A method of treatment of a cancer by antagonizing prostaglandin 2 receptors EP2 and/or EP4, wherein said cancer is selected from melanoma, lung cancer, bladder cancer, renal carcinomas, gastro-intestinal cancers, endometrial cancer, ovarian cancer, cervical cancer, neuroblastoma, and prostate cancer;
- wherein said cancer is treated by modulating an immune response comprising a reactivation of the immune system in the tumor;
- comprising administering to a subject in need thereof an effective amount of a compound of formula (I)
- or of a pharmaceutically acceptable salt thereof;
- and optionally administering one or more chemotherapy agents and/or radiotherapy and/or targeted therapy;
- wherein in the compounds of the formula (I)
- ring (A) in the fragment:
- represents an aromatic 5- or 6-membered ring or a non-aromatic 5- or 6-membered ring, which ring (A) is fused to the phenyl group, wherein independently 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 amino;
- R3 represents hydrogen, methyl or trifluoromethyl;
- R4a and R4b independently represent hydrogen, methyl, or R4a and R4b together with the carbon atom to which they are attached represent a cycloprop-1,1-diyl group;
- R5a and R5b independently represent hydrogen, methyl, or R5a and R5b together with the carbon atom to which they are attached represent a cycloprop-1,1-diyl group;
- Ar1 represents
- phenyl, or a 5- or 6-membered heteroaryl;
- wherein said phenyl or 5- or 6-membered heteroaryl independently is mono-, di- or tri-substituted, wherein the substituents are independently selected from
- (C1-6)alkyl;
- (C1-4)alkoxy;
- (C1-3)fluoroalkyl, wherein said (C1-3)fluoroalkyl is optionally substituted with hydroxy;
- (C1-3)fluoroalkoxy;
- halogen;
- cyano;
- (C3-6)cycloalkyl, wherein said (C3-6) cycloalkyl is unsubstituted or mono-substituted with amino;
- (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;
- (C3-6)cycloalkyl-oxy;
- 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—, —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-;
- —CO—CH2—OH;
- 2-hydroxy-3,4-dioxo-cyclobut-1-enyl;
- hydroxy-(C1-4)alkyl;
- dihydroxy-(C2-4)alkyl;
- hydroxy-(C2-4)alkoxy;
- (C1-4)alkoxy-(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;
- —X2NRN1RN2, wherein X2 represents —(CH2)m—, wherein m represents the integer 0 or 1;
- 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, (C1-4)alkoxy-(C2-4)alkyl, (C3-6)cycloalkyl, or (C2-3)fluoroalkyl;
- or RN1 independently represents hydrogen or (C1-4)alkyl, and RN2 independently represents —CO—H, —CO—(C1-3)alkyl, —CO—(C1-3)alkylene-OH, or —CO—O—(C1-3)alkyl;
- or RN1 and RN2 together with the nitrogen to which they are attached form a 4-, 5- or 6-membered saturated ring optionally containing one ring oxygen or ring sulfur atom, wherein said ring is unsubstituted, or mono-substituted with oxo on a ring carbon atom, or disubstituted with oxo on a ring sulfur atom;
- —NH—CO—NRN5RN6 wherein RN5 and RN6 independently represent hydrogen or (C1-4)alkyl;
- —SO2—RS1 wherein RS1 represents hydroxy, (C1-4)alkyl, or —NRN7RN8 wherein RN7 and RN8 independently represent hydrogen or (C1-3)alkyl;
- —S—RS2 wherein RS2 represents (C1-4)alkyl or (C3-6)cycloalkyl optionally containing one ring oxygen atom;
- —(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;
- and
- —(CH2)p—HET, wherein p represents the integer 0 or 1;
- and wherein HET represents a 5- or 6-membered heteroaryl, wherein said 5- or 6-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, and —NRN9RN10 wherein RN9 and RN″ independently represent hydrogen, (C1-3)alkyl, or hydroxy-(C2-4)alkyl;
- or Ar1 represents an 8- to 10-membered bicyclic heteroaryl;
- wherein said 8- to 10-membered bicyclic heteroaryl independently is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from (C1-4)alkyl;
- (C1-4)alkoxy;
- (C1-3)fluoroalkyl;
- (C1-3)fluoroalkoxy;
- halogen;
- cyano;
- hydroxy, and —(C0-3)alkylene-COORO2 wherein RO2 represents hydrogen or (C1-4)alkyl;
- or Ar′ represents a group of the structure (Ar-III):
- wherein ring (B) represents a non-aromatic 5- or 6-membered ring fused to the phenyl group, wherein ring (B) comprises one or two heteroatoms independently selected from nitrogen and oxygen;
- wherein said ring (B) independently is unsubstituted, mono-, or di-substituted, wherein the substituents are independently selected from oxo, (C1-6)alkyl and —(C0-3)alkylene-COORO3 wherein RO3 represents hydrogen or (C1-3)alkyl.