Pyrazole oxadiazole derivatives as S1P1 agonists

A process for the preparation of a compound of formula (I):

• wherein
• R1 is
• R2 is selected from the following groups:
• R3 is Ar2, Het1, Cyc, A, CH3, or S—(C1-C6-alkyl);
• A is a branched or linear alkyl having 2 to 12 C-atoms, wherein one or more H-atoms may be replaced by Hal, OR4, CN, CO2R4, or CF3;
• cycloalkyl having 3 to 7 ring carbon atoms;
• Ar2, or N(R4)2 and wherein one or more non-adjacent CH2-groups may be replaced by O, NR4, —CO—, NR4CO2—, —CO2—, —NR4CONR4—, —CH═CH—, —C≡C—, or A is cycloalkyl or cycloalkylalkylene having 3-7 ring C atoms, or A is Het2;
• Z is a branched or linear alkyl having 2 to 12 C-atoms, wherein one or more H-atoms are replaced by Hal, OR4, CN, CO2R4, CF3, cycloalkyl having 3 to 7 ring carbon atoms, Ar2, N(R4)2 and/or wherein one or more CH2-groups are replaced by O, NR4, S, —CO—, NR4CO2—, —NR4CONR4—, —CH═CH—, —C≡O—, or Z is cycloalkyl or cycloalkylalkylene having 3-7 ring C atoms;
• Hal is F, CI, Br or I;
• Ar2 is a monocyclic or bicyclic, unsaturated or aromatic carbocyclic ring having 6 to 14 carbon atoms which may be unsubstituted, monosubstituted, disubstituted or trisubstituted by substituents selected from Z, F, Br, I, —OR4, —(CH2)OR4, —(CH2)N(R4)2, Perfluoro-alkoxy, —SO2R4, —CN, —NO2, —N(R4)2, —CO(NR4)2, (NR4)COR4, —CO2R4, —COR4, —SO2N(R4)2, —SO2alkyl, NR4SO2(C1-C6)alkyl, —(CH2)nHet1, —OHet1, or CF3;
• Het1 is a monocyclic saturated, unsaturated or aromatic heterocyclic ring or a bicyclic, saturated, or unsaturated heterocyclic ring having 1 to 4 N, O and/or S atoms which may be unsubstituted, monosubstituted, disubstituted or trisubstituted by substituents selected from A, Hal, —OR4, —(CH2)OR4, Perfluoro-alkyl, Perfluoro-alkoxy, —SO2(R4)2, CN, NO2, —N(R4)2, —CO(NR4)2, (NR4)COR4, —CO2R4, —COR4, —SO2N(R4)2, —SO2alkyl, NR4SO2alkyl, NR4SO2alkyl, or C1-C6 alkyl;
• Cyc is a saturated or unsaturated carbocyclic ring containing 3 to 7 carbon atoms which may be substituted by Hal, A, (C1-C6)alkyl, —[C(R4)2]n-cycloalkyl, OR4, CF3, OCF3, N(R4)2, NR4CON(R4)2, NO2, CN, —[C(R4)2]n—COOR4, —[C(R4)2]n,—CON(R4)2, NR4COA, NR4SO2A, COR4, SO2N(R4)2, SOA, and/or SO2A;
• R4 is H, A, Cyc or (C1-C6)alkyl;
• and
• n is 0, 1, 2, 3 or 4;
• said method comprising the step of reacting a compound of formula (V)
• with a compound of formula (IV)
• or (VI)
• wherein R1, R2, R3 and R4 are as defined above.

A process for the preparation of compounds of formula (I)

• wherein
• R1 is
• R2 is selected from the following groups:
• R3 is Ar2, Het1, Cyc, A, CH3, or S—(C1-C6-alkyl);
• A is a branched or linear alkyl having 2 to 12 C-atoms, wherein one or more H-atoms may be replaced by Hal, OR4, CN, CO2R4, or CF3;
• cycloalkyl having 3 to 7 ring carbon atoms;
• Ar2, or N(R4)2 and wherein one or more non-adjacent CH2-groups may be replaced by O, NR4, —CO—, NR4CO2—, —CO2—, —NR4CONR4—, —CH═CH—, —C≡O—, or A is cycloalkyl or cycloalkylalkylene having 3-7 ring C atoms, or A is Het2;
• Z is a branched or linear alkyl having 2 to 12 C-atoms, wherein one or more H-atoms are replaced by Hal, OR4, CN, CO2R4, CF3, cycloalkyl having 3 to 7 ring carbon atoms, Ar2, N(R4)2 and/or wherein one or more CH2-groups are replaced by O, NR4, S, —CO—, NR4CO2—, —NR4CONR4—, —CH═CH—, —C≡O—, or Z is cycloalkyl or cycloalkylalkylene having 3-7 ring C atoms;
• Hal is F, CI, Br or I;
• Ar2 is a monocyclic or bicyclic, unsaturated or aromatic carbocyclic ring having 6 to 14 carbon atoms which may be unsubstituted, monosubstituted, disubstituted or trisubstituted by substituents selected from Z, F, Br, I, —OR4,—(CH2)OR4, —(CH2)N(R4)2, Perfluoro-alkoxy, —SO2R4, —CN, —NO2, —N(R4)2, —CO(NR4)2, (NR4)COR4, —CO2R4, —COR4, —SO2N(R4)2, —SO2alkyl, NR4SO2(C1-C6)alkyl, —(CH2)nHet1, —OHet1, or CF3;
• Het1 is a monocyclic saturated, unsaturated or aromatic heterocyclic ring or a bicyclic, saturated, or unsaturated heterocyclic ring having 1 to 4 N, O and/or S atoms which may be unsubstituted, monosubstituted, disubstituted or trisubstituted by substituents selected from A, Hal, —OR4, —(CH2)OR4, Perfluoro-alkyl, Perfluoro-alkoxy, —SO2(R4)2, CN, NO2, —N(R4)2, —CO(NR4)2, (NR4)COR4, —CO2R4, —COR4, —SO2N(R4)2, —SO2alkyl, NR4SO2alkyl, NR4SO2alkyl, or C1-C6 alkyl;
• Cyc is a saturated or unsaturated carbocyclic ring containing 3 to 7 carbon atoms which may be substituted by Hal, A, (C1-C6)alkyl, —[C(R4)2]n-cycloalkyl, OR4, CF3, OCF3, N(R4)2, NR4CON(R4)2, NO2, CN, —[C(R4)2]n—COOR4, —[C(R4)2]n—CON(R4)2, NR4COA, NR4SO2A, COR4, SO2N(R4)2, SOA, and/or SO2A;
• R4 is H, A, Cyc or (C1-C6)alkyl;
• and
• n is 0, 1, 2, 3 or 4;
• said method comprising the step of reacting a compound of formula (XI)
• with a compound of Formula (XII)
• wherein R1, R2, R3 and R4 are as defined above.