Pyrazole compounds and method for making and using the compounds

Patent metadata

Field	Value
Publication number	US-9982000-B2
Application number	US-201615136508-A
Country	US
Kind code	B2
Filing date	Apr 22, 2016
Priority date	Apr 22, 2015
Publication date	May 29, 2018
Grant date	May 29, 2018

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 compound, having a formula

or salt thereof, wherein:
Het-1 is 5-membered heteroaryl;
y is from 1 to 2;
R 2 is H, aliphatic, heteroaliphatic, heterocycloaliphatic, aryl, amide, heterocyclyl or araliphatic;
each R 3 independently is H, aliphatic, halogen, heteroaliphatic, —O-aliphatic, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl, sulfinyl, haloalkyl, alkylphosphate, or alkylphosphonate, wherein R 3 is not pyridinyl;
R 4 , R 5 , R 6 and R 7 are each independently H, aliphatic, heteroaliphatic, alkoxy, heterocyclyl, aryl, araliphatic, —O-heterocyclyl, hydroxyl, haloalkyl, halogen, nitro, cyano, carboxyl, carboxyl ester, acyl, amide, amino, sulfonyl, sulfonamide, sulfanyl or sulfinyl;
R 8 and R 9 are each independently H, aliphatic, heteroaliphatic, aryl, heterocyclyl, sulfonyl, nitro, halogen, haloalkyl, carboxyl ester, cyano or amino; and
R 10 is H, aliphatic, alkoxy, heteroaliphatic, carboxyl ester, araliphatic, NO 2 , CN, OH, haloalkyl, acyl, alkyl phosphate or alkylphosphonate.

2. The compound of claim 1 , wherein each of R 4 , R 6 , and R 7 independently is H, F or CF 3 , and R 5 is H, F, CF 3 , methoxy, morpholin-4-yl, 1-methylpiperidin-4-yl, —O—CH 2 C(CH 3 ) 2 OH, or —O-(oxetan-3-yl).

3. The compound of claim 1 , wherein R 8 and R 9 are each independently H, halogen, haloalkyl, or alkyl.

4. The compound of claim 1 , wherein R 10 is H, alkyl, carboxyl ester, acyl, alkyl phosphate, alkyl phosphonate or aralkyl.

5. The compound of claim 1 , wherein:
R 2 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 or —(CH 2 ) n —R b ;
each of R 4 , R 5 , R 6 , and R 7 independently is R a , R b , Ra substituted with R c , —OR a , —O—(CR a R a ) p —R b ;
R 10 is R a , R b , R a substituted with —OP(O)(R f ) 2 , R a substituted with 1, 2 or 3 R b , R a substituted with R c , R a substituted with —P(O)(R f ) 2 , aralkyl, —(CR a R a ) n —R a , —(CH 2 ) n —R a or —C(O)C(R a ) 2 NR a R b
n is 1, 2 or 3;
p is 1, 2, or 3;
R a is independently for each occurrence H, D, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl or C 3-6 heteroalicyclyl;
R b is independently for each occurrence —OH, —CF 3 , —OR c , —NR d R d , —C(O)OH, —C(O)R c , —C(O)OR c , —C(O)NR d R d 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 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, C 1-6 alkyl substituted with 1, 2 or 3 R e , C 3-6 cycloalkyl, C 3-6 cycloalkyl 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, such as morpholinyl, piperidinyl, N-methylpiperidinyl or pyrrolidinyl;
R e is independently for each occurrence halogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 heteroalicyclyl, C 1-6 alkyl-OH, —OR a , —OC(O)R a or —O-aralkyl;
R f is independently for each occurrence —OR a , —O − M + or —O − [M 2+ ] 0.5 ;
each M + independently is an alkali metal ion or an ammonium ion; and
M 2+ is an alkaline metal earth ion.

6. The compound of claim 1 , wherein the compound has a formula

R 8 and R 9 are each independently H, aliphatic, heteroaliphatic, aryl, heterocyclyl, sulfonyl, nitro, halogen, haloalkyl, carboxyl ester, cyano or amino;
R 10 is H, aliphatic, alkoxy, heteroaliphatic, carboxyl ester, araliphatic, NO 2 , CN, OH, haloalkyl, acyl, alkyl phosphate or alkylphosphonate; and
R 11 , R 12 , and R 14 are each independently H or aliphatic.

7. The compound of claim 1 , wherein the compound is a salt.

8. The compound of claim 1 , wherein the compound is selected from
I-1: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide 2,2,2-trifluoroacetate;
I-2: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamide;
I-3: N-(1-(2-hydroxy-2-methylpropyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-4: tert-butyl 4-(5-((1-(2-ethoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate;
I-5: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-6: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide formic acid;
I-9: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide;
I-10: di-tert-butyl ((4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl) phosphate;
I-11: tert-butyl ((4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl) hydrogen phosphate;
I-12: (4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl dihydrogen phosphate;
I-13: N-(1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-(trifluoromethyl)-1H-pyrazol-4-yl)furan-2-carboxamide;
I-14: sodium (4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)methyl phosphate;
I-16: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-17: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide hydrochloride salt;
I-18: N-(1-(2-(2-methoxyethoxy)ethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide;
I-19: 1-(isobutyryloxy)ethyl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate;
I-20: tert-butyl (S)-(1-(4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazol-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate;
I-21: 1-methylcyclopropyl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate;
I-22: 1-((4-methoxybenzyl)oxy)-2-methylpropan-2-yl 4-(5-((1-(2-methoxyethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)carbamoyl)furan-2-yl)-1H-pyrazole-1-carboxylate;
I-23: 5-(1H-pyrazol-4-yl)-N-(3-(pyridin-2-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;
I-24: 5-(5-nitro-1H-pyrrol-3-yl)-N-(1-(propoxymethyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;
I-25: N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-26: 5-(1-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;
I-27: N-(1-((1,3-trans)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-28: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;
I-29: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(3-methyl-1H-pyrazol-4-yl)furan-2-carboxamide;
I-30: 5-(3-methyl-1H-pyrazol-4-yl)-N-(1-(oxetan-3-yl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)furan-2-carboxamide;
I-31: N-(1-((1,3-cis)-3-ethoxycyclobutyl)-3-(pyridin-2-yl)-1H-pyrazol-4-yl)-5-(1-methyl-1H-pyrazol-4-yl)furan-2-carboxamid

Assignees

• Rigel Pharmaceuticals Inc

Inventors

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

Classifications

• A61P39/02

  Antidotes · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title