Amide compounds and method for making and using

Patent metadata

Field	Value
Publication number	US-11530194-B2
Application number	US-202117184199-A
Country	US
Kind code	B2
Filing date	Feb 24, 2021
Priority date	Oct 26, 2016
Publication date	Dec 20, 2022
Grant date	Dec 20, 2022

Abstract

Disclosed embodiments concern novel interleukin receptor associated kinases (IRAK) inhibitors 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 method for inhibiting IRAK in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound, or a composition comprising the compound according to formula 1

or a salt thereof, wherein:
ring A is heteroaryl or 6-membered heterocycloaliphatic;
R 1 is H, aliphatic, or heteroaliphatic;
R 2 is H, aliphatic, heteroaliphatic, or heterocyclyl;
each of Z 1 , Z 2 , Z 3 , and Z 4 , independently is N or CR 3 , wherein at least one of Z 1 , Z 2 , Z 3 , and Z 4 is N;
each R 3 independently is H, aliphatic, or heteroaliphatic; and
R 4 is halogen, heterocycloaliphatic, aromatic, —O-aromatic, or —NH-aromatic.

2. The method of claim 1 , wherein ring A is pyridinyl, pyrazinyl, piperidinyl, or morpholino.

3. The method of claim 1 , wherein ring A is

4. The method of claim 1 , wherein the subject has a disease or condition comprising gout, gout flares, pseudogout, pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, dermatomyositis, ichthyosis vulgaris, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, dermatitis, atopic dermatitis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, lupus, psoriasis, psoriatic arthritis, osteoarthritis, pyoderma, Waldenström's macroglobulinemia, myelodysplastic syndrome, alcoholic liver disease, alcoholic cirrhosis, non-alcoholic steatohepatitis (NASH), primary biliary cirrhosis, sclerosing cholangitis, adult onset Still's disease, periodic fever syndrome, hyperimmunoglobulinemia d syndrome, cryopyrin-associated periodic syndrome, Schnitzler's syndrome, uveitis, Behcet's disease, dermatomyositis, vasculitis or systemic juvenile idiopathic arthritis.

5. The method of claim 4 , wherein the disease or condition is selected from aplastic anemia, psoriasis, primary biliary cirrhosis, pyoderma, sclerosing cholangitis, systemic juvenile idiopathic arthritis or a combination thereof.

6. The method of claim 4 , wherein the disease is dermatitis.

7. The method of claim 1 , wherein the disease is pustular psoriasis.

8. The method of claim 1 , wherein the disease is myelodysplastic syndrome.

9. The method of claim 1 , wherein the disease is Waldenström's macroglobulinemia.

10. The method of claim 4 , wherein the compound has a formula

and each of R 8 , R 9 , R 10 and R 11 independently is H, aliphatic, halogen, heterocycloaliphatic, alkoxy, or —O-heterocycloaliphatic.

11. The method of claim 10 , wherein each of R 8 , R 9 , R 10 and R 11 independently is H, halogen, 3- to 6-membered heterocycloaliphatic, alkoxy, or —O-(3- to 6-membered heterocycloaliphatic).

12. The method of claim 11 , wherein:
R 8 is H or halogen;
R 9 and R 11 are H;
R 10 is H, F, morpholino, N-methylpiperidin-1-yl, methoxy, 2-hydroxy-2-methylpropoxy, or —O-oxetanyl; or
a combination thereof.

13. The method of claim 10 , wherein the compound has a formula

14. The method of claim 1 , wherein:
R 1 is H or C 1-6 alkyl;
R 2 is H, 3- to 10-membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, cyclobutyl substituted with alkoxy and/or hydroxy, cyclohexyl, cyclohexyl substituted with alkoxy and/or hydroxy, unsubstituted C 1-6 alkyl, or C 1-6 alkyl substituted with —OH, amino, alkoxy, or heterocycloaliphatic;
each R 3 independently is H, or C 1-6 alkyl;
R 4 is halogen, heterocycloaliphatic, aryl, heteroaryl, —NH-heteroaryl, or —O-heteroaryl;
Z 1 is N;
or a combination thereof.

15. The method of claim 1 , wherein R 2 is H, CH 3 ,

16. The method of claim 4 , wherein:
Z 1 is N, and Z 2 , Z 3 , and Z 4 are CR 3 ;
Z 1 and Z 2 are N, and Z 3 and Z 4 are CR 3 ;
Z 1 and Z 3 are N, and Z 2 and Z 4 are CR 3 ;
Z 1 and Z 4 are N, and Z 2 and Z 3 are CR 3 ; or
Z 3 is N, and Z 1 , Z 2 , and Z 4 are CR 3 .

17. The method of claim 4 , wherein R 4 is Br, 5- to 10-membered heteroaryl, 3- to 6-membered heterocycloaliphatic, 6- to 10-membered aryl, —NH-(5- to 10-membered heteroaryl), or —O-(5- to 10-membered heteroaryl).

18. The method of claim 4 , wherein R 4 is pyridinyl, pyrimidinyl, pyrazolyl, —NH-pyrazolyl, pyrrolyl, —O-pyridinyl, —NH-pyridinyl, indolyl, furanyl, —NH-benzopyrazolyl, pyrrolopyridinyl, phenyl, tetrahydropyridinyl, piperidinyl, or 2-oxo-1,2-dihydropyridinyl.

19. The method of claim 16 , wherein R 4 is Br,

where y is 0, 1 or 2, and each R p independently is R a , R b , R a substituted with R b , or R a substituted with R c ;
R a is independently for each occurrence H, D, C 1-6 alkyl, C 3-6 cycloalkyl, C 5-10 aromatic, or C 3-6 heterocycloaliphatic;
R b is independently for each occurrence —OH, —CF 3 , —CN, —OR c , —SO 2 R c , —NR d R d , —N(H)SO 2 R c , —C(O)OH, —N(H)C(O)R c , —C(O)OR c , —C(O)NR d R d , ═O, or halogen;
R c is independently for each occurrence C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heteroalicyclyl, aralkyl, C 1-6 alkyl substituted with 1, 2 or 3 R e , C 5-10 aromatic, C 5-10 aromatic 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 , C 3-6 cycloalkyl optionally substituted with 1, 2 or 3 R e , C 3-6 heteroalicyclyl optionally substituted with 1, 2 or 3 R e , C 5-10 aromatic optionally substituted with 1, 2 or 3 R a or R b , 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 H, C 1-10 aliphatic, heteroaliphatic, or cycloaliphatic; and
R e is independently for each occurrence halogen, C 1-6 alkyl, C 3-6 cycloalkyl, or —OR a .

20. The method of claim 19 , wherein each R p independently is —CH 3 , —OCH 3 , —NH 2 , —CF 3 , F, —CN,

21. The method of claim 10 , wherein:
R 1 is H;
R 2 is H, 3- to 10-membered heteroaliphatic, tetrahydropyranyl, oxetanyl, cyclobutyl, cyclobutyl substituted with alkoxy and/or hydroxy, cyclohexyl, cyclohexyl substituted with alkoxy and/or hydroxy, unsubstituted C 1-6 alkyl, or C 1-6 alkyl substituted with —OH, amino, alkoxy, or heterocycloaliphatic;
R 4 is Br; unsubstituted pyridinyl; pyridinyl substituted with C 1-6 alkyl, haloalkyl, amino, heterocycloaliphatic, cycloalkyl, —CN, alkoxy, —O-heterocycloaliphatic, —NH-heterocycloaliphatic, halogen, sulfonamide, —O-benzyl, carboxyl, sulfonyl, —NH-cycloalkyl, or amide; unsubstituted pyrimidinyl; unsubstituted pyrazolyl; pyrazolyl substituted with C 1-6 alkyl; unsubstituted —NH-pyrazolyl; —NH-pyrazolyl substituted with C 1-6 alkyl, or heteroaryl; pyrrolyl; unsubstituted —O-pyridinyl; —O-pyridinyl substituted with amino; —NH-pyridinyl substituted with C 1-6 alkyl, haloalkyl, or heterocycloaliphatic; unsubs

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Tso Kin
• Li Hui
• Chen Yan
• Yen Rose
• Taylor Vanessa
• Heckrodt Thilo
• Singh Rajinder
• Shaw Simon

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P29/00

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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title