyanate form of R 2 ; alkali 1, alkali 2 and alkali 3 are each independently selected from the group consisting of triethylamine, diisopropyl ethylamine, potassium carbonate, cesium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide.
9. The method according to claim 8 , wherein Pg 1 is tert-butoxycarbonyl or benzyloxycarbonyl.
10. A method for preventing and/or treating JAK-mediated diseases, comprising administering the compound or tautomers, mesomers, racemates, enantiomers, diastereoisomers, or mixtures thereof, pharmaceutically acceptable salts, polymorphs, solvates, or isotope derivatives thereof according to claim 1 , optionally in combination with additional one or more agents, anticarcinogen or anti-inflammatory agents that regulate immune systems of mammals to a subject.
11. The method according to claim 10 , wherein the JAK-mediated diseases is selected from immune system diseases; autoimmune diseases; dermatosis; allergic diseases; viral diseases; type 1 diabetes and diabetic complication; alzheimer disease; xerophthalmia; myelofibrosis; thrombocytosis; polycythemia or leukemia; cancers; inflammatory bowel disease; myelodysplastic syndrome; and myeloma.
12. The method according to claim 11 , wherein the immune system disease is allograft rejection or graft-versus-host disease.
13. The method according to claim 11 , wherein the autoimmune disease is lupus, multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriasis, ulcerative colitis, Crohn's disease, or an autoimmune thyroid disease.
14. The method according to claim 11 , wherein the dermatosis is psora, skin rash, or atopic dermatitis.
15. The method according to claim 11 , wherein the allergic disease is allergies, asthma, or rhinitis.
16. The method according to claim 11 , wherein the viral disease is hepatitis B, hepatitis C, or varicella-zoster virus.
17. The method according to claim 11 , wherein the cancer is solid tumor, hematologic malignancy, or skin cancer.
18. The method according to claim 17 , wherein the solid tumor is prostate cancer, renal carcinoma, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head-neck carcinoma, thyroid cancer, glioblastoma, or melanoma.
19. The method according to claim 17 , wherein the hematologic malignancy is lymphoma or leukemia.
20. The method according to claim 17 , wherein the skin cancer is cutaneous T-cell lymphoma or cutaneous B-cell lymphoma.