Carboxamide inhibitors of IRAK4 activity

1. A compound according to Formula I:

wherein:

B is N; D is N; E is CH; F is CH; G is N; and J is C;

X is O, S, CH 2 or N;

m is 0 or 1; n is 0, 1 or 2;

Ring A is pyridinyl, pyrazolyl, thiophenyl, furanyl or phenyl,

R 1 is independently selected from (C 1 -C 4 )alkyl, pyrimidine, piperidine and phenyl, each optionally substituted with (C 1 -C 4 )alkyl, OH, halo, O(C 1 -C 4 )alkyl, methyl-piperidine, S(O) 2 R c , C(O)N(R b ) 2 , or C(O)O(C 1 -C 4 )alkyl;

R 2 is absent or H and R 3 is independently selected from: (C 1 -C 4 )alkyl, pyranyl, cyclopentyl, cyclohexyl, cycloheptyl, thiopyranyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl each optionally substituted with one or more substituents independently selected from halo, OH, oxo, N(R b ) 2 , oxopyrrolidinyl, or morpholinyl, or R 2 and R 3 can be taken together with the nitrogen to which they are attached to form piperazine or morpholine, each optionally substituted with oxo;

R 4 is independently H or methyl;

R b is independently selected from H and (C 1 -C 4 )alkyl; and

R c is methyl;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 of Formula II:

wherein:

X is O, S, CH 2 or N;

m is 0 or 1;

R 1 is independently selected from (C 1 -C 4 )alkyl, pyrimidine, piperidine and phenyl, each optionally substituted with (C 1 -C 4 )alkyl, OH, halo, O(C 1 -C 4 )alkyl, methyl-piperidine, S(O) 2 R c , C(O)N(R b ) 2 , or C(O)O(C 1 -C 4 )alkyl;

R 2 is absent or H and R 3 is independently selected from: (C 1 -C 4 )alkyl, pyranyl, cyclopentyl, cyclohexyl, cycloheptyl, thiopyranyl, pyrazolyl, piperidinyl, morpholinyl, piperazinyl each optionally substituted with one or more substituents independently selected from halo, OH, oxo, N(R b ) 2 , oxopyrrolidinyl, or morpholinyl, or R 2 and R 3 can be taken together with the nitrogen to which they are attached to form piperazine or morpholine, each optionally substituted with oxo;

R 4 is independently H or methyl;

R b is independently selected from H and (C 1 -C 4 )alkyl; and

R c is methyl;

or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring A is pyrazole.

4. A compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein X is N.

5. A compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein X is N.

6. A compound which is selected from:

5-{[(3R,4R)-4-aminotetrahydro-2H-pyran-3-yl]amino}-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(3R,4R)-3-aminotetrahydro-2H-pyran-4-yl]amino}-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1R,2R)-2-amino-3,3-difluorocyclohexyl]amino}-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(3S,4S)-3-amino-1,1-dioxidotetrahydro-2H-thiopyran-4-yl]amino}-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(3R,4R)-4-amino-1,1-dioxidotetrahydro-2H-thiopyran-3-yl]amino}-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1 S,2R)-2-aminocyclohexyl]amino}-N-(3-carbamoyl-1-pyridin-3-yl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1 S,2R)-2-aminocyclohexyl]amino}-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1R,2R)-2-aminocyclohexyl]amino}-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1 S,2R)-2-aminocyclohexyl]amino}-N-[3-carbamoyl-1-(1-methylpiperidin-3-yl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-[(2-aminoethyl)amino]-N-(3-carbamoyl-1-pyridin-3-yl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-[(2-aminocyclopentyl)amino]-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-[(2-aminocycloheptyl)amino]-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-5-(pyrrolidin-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-5-(piperidin-3-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1 S,2R)-2-aminocyclohexyl]amino}-N-[1-methyl-3-(methylcarbamoyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1 S,2R)-2-aminocyclohexyl]amino}-N-[3-(dimethylcarbamoyl)-1-methyl-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1 S,2R)-2-aminocyclohexyl]amino}-N-{3-carbamoyl-1-[1-(methylsulfonyl)piperidin-4-yl]-1H-pyrazol-4-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1 S,2R)-2-aminocyclohexyl]amino}-N-[3-carbamoyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl]-7aH-pyrazolo[4,3-b]pyridine-3-carboxamide;

5-{[(1 S,2R)-2-aminocyclohexyl]amino}-N-{3-carbamoyl-1-[1-(methylsulfonyl)piperidin-3-yl]-1H-pyrazol-4-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1R,2S)-2-aminocyclohexyl]amino}-N-(3-carbamoyl-1-ethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1R,2 S)-2-aminocyclohexyl]amino}-N-[3-carbamoyl-1-(1-methylethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1R,2 S)-2-aminocyclohexyl]amino}-N-[3-carbamoyl-1-(2-hydroxyethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1R,2 S)-2-aminocyclohexyl]amino}-N-[3-carbamoyl-1-(2-methoxyethyl)-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1R,2S)-2-aminocyclohexyl]amino}-N-{3-carbamoyl-1-[(1-methylpiperidin-3-yl)methyl]-1H-pyrazol-4-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-5-(cyclohexylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-5-[(2-hydroxycyclohexyl)amino]pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-[(2-aminoethyl)amino]-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-5-{[(5-oxopyrrolidin-3-yl)methyl]amino}pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-5-morpholin-4-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-5-piperazin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-{[(1R,2S)-2-aminocyclohexyl]amino}-N-[1-(2-amino-2-oxoethyl)-3-carbamoyl-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-{3-carbamoyl-1-[4-(methylsulfamoyl)phenyl]-1H-pyrazol-4-yl}-5-piperazin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoyl-1-pyridin-4-yl-1H-pyrazol-4-yl)-5-piperazin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(5-carbamoyl-1-pyridin-4-yl-1H-pyrazol-4-yl)-5-piperazin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoyl-1-pyridin-3-yl-1H-pyrazol-4-yl)-5-piperazin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoyl-1-pyridin-2-yl-1H-pyrazol-4-yl)-5-piperazin-1-ylpyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)-5-(3-oxopiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-(2-aminoethoxy)-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

5-(3-aminopropyl)-N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-carbamoylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoyl-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoyl-1-pyridin-3-yl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(4-carbamoylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

tert-butyl 4-{3-carbamoyl-4-[(pyrazolo[1,5-a]pyrimidin-3-ylcarbonyl)amino]-1H-pyrazol-1-yl}piperidine-1-carboxylate;

N-(3-carbamoyl-1-piperidin-4-yl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-{3-carbamoyl-1-[1-(methylsulfonyl)piperidin-4-yl]-1H-pyrazol-4-yl}pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoylpyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-carbamoylthiophen-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(5-tert-butyl-2-carbamoylthiophen-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-carbamoylphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(3-carbamoyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

N-(2-carbamoyl-5-chloro-4-sulfamoylphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide; and

N-(4-bromo-2-carbamoylphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;

or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a compound of claim 1 .

8. A method for treating an inflammatory disease which comprises administering to a mammal in need thereof a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.

9. The method according to claim 8 wherein the inflammatory A disease is selected from rheumatoid arthritis, and inflammatory bowel disease.

10. A method of treating an inflammatory disease which comprises administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a second therapeutic agent.

11. The method of claim 10 wherein the second therapeutic agent is an anti-inflammatory agent.