Carboxamide compounds as pge2 receptor antagonists

A compound of Formula I or a pharmaceutically acceptable salt thereof:

• wherein:
• R1 represents —CO2H, —C(O)NHS(O)2R7, —NHC(O)NHSO2R7, -1H-tetrazolyl, —P(O)(OH)2, -1,2,4-oxadiazol-5(4H) -one or -tetrazol-5(4H)-one;
• Y is N, CR3 or
• is a bond;
• when Y is CR3,
• includes both R and S configurations;
• R2, R3 are independently selected from the group consisting of:
• hydrogen, C1-6alkyl, C3-6cyclolkyl, C1-6fluorocycloalkyl, C1-6fluoroalkyl, or R2, R3, together with the carbon atom to which they are both attached to, complete a three- to six-membered carbocyclic ring which is optionally substituted with Rc or a three- to six-membered ring which contains one or two heteroatom(s) such as S, O or NRb, wherein Rb is selected from the group consisting of hydrogen, C1-6alkyl, C3-6cyclolkyl, C3-6fluorocycloalkyl, C1-6fluoroalkyl, C0-6alkylene-aryl, C0-6alkylene-heteroaryl, C(O) C1-6alkyl, C(O)aryl, S(0)2C1-6alkyl, S(0)2C3-6cycloalkyl or S(O)2aryl;
• X is absent or is independently halogen, —CN, C1-6alkyl, OC1-6alkyl, C1-6haloalkyl C3-6cycloalkyl or OC1-6haloalkyl;
• is selected from the following structures:
• Z is O, S or NR8;
• X1 is N or CR4;
• X2, X3 are independently N, CR4 or a carbon atom which is connected with —Y2—Ar2 with a proviso that at least one of X2 or X3 is a carbon atom which is connected with —Y2—Ar2;
• X4 is O, S, N, NR5 or CR5;
• X5 is O, S, N, CR6 or —C(O)—;
• X6, X7 and X8 are independently N or C;
• Y2 is —C(O)—, —(CRaR1a)n—, —CH═CH, —C≡C—, —O—, —S—, S(O)2—, —S(O)2NRb—, —NRbS(O)2—, —C(O)NRb—, —NRbC(O)—, NRbC(O)NRb—, NRbS(O)2NRb—, —NRb— or Y2 is absent and Ar2 is directly connected X2 or X3;
• Y1 is —O—, —S—, —NRb—, —C(O)—, or —CRaR1a—;
• Y3 is —(CRa2)m—;
• n and m are independently 0, 1, 2 or 3;
• r is 1 or 2;
• each Ra and R1a are independently hydrogen, halogen, C1-6alkyl or C1-6haloalkyl, or two Ra and R1a, together with the carbon atom to which they are attached to form a 3- to 6-menbered cycloalkyl or heterocyclyl;
• R4, R5, and R6 are each independently hydrogen, alkyl, halogen, —OR8, —NR8R9, —SR9, —S(O)2NR8R9, —S(O)2R11, —CN, C3-6cyclolkyl, —C0-6alkylene-aryl, —C0-6alkylene-heteroaryl or haloalkyl;
• Ar1 and Ar2 are independently selected from the group consisting of:
• —OR′, —SR′, NR′R9, C1-10alkyl, C1-10haloalkyl, —C0-6alkylene-C3-6cycloalkyl, —C0-6alkylene-aryl, —C0-6alkylene-heteroaryl and —C0-6alkylene-heterocyclyl, or a fused analog of C3-6cycloalkyl;
• wherein Ar1 and Ar2 are independently substituted with one to three Rc groups;
• two Ar2 on the adjacent carbon atoms together with carbon atoms can form a three- to six-membered carbocyclic ring, four- to eight-membered bicyclic ring, C5 to C10 aromatic ring which is optionally substituted with one or more Rc, C2 to C10 heteroaromatic ring which is unsubstituted or substituted with one or more Rc or a three- to six-membered carbocyclic ring, four- to eight-membered bicyclic ring or five- to eight-membered spirocyclic ring which contains one, two or three heteroatom(s) such as S, O or NRb;
• each Re is independently halogen, hydrogen, C1-6alkyl, C3-6cycloalkyl, C1-6fluorocycloalkyl, C1-6fluoroalkyl, —C2-C9alkynyl, —C0-6alkylene-heterocyclyl, —C0-6alkylene-aryl, —C0-6alkylene-heteroaryl, SF5, —C0-6alkylene-OR8, —C0-6alkylene-P(O)Me2, —C0-6alkylene-NR′R9, —C0-6alkylene-C(O)NR8R9, —C0-6alkylene-NR8(O)NR8R9, —C0-6alkylene-SR′, —C0-6alkylene-S(O)2NR8R9, —C0-6alkylene-S(O)2R10 or —C0-6alkylene-CN, wherein C1-6 alkyl, C2-9 alkenyl, C2-9 alkynyl, —C0-6alkylene-cycloalkyl, —C0-6alkylene-heterocyclyl, —C0-6alkylene-aryl, and —C0-6alkylene-heteroaryl;
• Rcunsubstituted or substituted with one, two, or three RV;
• Rv is independently alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, halogen, —OR8, —NR′R9, —CN, —C(O)R10, —C(O)NR′R9, —NR′C(O)R10, —NR′C(O)OR9, —NR10 C(O)NR8R9, —OC(O)NR′R9, —S(O)2R10, —S(O)R10, —SR′, —S(O)2NR8R9, —S(O)NR8R9, —NR8S(O)R10, —NR8S(O)2R10, or —NR10 S(O)2NR8R9;
• wherein alkyl is unsubstituted or substituted with —OR8 or —NR8R9 and wherein cycloalkyl and heterocyclyl are optionally substituted with one, two, or three groups selected from halogen, alkyl, and haloalkyl;
• R7 is selected from C1-6alkyl, C1-6haloalkyl, C3-6cycloalkyl, C3-6cyclohaloalkyl, aryl and heteroaryl;
• each R′ and each R9 are independently hydrogen, alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are optionally substituted with one, two, or three groups selected from halogen, alkyl, and haloalkyl;
• or R1 and R9, together with the atom or atoms to which they are attached, form a heterocyclyl unsubstituted or substituted with one, two, or three groups selected from halogen, alkyl, and haloalkyl;
• each R10 is independently alkyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein cycloalkyl, heterocyclyl, aryl, and heteroaryl are unsubstituted or substituted with one, two, or three groups selected from halogen, alkyl, and haloalkyl;
• is selected from the following structures:
• is unsubstituted or substituted with one or more Re.