Macrocyclic compounds as IRAK4 inhibitors for the treatment of inflammatory diseases

1. A compound of Formula III, or a pharmaceutically acceptable salt thereof,

wherein

Z is S,

R 1 is hydrogen or lower alkyl,

R 2 is chosen from hydrogen and lower alkyl,

R 3 is chosen from hydrogen, lower alkyl optionally substituted with alkoxy, amino, N-(alkyl)amino, N,N-(dialkyl)amino, or phenyl, heterocycloalkyl, and heteroaryl,

wherein phenyl, heterocycloalkyl, and heteroaryl are optionally substituted with one or two groups independently chosen from lower alkyl and wherein alkoxy is optionally substituted with tri(alkyl)silyl, wherein heteroaryl is a 5-14 membered monocyclic-, bicyclic-, or tricyclic-ring system, having 1 to 10 heteroatoms independently selected from N, O or S, wherein N and S can be optionally oxidized to various oxidation states, and wherein at least one ring in the ring system is aromatic, and heterocycloalkyl is a completely saturated monocyclic, bicyclic or tricyclic heterocyclyl comprising 3-15 ring members, at least one of which is a heteroatom, and up to 10 of which may be heteroatoms, wherein the heteroatoms are independently selected from O, S and N, and wherein N and S can be optionally oxidized to various oxidation states;

R 4 is chosen from heteroarylene and arylene, each of which is optionally substituted, or R 4 and R 3 taken together with the nitrogen to which they are bound, form an optionally substituted 3- to 7-membered heterocycloalkyl ring, or R 4 is an alkylene chain having 1-3 carbon atoms that is optionally substituted with one or two groups independently chosen from lower alkyl and cycloalkyl, each of which groups is optionally substituted with hydroxyl or alkoxy, or R 4 is absent, wherein heteroarylene is a divalent 5-14 membered monocyclic-, bicyclic-, or tricyclic-ring system, having 1 to 10 heteroatoms independently selected from N, O or S, wherein N and S can be optionally oxidized to various oxidation states, and wherein at least one ring in the ring system is aromatic, and arylene is divalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon groups having from 6 to 14 carbon atoms in the ring portion, and the 3- to 7-membered heterocycloalkyl ring is a completely saturated monocyclic, bicyclic or tricyclic heterocyclyl comprising at least one of which is a heteroatom, wherein the heteroatoms are independently selected from O, S and N, and wherein N and S can be optionally oxidized to various oxidation states;

R 5 is chosen from C(O)NR 51 , NR 52 , and O, or R 5 is absent, provided that if R 4 is absent, then R 5 is absent,

R 6 is an alkylene or alkenylene chain having one or two double bonds,

wherein the alkylene or alkenylene chain has 2 to 10 carbon atoms,

wherein the alkylene or alkenylene chain is optionally substituted with one or two groups independently chosen from lower alkyl and cycloalkyl, each of which groups is optionally substituted with hydroxyl or alkoxy, and

further wherein one or two of the carbon atoms in the alkylene chain is optionally replaced by an O, S, SO, SO 2 , or NR 61 , and

wherein two of the carbon atoms in the alkylene chain, are optionally connected by a two or three carbon atom alkylene chain to form a 5- to 7-membered ring,

R 7 is chosen from NR 71 and O, or R 7 is absent,

R 51 is chosen from hydrogen and lower alkyl,

R 52 is chosen from hydrogen, lower alkyl, and C(O)OR 81 ,

R 61 is chosen from hydrogen, lower alkyl, and C(O)OR 81 ,

R 71 is chosen from hydrogen, lower alkyl, and —C(O)OR 81 , and

R 81 is lower alkyl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof,

wherein, R 4 is heteroarylene optionally substituted with one or more R 41 wherein for each occurrence, R 41 is independently chosen from

heterocycloalkyl,

lower alkyl optionally substituted with —C(O)OR 9 , —C(O)NR 10 R 11 , hydroxy, amino, N-(alkyl)amino, N,N-(dialkyl)amino, cycloalkyl, or heterocycloalkyl,

—C(O)OR 9 ,

hydroxyl, and

—C(O)NR 10 R 11 ,

wherein R 9 is chosen from hydrogen and lower alkyl,

wherein R 10 and R 11 are independently hydrogen and lower alkyl, or R 10 and R 11 , together with the nitrogen to which they are bound form a heterocycloalkyl, and

wherein each lower alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one, two, or three groups independently chosen from —C(O)OR 9 , lower alkyl, lower alkoxy, hydroxyl, halogen, amino, N-(alkyl)amino, N,N-(dialkyl)amino, and heterocycloalkyl.

3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula III is chosen from compounds of Formula VI

4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein the compound of Formula III is chosen from compounds of Formula VIII

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is arylene optionally substituted with one or more R 42 wherein for each occurrence, R 42 is independently chosen from

heterocycloalkyl,

lower alkyl optionally substituted with —C(O)OR 9 , amino, N-(alkyl)amino, N,N-(dialkyl)amino, cycloalkyl, or heterocycloalkyl,

—C(O)OR 9 ,

hydroxyl, and

—C(O)NR 10 R 11 ,

wherein R 9 is chosen from hydrogen and lower alkyl,

wherein R 10 and R 11 are independently hydrogen and lower alkyl, or R 9 and R 10 , together with the nitrogen to which they are bound form a heterocycloalkyl, and

wherein each lower alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one, two, or three groups independently chosen from —C(O)OR 9 , lower alkyl, lower alkoxy, hydroxyl, halogen, amino, N-(alkyl)amino, N,N-(dialkyl)amino, and heterocycloalkyl.

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 taken together with the nitrogen to which they are bound, form a 3- to 7-membered heterocycloalkyl ring optionally substituted with one or more R 44 wherein for each occurrence, R 44 is independently chosen from

heterocycloalkyl,

lower alkyl optionally substituted with —C(O)OR 9 , amino, N-(alkyl)amino, N,N-(dialkyl)amino, cycloalkyl, or heterocycloalkyl,

—C(O)OR 9 ,

hydroxyl, and

—C(O)NR 10 R 11 ,

wherein R 9 is chosen from hydrogen and lower alkyl,

wherein R 10 and R 11 are independently hydrogen and lower alkyl, or R 10 and R 11 , together with the nitrogen to which they are bound form a heterocycloalkyl, and

wherein each lower alkyl, cycloalkyl and heterocycloalkyl is optionally substituted with one, two, or three groups independently chosen from —C(O)OR 9 , lower alkyl, lower alkoxy, hydroxyl, halogen, amino, N-(alkyl)amino, N,N-(dialkyl)amino, and heterocycloalkyl.

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is chosen from hydrogen, lower alkyl optionally substituted with amino, N-(alkyl)amino) or N,N-(dialkyl)amino, benzyl, piperidin-1-yl, and 1H-pyrazol-4-yl, wherein each of benzyl, piperidin-1-yl, and 1H-pyrazol-4-yl is optionally substituted with one or two groups independently chosen from lower alkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is —C(O)NR 51 —, O or absent.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is NR 71 or O.

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is absent.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is an alkylene or alkenylene chain having one or two double bonds, wherein the alkylene or alkenylene chain has 4 to 8 carbon atoms and wherein the alkylene or alkenylene chain is optionally substituted with one or two groups independently chosen from lower alkyl and cycloalkyl, each of which groups is optionally substituted with hydroxyl or alkoxy, and further wherein one or two of the carbon atoms in the alkylene chain is optionally replaced by an O, S, SO, SO 2 , or NR 61 , and further wherein two of the carbon atoms in the alkylene chain, are optionally connected by a two or three carbon atom alkylene chain to form a 5- to 7-membered ring.

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is selected from one of the following compounds:

13. A pharmaceutical composition comprising at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.