A method of treating rheumatoid arthritis and/or one or more symptoms associated therewith in a mammal, the method comprising administering to the mammal an effective amount of a compound of formula (I) and one or more additional compounds selected from a steroid, a membrane stabilizer, a 5LO inhibitor, a leukotriene synthesis inhibitor, a leukotriene receptor inhibitor, an inhibitor of IgE isotype switching, an inhibitor of IgE synthesis, an inhibitor of IgG isotype switching, an inhibitor of IgG synthesis, a β-agonist, a tryptase inhibitor, aspirin, a COX inhibitor, methotrexate, an anti-TNF drug, rituxan, a PD4 inhibitor, a p38 inhibitor, a PDE4 inhibitor, and an antihistamine, wherein the compound of formula (I) is:
- and salts, hydrates, solvates and N-oxides thereof, wherein:
- L1 and L2 are each a direct bond;
- R2 is selected from the group consisting of phenyl mono-substituted at the 3- or 5-position with an R8 group, phenyl di or tri-substituted with one or more of the same or different R8 group, and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
- R4 is selected from the group consisting of phenyl substituted with one or more of the same or different R8 groups, and 5-15 membered heteroaryl optionally substituted with one or more of the same or different R8 groups;
- wherein at least one of R2 and R4 is pyrid[1,4]oxazinyl;
- R5 is selected from the group consisting of —CN, —NC, —NO2, fluoro, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, (C1-C3) haloalkoxy, (C1-C3) perhaloalkoxy, —C(O)Ra, —C(O)ORa, —C(O)CF3 and —C(O)OCF3;
- R6 is hydrogen;
- R8 is selected from the group consisting of Re, Rb, Re substituted with one or more of the same or different Ra or Rb, —ORa substituted with one or more of the same or different Ra or Rb, —B(ORa)2, —B(NRcRc)2, —(CH2)m—Rb, —(CHRa)m—Rb, —O—(CH2)m—Rb, —S—(CH2)m—Rb, —O—CHRaRb, —O—CRa(Rb)2, —O—(CHRa)m—Rb, —O—(CH2)m—CH[(CH2)mRb]Rb, —S—(CHRa)m—Rb, —C(O)NH—(CH2)m—Rb, —C(O)NH—(CHRa)m—Rb, —O—(CH2)m—C(O)NH—(CH2)m—Rb, —S—(CH2)m—C(O)NH—(CH2)m—Rb, —O—(CHRa)m—C(O)NH—(CHRa)m—Rb, —S—(CHRa)m—C(O)NH—(CHRa)m—Rb, —NH—(CH2)m—Rb, —NH—(CHRa)m—Rb, —NH[(CH2)mRb], —N[(CH2)mRb]2, —NH—C(O)—NH—(CH2)m—Rb, —NH—C(O)—(CH2)m—CHRbRb and —NH—(CH2)m—C(O)—NH—(CH2)m—Rb;
- each Ra is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
- each Rb is a suitable group independently selected from the group consisting of ═O, —ORd, (C1-C3) haloalkyloxy, ═S, —SRd, ═NRd, ═NORd, —NRcRc, halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Rd, —S(O)2Rd, —S(O)2ORd, —S(O)NRcRc, —S(O)2NRcRc, —OS(O)Rd, —OS(O)2Rd, —OS(O)2ORd, —OS(O)2NRcRc, —C(O)Rd, —C(O)ORd, —C(O)NRcRc, —C(NH)NRcRc, —C(NRa)NRcRc, —C(NOH)Ra, —C(NOH)NRcRc, —OC(O)Rd, —OC(O)ORd, —OC(O)NRcRc, —OC(NH)NRcRc, —OC(NRa)NRcRc, —[NHC(O)]nRd, —[NRaC(O)]nRd, —[NHC(O)]nORd, —[NRaC(O)]nORd, —[NHC(O)]nNRcRc, —[NRaC(O)]nNRcRc, —[NHC(NH)]nNRcRc and —[NRaC(NRa)]nNRcRc;
- each Rc is independently a protecting group or Ra, or, alternatively, two Rc are taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different Ra or suitable Rb groups;
- each Rd is independently an Ra;
- each Re is independently selected from the group consisting of (C1-C6) alkyl, (C3-C8) cycloalkyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, (C6-C16) arylalkyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl, and 6-16 membered heteroarylalkyl;
- each m is independently an integer from 1 to 3;
- and
- each n is independently an integer from 0 to 3,
- wherein one or both of R2 and R4, independently of one another, is an optionally substituted heteroaryl selected from the group consisting of:
- wherein:
- p is an integer from one to three;
- each independently represents a single bond or a double bond;
- R35 is hydrogen or R8;
- X is selected from the group consisting of CH, N and N—O;
- each Y is independently selected from the group consisting of O, S and NH;
- each Y1 is independently selected from the group consisting of O, S, SO, SO2, SONR36, NH and NR37;
- each Y2 is independently selected from the group consisting of CH, CH2, O, S, N, NH and NR37;
- R36 is hydrogen or alkyl;
- R37 is selected from the group consisting of hydrogen, aryl, arylalkyl, heteroaryl, Ra, Rb, CRaRb—O—C(O)R8, —CRaRb—O—PO(OR8)2, —CH2—O—PO(OR8)2, —CH2—PO(OR8)2, —C(O)—CRaRb—N(CH3)2, —CRaRb—O—C(O)—CRaRb—N(CH3)2, —C(O)R8, —C(O)CF3 and —C(O)—NR8—C(O)R8;
- R38 is selected from the group consisting of alkyl and aryl;
- A is selected from the group consisting of O, NH and NR38;
- R9, R10, R11 and R12 are each, independently of one another, selected from the group consisting of alkyl, alkoxy, halogen, haloalkoxy, aminoalkyl and hydroxyalkyl, or, alternatively, R9 and R10 and/or R11 and R12 are taken together form an oxo group;
- each Z is selected from the group consisting of hydroxyl, alkoxy, aryloxy, ester, and carbamate;
- Q is selected from the group consisting of —OH, —OR8, —NRcRc, —NHR39—C(O)R8, —NHR39—C(O)OR8, —NR39—CHR40—Rb, and —NR39—(CH2)m—Rb;
- R39 and R40 are each, independently of one another, selected from the group consisting of hydrogen, alkyl, aryl, and arylalkyl.