US 11,839,613 B2
Pyrimidine derivatives as PGE2 receptor modulators
Christoph Boss, Allschwil (CH); Olivier Corminboeuf, Allschwil (CH); Heinz Fretz, Gunten (CH); Isabelle Lyothier, Allschwil (CH); Davide Pozzi, Allschwil (CH); Sylvia Richard-Bildstein, Allschwil (CH); Hervé Siendt, Allschwil (CH); and Thierry Sifferlen, Allschwil (CH)
Assigned to Idorsia Pharmaceuticals Ltd, Allschwil (CH)
Appl. No. 16/614,209
Filed by IDORSIA PHARMACEUTICALS LTD, Allschwil (CH)
PCT Filed May 17, 2018, PCT No. PCT/EP2018/062844
§ 371(c)(1), (2) Date Nov. 15, 2019,
PCT Pub. No. WO2018/210988, PCT Pub. Date Nov. 22, 2018.
Claims priority of application No. PCT/EP2017/061989 (WO), filed on May 18, 2017.
Prior Publication US 2021/0113559 A1, Apr. 22, 2021
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/506 (2006.01); A61K 45/06 (2006.01); C07D 409/12 (2006.01); C07D 409/14 (2006.01); C07D 239/26 (2006.01); A61K 31/505 (2006.01); C07D 405/14 (2006.01); C07D 405/12 (2006.01); C07D 413/14 (2006.01); C07D 401/14 (2006.01); A61K 31/5355 (2006.01); C07D 417/14 (2006.01); A61P 35/00 (2006.01); C07D 401/12 (2006.01); C07D 403/12 (2006.01); C07D 413/12 (2006.01)
CPC A61K 31/506 (2013.01) [A61K 31/505 (2013.01); A61K 31/5355 (2013.01); A61K 45/06 (2013.01); A61P 35/00 (2018.01); C07D 239/26 (2013.01); C07D 401/12 (2013.01); C07D 401/14 (2013.01); C07D 403/12 (2013.01); C07D 405/12 (2013.01); C07D 405/14 (2013.01); C07D 409/12 (2013.01); C07D 409/14 (2013.01); C07D 413/12 (2013.01); C07D 413/14 (2013.01); C07D 417/14 (2013.01)] 20 Claims
 
1. A compound of formula (II)

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wherein in compounds of the formula (II)
ring (A) in the fragment:

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represents an aromatic 5- or 6-membered ring or a non-aromatic 5- to 7-membered ring, which ring (A) is fused to the phenyl group, wherein said ring (A) optionally contains one or two heteroatoms independently selected from nitrogen, oxygen, and sulfur; wherein said fragment is optionally substituted with (R1)n; wherein (R1)n represents one, two, three, or four optional substituents, wherein said substituents R1 are independently selected from (C1-3)alkyl, (C2-3)alkenyl, (C2-3)alkynyl, (C1-3)alkoxy, halogen, —S—(C1-3)alkyl, (C1-3)fluoroalkyl, (C1-3)fluoroalkoxy, cyano, oxo, and —NRN7RN8 wherein RN7 and RN8 independently represent hydrogen or (C1-4)alkyl;
R3 represents hydrogen, or methyl;
Ar1 represents
a phenyl group of the structure (Ar-I):

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wherein
Rp represents
(C4-6)cycloalkyl containing a ring oxygen atom, wherein said (C4-6)cycloalkyl containing a ring oxygen atom is unsubstituted or mono-substituted with hydroxy;
hydroxy;
—X1—CO—RO1, wherein
 X1 represents a direct bond, (C1-3)alkylene, —O—(C1-3)alkylene-*, —NH—(C1-3)alkylene-*, —S—CH2—* , —CF2—, —CH═CH—, ethen-1,1-diyl, —C≡C—, —NH—CO—* , —CO—, or (C3-5)cycloalkylene; wherein the asterisks indicate the bond that is linked to the —CO—RO1 group; and
 RO1 represents
 —OH;
 —O—(C1-4)alkyl;
 —NH—SO2—RS3 wherein RS3 represents (C1-4)alkyl, (C3-6)cycloalkyl wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C3-6)cycloalkyl-(C1-3)alkylene wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C1-3)fluoroalkyl, or —NH2;
 —O—CH2—CO—RO4, wherein RO4 represents hydroxy, or (C1-4)alkoxy, or —N[(C1-4)alkyl]2;
 —O—CH2—O—CO—RO5, wherein RO5 represents (C1-4)alkyl or (C1-4)alkoxy;
 —O—CH2—CH2—N[(C1-4)alkyl]2; or
 (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;

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2-hydroxy-3,4-dioxo-cyclobut-1-enyl;
hydroxy-(C1-4)alkyl;
hydroxy-(C2-4)alkoxy;
—(CH2)r—CO—NRN3RN4 wherein r represents the integer 0 or 1; and wherein RN3 and RN4 independently represent hydrogen, (C1-4)alkyl, hydroxy-(C2-4)alkyl, (C1-3)alkoxy-(C2-4)alkyl, or hydroxy;
—NRN1RN2, wherein RN1 independently represents hydrogen or (C1-4)alkyl, and RN2 independently represents —CO—H, —CO—(C1-3)alkyl, or —CO—(C1-3)alkylene-OH;
—NH—CO—NRN5RN6 wherein RN5 and RN6 independently represent hydrogen or (C1-4)alkyl;
—SO2—RS1 wherein RS1 represents (C1-4)alkyl, or —NRN7RN8 wherein RN7 and RN8 independently represent hydrogen or (C1-3)alkyl;
—(CH2)q-HET1, wherein q represents the integer 0, 1 or 2; and wherein HET1 represents 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl, 3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl, or 5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl; or
—(CH2)p-HET, wherein p represents the integer 0 or 1; and wherein HET represents a 5-membered heteroaryl, wherein said 5-membered heteroaryl is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl, (C1-4)alkoxy, —COOH, hydroxy, hydroxy-(C1-3)alkyl, (C3-5)cycloalkyl optionally containing one ring oxygen atom, or —NRN9RN10 wherein RN9 and RN10 independently represent hydrogen, (C1-3)alkyl, or hydroxy-(C2-4)alkyl;
Rm1 represents
hydrogen;
(C1-6)alkyl;
(C1-4)alkoxy;
(C1-3)fluoroalkyl;
(C1-3)fluoroalkoxy;
halogen;
(C3-6)cycloalkyl;
(C3-6)cycloalkyl-oxy;
hydroxy;
hydroxy-(C2-4)alkoxy;
—X2—NRN1RN2, wherein X2 represents a direct bond; or X2 represents —O—CH2—CH2—* , wherein the asterisk indicates the bond that is linked to the —NRN1RN2 group; and wherein RN1 and RN2 independently represent hydrogen, (C1-4)alkyl, or (C3-6)cycloalkyl; or
—S—RS2 wherein RS2 represents (C1-4)alkyl, or (C3-6)cycloalkyl optionally containing one ring oxygen atom;
Rm2 represents hydrogen, methyl, fluoro, or chloro; and
Ro1 represents hydrogen; or, in case Rm2 represents hydrogen, Ro1 represents hydrogen or fluoro;
or Ar1 represents a 5-membered heteroaryl group of the structure (Ar-II):

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wherein
Y represents CR8 wherein R8 represents hydrogen or halogen; or Y represents N;
R7 represents
(C4-6)cycloalkyl containing a ring oxygen atom, wherein said (C4-6)cycloalkyl containing a ring oxygen atom is unsubstituted or mono-substituted with hydroxy;
—X1—CO—RO1, wherein
 X1 represents a direct bond, (C1-3)alkylene, —O—(C1-3)alkylene-*, —NH—(C1-3)alkylene-*, —S—CH2—* , —CF2—, —CH═CH—, —C≡C—, —NH—CO—* , —CO—, or (C3-5)cycloalkylene; wherein the asterisks indicate the bond that is linked to the —CO—RO1 group; and
 RO1 represents
 —OH;
 —O—(C1-4)alkyl;
 —NH—SO2—RS3 wherein RS3 represents (C1-4)alkyl, (C3-6)cycloalkyl wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C3-6)cycloalkyl-(C1-3)alkylene wherein the (C3-6)cycloalkyl optionally contains a ring oxygen atom, (C1-3)fluoroalkyl, or —NH2;
 —O—CH2—CO—RO4, wherein RO4 represents hydroxy, or (C1-4)alkoxy, or —N[(C1-4)alkyl]2;
 —O—CH2—O—CO—RO5, wherein RO5 represents (C1-4)alkyl or (C1-4)alkoxy;
 —O—CH2—CH2—N[(C1-4)alkyl]2; or
 (5-methyl-2-oxo-[1,3]dioxol-4-yl)-methyloxy-;

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2-hydroxy-3,4-dioxo-cyclobut-1-enyl;
hydroxy-(C1-4)alkyl;
hydroxy-(C2-4)alkoxy;
—(CH2)r—CO—NRN3RN4 wherein r represents the integer 0 or 1; and wherein RN3 and RN4 independently represent hydrogen, (C1-4)alkyl, hydroxy-(C2-4)alkyl, (C1-3)alkoxy-(C2-4)alkyl, or hydroxy;
—NRN1RN2, wherein RN1 independently represents hydrogen or (C1-4)alkyl, and RN2 independently represents —CO—H, —CO—(C1-3)alkyl, or —CO—(C1-3)alkylene-OH;
—NH—CO—NRN5RN6 wherein RN5 and RN6 independently represent hydrogen or (C1-4)alkyl;
—SO2—RS1 wherein RSI represents (C1-4)alkyl, or —NRN7RN8 wherein RN7 and RN8 independently represent hydrogen or (C1-3)alkyl;
—(CH2)q-HET1, wherein q represents the integer 0, 1 or 2; and wherein HET1 represents 5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl, 3-oxo-2,3-dihydro-[1,2,4]oxadiazol-5-yl, or 5-thioxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl; or
—(CH2)p-HET, wherein p represents the integer 0 or 1; and wherein HET represents a 5-membered heteroaryl, wherein said 5-membered heteroaryl is unsubstituted, or mono- or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl, (C1-4)alkoxy, —COOH, hydroxy, hydroxy-(C1-3)alkyl, (C3-5)cycloalkyl optionally containing one ring oxygen atom, or —NRN9RN10 wherein RN9 and RN10 independently represent hydrogen, (C1-3)alkyl, or hydroxy-(C2-4)alkyl;
R6 represents
(C1-6)alkyl;
(C1-4)alkoxy;
(C1-3)fluoroalkyl;
(C1-3)fluoroalkoxy;
halogen;
hydroxy;
(C3-6)cycloalkyl;
(C3-6)cycloalkyl-oxy;
hydroxy-(C2-4)alkoxy;
—X2—NRN1RN2, wherein X2 represents a direct bond; or X2 represents-O—CH2—CH2—* , wherein the asterisk indicates the bond that is linked to the —NRN1RN2 group; and wherein RN1 and RN2 independently represent hydrogen, (C1-4)alkyl, or (C3-6)cycloalkyl; or
—S—RS2 wherein RS2 represents (C1-4)alkyl, or (C3-6)cycloalkyl optionally containing one ring oxygen atom;
or Ar1 represents 8- to 10-membered bicyclic heteroaryl; wherein said 8- to 10-membered bicyclic heteroaryl independently is mono-substituted with —(C0-3)alkylene-COORO2 wherein RO2 represents hydrogen or (C1-4)alkyl;
or Ar1 represents a group of the structure (Ar-III):

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which is selected from 2-oxo-2,3-dihydro-benzooxazol-6-yl, 3-methyl-2-oxo-2,3-dihydro-benzooxazol-5-yl, 1-methyl-3-oxo-2,3-dihydro-1H-indazol-6-yl, 2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl, 1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-6-yl, 1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl, 1-methyl-2-oxo-1,2,3,4-tetrahydro-quinazolin-7-yl, and 1-oxo-1,2,3,4-tetrahydro-isoquinolin-7-yl;
or a pharmaceutically acceptable salt thereof.