IRAK inhibitors and method for making and using

Patent metadata

Field	Value
Publication number	US-10370367-B2
Application number	US-201715793770-A
Country	US
Kind code	B2
Filing date	Oct 25, 2017
Priority date	Oct 26, 2016
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

Abstract

Disclosed embodiments concern interleukin receptor associated kinases (IRAK) inhibitors, such as oxazole compounds, and compositions comprising such inhibitors. Also disclosed are methods of making and using the compounds and compositions. The disclosed compounds and/or compositions may be used to treat or prevent an IRAK-associated disease or condition.

First claim

We claim:

1. A compound, having a formula

and/or a salt thereof, wherein:
at least one of R 1 and R 2 is heteroaryl, and the remaining R 1 or R 2 is H, alkyl, or haloalkyl;
R 3 is H, aliphatic, heteroaliphatic, heterocyclyl, amide, aromatic, or araliphatic;
R 4 is H or alkyl;
R 5 is H or alkyl; and
each R 6 independently is H, alkyl, haloalkyl, halogen, alkyl phosphate or alkylphosphonate.

2. The compound of claim 1 , wherein R 1 is heteroaryl and R 2 is H.

3. The compound of claim 1 , wherein at least one of R 1 and R 2 is nitrogen-containing heteroaryl.

4. The compound of claim 1 , wherein at least one of R 1 and R 2 is 6-membered heteroaryl.

5. The compound of claim 1 , wherein R 3 is R a , R b ,R a substituted with 1, 2, or 3 R b , R a substituted with R b and R c , R a substituted with R c , —(CR a R a ) n —R a , —(CH 2 ) n —R a , —(CR a R a ) n —R b , —(CH 2 ) n —R b , —[(CH 2 ) m —O—] n —R a , —[(CH 2 ) m —O—] n —[R a substituted with 1, 2 or 3 R b ], or —(CH 2 ) m —O—(CH 2 ) m —O—R a wherein each m and n independently are 1, 2 or 3;
R a is independently for each occurrence H, D, C 1-6 alkyl, C 1-6 haloalkyl C 3-6 cycloalkyl, C 3-6 heteroalicyclyl,

where Y and Z independently are —CH 2 , —CHR b , O or NR d ;
R b is independently for each occurrence —OH, —CF 3 , —OR c , —NR d R d , or halogen;
R c is independently for each occurrence C 1-6 alkyl, C 3-6 heteroalicyclyl, C 1-6 alkyl substituted with 1, 2 or 3 R e , C 3-6 cycloalkyl substituted with 1, 2 or 3 R e , or C 3-6 heteroalicyclyl substituted with 1, 2 or 3 R e ;
R d is independently for each occurrence H, C 1-6 alkyl optionally substituted with 1, 2 or 3 R e , or two R d groups together with the nitrogen bound thereto form a C 3-6 heteroalicyclyl moiety optionally substituted with C 1-6 alkyl and optionally interrupted with one or two —O— or —N(R g ) wherein R g is R 70 ; and
R e is independently for each occurrence C 1-6 alkyl, or —OR a .

6. The compound of claim 5 , wherein each R 6 independently is H, halogen, alkyl, or R a substituted with —OP(O)(R f ) 2 , and R f is independently for each occurrence —OR a , —O − M + where each M + independently is an alkali metal ion or an ammonium ion.

7. The compound of claim 1 , wherein the compound, and/or salt thereof, has a formula

R 7 is H, alkyl, alkyl phosphate or alkylphosphonate; and
each of R 8 and R 9 is independently H, alkyl, haloalkyl, halogen.

8. The compound of claim 7 , wherein one of R 8 and R 9 is H and the other of R 8 and R 9 is H or F.

9. The compound of claim 7 , wherein R 7 is H.

10. The compound of claim 7 , wherein R 7 is CH 2 OP(═O)(OR′) 2 , and each OR′ independently is OH, —Oalkyl, or —O − M + where M + is a positive counter ion.

11. The compound of claim 1 , wherein R 1 is

each of Z 1 , Z 2 , Z 3 and Z 4 independently is N or CR 10 , where at least one of Z 1 , Z 2 , Z 3 and Z 4 is N; and
each R 10 independently is H, halogen, or aliphatic.

12. The compound of claim 11 , wherein the compound, and/or a salt thereof, has a formula

R 7 is H, alkyl, alkyl phosphate or alkylphosphonate; and
each of R 8 and R 9 is independently H, alkyl, haloalkyl, halogen.

13. The compound of claim 12 , wherein the compound, and/or salt thereof, has a formula selected from

and
R 11 , R 12 , R 13 , and R 14 , if present, are independently H, halogen, or alkyl.

14. The compound of claim 13 , wherein the compound has a formula

15. The compound of claim 14 , wherein R 11 , R 12 , R 13 , and R 14 independently is H, F, CF 3 , or CF 2 .

16. The compound of claim 15 , wherein R 2 , R 4 and R 5 are H.

17. The compound of claim 16 , wherein R 3 is H, alkyl, cycloalkyl, heteroaliphatic, or heterocycloaliphatic.

18. The compound of claim 16 , wherein R 3 is C 1-6 alkyl, tetrahydropyran, unsubstituted heteroaliphatic, heteroaliphatic substituted with halogen, unsubstituted cyclobutyl, cyclobutyl substituted with OH, alkoxy, or heterocycloaliphatic, unsubstituted cyclohexyl, or cyclohexyl substituted with —OH, alkoxy or heterocycloaliphatic.

19. A compound, selected from:
I-1: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-2: N-(1-((1r,4r)-4-morpholinocyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-3: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-2-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-4: N-(3-(6-(difluoromethyl)pyridin-2-yl)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-5: N-(3-(6-(difluoromethyl)pyridin-2-yl)-1-((1R,4r)-4-((2R,6S)-2,6-dimethylmorpholino)cyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-6: N-(1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrimidin-4-yl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-7: N-(3-(3-fluoro-6-(trifluoromethyl)pyridin-2-yl)-1-((1r,4r)-4-morpholinocyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-8: sodium (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate;
I-9: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-10: N-(3-(3,6-difluoropyridin-2-yl)-1-((1s,3s)-3-ethoxycyclobutyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-11: N-(3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-hydroxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-12: (4-(4-((3-(3,6-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate;
I-13: N-(3-(3,5-difluoropyridin-2-yl)-1-((1r,4r)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-14: N-(5-(3,6-difluoropyridin-2-yl)-1-((1r,4R)-4-ethoxycyclohexyl)-1H-pyrazol-4-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-15: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(2-(2,2,2-trifluoroethoxy)ethyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-16: di-tert-butyl ((4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl) phosphate;
I-17: (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate;
I-18: sodium (4-(4-((1-((1r,4r)-4-ethoxycyclohexyl)-3-(pyrazin-2-yl)-1H-pyrazol-4-yl)carbamoyl)oxazol-2-yl)-1H-pyrazol-1-yl)methyl phosphate;
I-19: 2-(1-(cyclopropylmethyl)-1H-pyrazol-4-yl)-N-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxamide;
I-20: 2-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Li Hui
• Heckrodt Thilo
• Chen Yan
• Kelley Ryan
• Mcmurtrie Darren
• Tso Kin
• Taylor Vanessa
• Singh Rajinder
• Yen Rose
• Maung Jack

Classifications

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• C07D413/14 Primary

  containing three or more hetero rings · CPC title