JPWO2021044413A5 - - Google Patents

Claims (27)

A compound of general formula I,

A compound of formula I, or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof, wherein Y is N, CH or N(→O),
A is a moiety of formula II that is attached to any carbon atom of the pyridine, phenyl, or pyridine oxide ring through a terminal NH group of formula II;

R ₁ is each independently 1, 2 or 3 substituents of the formula -CON(R ₄ ) ₂ ;
R ₂ is H, -OH, -O-(C ₁ -C ₈ )alkyl, -CO-(C ₁ -C ₈ )alkyl, -COO-(C ₁ -C ₈ )alkyl, -CN, -CONH ₂ or -NH ₂ ,
R ₃ is (C _{1 -C 12} )alkyl, (C ₃ -C ₁₀ )cycloalkyl, optionally substituted with (C 6 -C ₁₀ )aryl, or 6-10 membered heteroaryl, 3 ~7-membered ring heterocyclyl, (C ₆ - C ₁₀ ) aryl, or 5- to 10-membered heteroaryl,
One of R ₄ is H, and the other one of R ₄ is -OR ₅ , -OSO ₃ ^- , -OPO ₃ ^2- , -OCF ₃ , -CF ₃ , -OCOR ₅ , -COR ₅ , - COOR ₅ , -OCOOR ₅ , -OCON(R ₅ ) ₂ , -(C ₁ -C ₈ )alkylene-COOR ₅ , -CN, -NO ₂ , -ONO ₂ , -SR ₅ , -N(R ₅ ) ₂ , -CON(R ₅ ) ₂ , -SO ₂ R ₅ , -S(=O)R ₅ , or glucuronic acid bonded via the hydroxyl or carboxyl group of glucuronic acid ( C ₁ -C ₈ )alkyl optionally substituted with one or more groups, and R ₅ is each independently H, (C ₁ -C 8 )alkyl, (C ₂ -C ₈ )alkyl; ₈ ) selected from alkenyl or (C ₂ -C ₈ )alkynyl,
A compound or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof. (i) Y is N, and A is bonded to the 2-, 3-, or 4-position of the pyridine ring, and (ii) Y is CH, and A is bonded to any position of the phenyl ring. or (iii) Y is N(→O) and A is bonded to the 2-position, 3-position or 4-position of the 1-oxypyridine ring. One of R ₄ is H, and the other one of R ₄ is -CH ₂ OH, -(CH ₂ ) ₂ -OH, -(CH ₂ ) ₃ -OH, or -(CH ₂ ) ₄ -OH The compound according to claim 1 or 2 , which is _3. A compound according to claim 1 or 2, wherein R2 is -CN . R ₃ is (C ₆ to C ₁₀ ) aryl or 6 to 10-membered heteroaryl, or (C ₃ to
3. A compound according to claim 1 or 2, which is (C ₁ -C ₁₂ )alkyl optionally substituted with C ₁₀ )cycloalkyl. 6. A compound according to claim 5 , wherein R ₃ is branched (C ₄ -C ₈ ) alkyl such as -C(CH ₃ ) ₂ CH ₂ CH ₃ (2-methylbutyl-2-yl). 3. A compound according to claim 1 or 2, wherein R ₅ is each independently H or (C ₁ -C ₈ )alkyl. Y is N, A is bonded to the 2-position, 3-position or 4-position of the pyridine ring, and each R ₁ is independently one , two or three substituents of the formula -CON(R ₄ ) ₂ , one of R ₄ is H, and the other one of R ₄ is -OR ₅ , -OSO ₃ ^- , -OPO ₃ ^2- , -COOR ₅ , -OCON(R ₅ ) ₂ , -NO ₂ , -ONO ₂ , -N(R ₅ ) ₂ , -CON(R ₅ ) ₂ , or 1 each independently selected from glucuronic acid bonded via the hydroxyl or carboxyl group of glucuronic acid (C ₁ -C ₈ )alkyl optionally substituted with one or more groups, R ₂ is -CN, and R ₃ is (C ₆ -C ₁₀ )aryl or 6-10 membered heterocyclic ring. aryl or (C ₁ -C ₁₂ )alkyl optionally substituted with (C ₃ -C ₁₀ )cycloalkyl, and each R ₅ is independently H, or (C ₁ -C ₈ )alkyl. 2. A compound according to claim 1, which is. One of R ₄ is H, and the other one of R ₄ is -CH ₂ OH, -(CH ₂ ) ₂ -OH, -(CH ₂ ) ₃ -OH, or -(CH ₂ ) ₄ -OH 9. A compound according to claim 8 , wherein R ₃ is branched (C ₄ -C ₈ ) alkyl. 10. A compound according to claim 9 , wherein R ₃ is 2-methylbutyl-2-yl. (i) A is attached to the 2-position of the pyridine ring, and R ₁ is attached to the group A in the ortho, meta, or para position; (ii) A is attached to the 3-position of the pyridine ring; and R ₁ is bonded to the group A in the ortho, meta, or para position, or (iii) A is bonded to the 4-position of the pyridine ring, and R ₁ is bonded to the group A in the ortho or meta position. A compound according to claim 9 or 10 . One of R ₄ is H, the other one of R ₄ is -CH ₂ CH ₂ OH, R ₃ is 2-methylbutyl-2-yl, and (i) A is and R ₁ is attached to the 3-, 4-, 5-, or 6-position of the pyridine ring, referred to herein as compounds 101, 102, 103, and 104, respectively;
(ii) A is attached to the 3-position of said pyridine ring, and R ₁ is attached to the 2-position, 4-position, 5-position, or 6-position of said pyridine ring, as herein defined in compounds 105, 106, respectively; 107, and 108, or (iii) A is attached to the 4-position of the pyridine ring, and R ₁ is attached to the 2- or 3-position of the pyridine ring, herein referred to as compounds 109 and 108, respectively. Referred to as 110,
12. The compound according to claim 11 . 13. A compound according to claim 12 , wherein A is attached to the 3-position of the pyridine ring and _R1 is attached to the 5-position of the pyridine ring. Y is CH, A is bonded to any position on the phenyl ring, each R ₁ is independently one , two or three substituents of the formula -CON(R ₄ ) ₂ , R One of ₄ is H, and the other one of R ₄ is -OR ₅ , -OSO ₃ ^- , -OPO ₃ ^2- , -COOR ₅ , -OCON(R ₅ ) ₂ , -NO ₂ , -ONO ₂ , -N(R ₅ ) ₂ , -CON(R ₅ ) ₂ , or one or more groups each independently selected from glucuronic acid bonded via a hydroxyl or carboxyl group of glucuronic acid (C ₁ -C ₈ )alkyl optionally substituted with (C 1 -C 8 )alkyl, R ₂ is -CN, and R ₃ is (C ₆ -C ₁₀ )aryl or 6-10 membered heteroaryl or (C ₃ -C ₁₀ ) cycloalkyl _, and each R ₅ is independently H, or (C _{1 -C 8} )alkyl. Compounds described in. R ₁ is -CON(R ₄ ) ₂ , one of R ₄ is H, and the other one of R ₄ is -CH ₂ OH, -(CH ₂ ) ₂ -OH, -(CH ₂ ) ₃ -OH, or -(CH ₂ ) ₄ -OH, and R ₃ is branched (C ₄ -C ₈ ) alkyl. 16. A compound according to claim 15 , wherein R ₃ is 2-methylbutyl-2-yl. 17. A compound according to claim 15 or 16 , wherein _R1 is attached to the group A in the ortho, meta, or para position, referred to herein as 111, 112, and 113, respectively. Y is N(→O), A is bonded to the pyridine oxide ring at the 2-, 3-, or 4-position, and each R ₁ is independently one of the formula -CON(R ₄ ) ₂ , 2 or 3 substituents, one of R ₄ is H, and the other one of R ₄ is -OR ₅ , -OSO ₃ ^- , -OPO ₃ ^2- , -COOR ₅ , -OCON( R ₅ ) ₂ , -NO ₂ , -ONO ₂ , -N(R ₅ ) ₂ , -CON(R ₅ ) ₂ , or each independently from glucuronic acid bonded via the hydroxyl group or carboxyl group of glucuronic acid _{( C 1} -C _{8 )} alkyl optionally substituted with _one or more groups selected from is (C ₁ -C ₁₂ )alkyl optionally substituted with 6-10 membered heteroaryl or (C ₃ -C ₁₀ )cycloalkyl, and R ₅ is each independently H, or (C ₁ The compound according to claim 1, which is -C ₈ )alkyl. R ₁ is -CON(R ₄ ) ₂ , one of R ₄ is H, and the other one of R ₄ is -CH ₂ OH, -(CH ₂ ) ₂ -OH, -(CH ₂ ) 19. The compound of claim 18 , wherein ₃ -OH, or -( _CH2 ) ₄ -OH, and _R3 is branched ( _C4 - _C8 ) alkyl. 20. A compound according to claim 19 , wherein R ₃ is 2-methylbutyl-2-yl. (i) A is attached to the pyridine oxide ring at the 2-position, and R ₁ is attached to the group A at the ortho, meta, or para position, as herein used in compounds 114, 115, 116, and 117, respectively. It is called,
(ii) A is attached to the pyridine oxide ring at the 3-position and R ₁ is attached to the group A at the ortho, meta, or para position, as herein used in compounds 118, 119, 120, and 121, respectively. or (iii) A is attached to the pyridine oxide ring in the 4-position and R ₁ is attached to the group A in the ortho or meta position, herein referred to as compounds 122 and 123, respectively. Ru,
A compound according to claim 19 or 20 . 2. A pharmaceutical composition comprising a compound according to any one of claims 1 to 1 , or an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. . Claim 2 Formulated for intravenous administration, intraarterial administration, intramuscular administration, intranasal administration, rectal administration, anal administration, intravaginal administration, intratracheal administration, intraperitoneal administration, or subcutaneous administration and inhalation. Pharmaceutical compositions as described. A compound according to any one of claims 1 to 21, an enantiomer, diastereomer, racemate thereof, for the prevention, treatment or management of pulmonary hypertension (pulmonary arterial hypertension or pulmonary venous pulmonary hypertension). or a pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 22 or 23. The pulmonary hypertension includes pulmonary arterial hypertension, pulmonary hypertension related to left heart disease, pulmonary hypertension related to pulmonary disease and/or hypoxemia, pulmonary hypertension due to chronic thrombotic disease and/or chronic embolic disease. A compound according to claim 24 , an enantiomer, diastereomer, racemate, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition selected from pulmonary hypertension, pulmonary hypertension, and pulmonary hypertension of other causes. A compound according to claim 24 for the prevention or management of acute, severe, perioperative pulmonary hypertension in a subject with a congenital heart defect undergoing surgical correction of a left-right cardiac shunt. Enantiomers, diastereomers, racemates, or pharmaceutically acceptable salts, or pharmaceutical compositions. A compound according to any one of claims 1 to 21 for the preparation of a pharmaceutical composition for the prevention, treatment or management of pulmonary hypertension (pulmonary arterial hypertension or pulmonary venous pulmonary hypertension). , or the use of its enantiomers, diastereomers, racemates, or pharmaceutically acceptable salts.