Trpm8 antagonists and their use in treatments

A compound of Formula I having the structure:

• a pharmaceutically-acceptable salt thereof, a tautomer thereof, a pharmaceutically-acceptable salt of the tautomer, a stereoisomer thereof, or a mixture thereof, wherein:
• m is 0, 1, 2 or 3;
• n is 0 or 1;
• X1 is C(R4) or N;
• X2 is CH, CF, or N;
• R1 is C1-6alk or a direct-bonded, C1-2alk-linked, C1-2alkO-linked, saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, but containing no more than one O or S atom, the C1-6alk and ring being substituted by 0, 1, 2 or 3 substituents independently selected from halo, oxo, C1-6alk, C1-6alkOH, C1-6alk-C(═O)Ra, C1-6alk-C(═O)ORa, C1-4haloalk, cyano, nitro, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Ra, —OC(═O)NRaRa, —OC(═O)N(Ra)S(═O)2Ra, —OC2-6alkNRaRa, —OC2-6alkORa, —SRa, ═S, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRaRa, —S(═O)2N(Ra)C(═O)Ra, —S(═O)2N(Ra)C(═O)ORa, —S(═O)2N(Ra)C(═O)NRaRa, —NRaRa, —N(Ra)C(═O)Ra, —N(Ra)C(═O)ORa, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Ra, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkNRaRa and —NRaC2-6alkORa, wherein the ring is additionally substituted by 0 or 1 directly bonded, SO2 linked, C(═O) linked or CH2 linked saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, but containing no more than one O or S atom, and substituted by 0, 1, 2 or 3 groups selected from halo, oxo, C1-6alk, C1-4haloalk, cyano, nitro, —C(═O)Ra, —C(═O)ORa, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Ra, —SRa, —S(═O)Ra, —S(═O)2Ra, —S(═O)2NRaRa, —NRaRa, and —N(Ra)C(═O)Ra;
• R2 is H, halo, cyano, Rc, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —OC(═O)NRaRa, —OC2-6alkNRaRa, —OC2-6alkORa, —SRa, —S(═O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —NRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkNRaRa and —NRaC2-6alkORa;
• or R2 is C1-6alk substituted by 0, 1, 2 or 3 substituents selected from C1-4haloalk, halo, cyano, nitro, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —OC(═O)NRaRa, —OC2-6alkNRaRa, —OC2-6alkORa, —SRa, —S(═O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —NRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkNRaRa and —NRaC2-6alkORa, or R2 is C1-6alk substituted by 0, 1, 2 or 3 halo substituents and additionally substituted by 0 or 1 substituents selected from Rc;
• R3 is H, C1-8alk, C1-8alkOH, C1-4haloalk, halo, cyano, —C(═O)Rb, —C(═O)ORb, —C(═O)NRaRa, —C(═NRa)NRaRa, —ORa, —OC(═O)Rb, —OC(═O)NRaRa, —OC2-6alkNRaRa, —OC2-6alkORa, —SRa, —S(═O)Rb, —S(═O)2Rb, —S(═O)2NRaRa, —NRaRa, —N(Ra)C(═O)Rb, —N(Ra)C(═O)ORb, —N(Ra)C(═O)NRaRa, —N(Ra)C(═NRa)NRaRa, —N(Ra)S(═O)2Rb, —N(Ra)S(═O)2NRaRa, —NRaC2-6alkNRaRa or —NRaC2-6alkORa;
• R4 is independently, at each instance, H, C1-6alk, —C1-3haloalk, —OC1-6alk, —OC1-3haloalk, —N(C1-6alk)C1-6alk, —NHC1-6alk, —NC(═O)C1-6alk, —N(C1-6alk)C1-6alk, F, Cl, Br, CN, OH or NH2;
• or R3 and R4 together form a four-atom unsaturated bridge containing 0 or 1 N atoms, wherein the bridge is substituted by 0, 1 or 2 R5 substituents;
• R5 is independently, in each instance, halo, ORa, CH3 or CF3;
• R6 is F, C1-6alk, or ORa;
• Ra is independently, at each instance, H or Rb;
• Rb is independently, at each instance, phenyl, benzyl or C1-6alk, the phenyl, benzyl and C1-6alk being substituted by 0, 1, 2 or 3 substituents selected from halo, oxo, C1-4alk, C1-3haloalk, —OC1-4alk, —OH, —NH2, —OC1-4alk, —OC1-4haloalk, —NHC1-4alk, and —N(C1-4alk)C1-4alk;
• and
• Rc is independently, at each instance, a saturated, partially saturated or unsaturated 4-, 5- or 6-membered monocyclic ring containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S, wherein the C1-6alkyl and ring are substituted by 0 or 1 oxo groups substituted by 0, 1, 2 or 3 substituents selected from C1-8alk, C1-4haloalk, halo and cyano.