2-methylprop anamides and their use as pharmaceuticals

A compound of Formula I:

• or pharmaceutically acceptable salt thereof, wherein:
• R1 is phenyl, Cy1-(CH2)m—O— or Cy1-(CH2)m—S—, wherein said phenyl is optionally substituted by 1, 2, 3, 4 or 5 R1a;
• R2 is —(CR4R5)nCy2, —(CR4R5)tCy3 or Cy4;
• R3 is H, C1-6 alkyl or C3-6 cycloalkyl;
• R4 and R5 are each, independently, H, halo, OH, CN, C1-4 alkyl, C1-4 alkoxy, wherein said C1-4 alkyl or C1-4 alkoxy is optionally substituted with one or more R4a;
• R6 is H or C1-6 alkyl optionally substituted by one or more OH;
• each R1a is independently halo, CN, NO2, ORa, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino, C2-8 dialkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C1-4 alkoxy, C1-4 haloalkoxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd;
• R1c is halo, OH, C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxyalkyl, C1-4 alkoxy, C1-4 haloalkoxy, phenyl, benzyl, C(O)ORg or ORg;
• R4a is halo, CN, NO2, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino;
• Cy1 is aryl, heteroaryl, cycloalkyl or heterocycloalkyl, each optionally substituted by 1, 2, 3, 4 or 5-W—X—Y—Z;
• Cy2 is:
• Cy3 is phenyl optionally substituted by one or more R1a;
• Cy4 is:
• U is CH2;
• W, W′ and W″ are each, independently, absent, C1-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, O, S, NRe, CO, COO, CONRe, SO, SO2, SONRe, or NReCONRf, wherein said C1-6 alkylenyl, C2-6 alkenylenyl or C2-6 alkynylenyl is each optionally substituted by 1, 2 or 3 halo, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino;
• X, X′ and X″ are each, independently, absent, C1-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C1-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by one or more halo, CN, NO2, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino;
• Y, Y′ and Y″ are each, independently, absent, C1-6 alkylenyl, C2-6 alkenylenyl, C2-6 alkynylenyl, O, S, NRe, CO, COO, CONRe, SO, SO2, SONRe, or NReCONRf, wherein said C1-6 alkylenyl, C2-6 alkenylenyl or C2-6 alkynylenyl is optionally substituted by 1, 2 or 3 halo, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino;
• Z, Z′ and Z″ are each, independently, H, halo, CN, NO2, OH, C1-4 alkoxy, C1-4 haloalkoxy, amino, C1-4 alkylamino or C2-8 dialkylamino, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl is optionally substituted by 1, 2 or 3 halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, CN, NO2, ORa, SRa, C(O)Rb, C(O)NRcRd, C(O)ORa, OC(O)Rb, OC(O)NRcRd, NRcRd, NRcC(O)Rd, NRcC(O)ORa, S(O)Rb, S(O)NRcRd, S(O)2Rb, or S(O)2NRcRd;
• wherein two —W—X—Y—Z together with two adjacent atoms to which they are attached optionally form a 3-20 membered cycloalkyl group or 3-20 membered heterocycloalkyl group, each optionally substituted by 1, 2 or 3-W′—X′—Y′—Z′;
• or wherein two —W—X—Y—Z together with two adjacent atoms to which they are attached optionally form a 5- or 6-membered aryl or 5- or 6-membered heteroaryl group, each optionally substituted by 1, 2 or 3-W″—X″—Y″—Z″;
• wherein —W—X—Y—Z is other than H;
• wherein —W′—X′—Y′—Z′ is other than H;
• wherein —W″—X″—Y″—Z″ is other than H;
• Ra is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;
• Rb is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, heteroaryl or heterocycloalkyl;
• Rc and Rd are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;
• or Rc and Rd together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
• Re and Rf are each, independently, H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, cycloalkyl, arylalkyl, or cycloalkylalkyl;
• or Re and Rf together with the N atom to which they are attached form a 4-, 5-, 6- or 7-membered heterocycloalkyl group;
• Rg is H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl or cycloalkylalkyl;
• j is 0, 1, 2, or 3;
• m is 0, 1, or 2;
• n is 0, 1, 2, or 3;
• q is 0, 1, 2, 3, 4 or 5;
• r is 1 or 2;
• and
• t is 2 or 3;
• with the provisos:
• a) when R1 is phenyl optionally substituted by 1, 2, 3, 4 or 5 R1a and R2 is (CR4R5)tCy3, at least one of R4 and R5 is other than H;
• b) when R1 is phenyl optionally substituted by 1, 2, 3, 4 or 5 R1a and R2 is Cy2, Cy2 is other than cyclohexyl substituted by one NRcRd;
• and
• c) when R2 is cyclohexyl, R1 is other than 3,5-di-tert-butyl-4-hydroxyphenyl.