IP Library › Granted Patent US 11,059,814

Granted Patent B2

US 11,059,814 · App. 16/789,131 · Granted Jul 13, 2021

Kinase inhibitors and methods for making and using

Inventors: Vanessa Taylor (San Francisco, CA); Yan Chen (Foster City, CA); Rose Yen (San Francisco, CA)

Assignee: Rigel Pharmaceuticals, Inc.

C07D417/14 A61P29/00 C07D401/04 C07D401/14 C07D405/04 C07D405/14 C07D413/14 C07D417/04

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 11,059,814
App. No.: 16/789,131
Granted: Jul 13, 2021
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Disclosed embodiments concern kinase inhibitors, such as interleukin receptor associated kinases (IRAK) inhibitors according to Formula 1, 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 a kinase-associated disease or condition, particularly an IRAK-associated disease or condition.

Claims (147)

1. A method for inhibiting an IRAK protein, comprising contacting the IRAK protein with an effective amount of a compound having a formula 1

or a pharmaceutically acceptable salt, hydrate, N-oxide e, or solvate thereof, wherein:

Het-1 is a 5- or 6-membered heteroaryl comprising at least one carbon atom and at least one heteroatom selected from N, O or S;

R 1 is H or alkyl;

R 2 is —N(R c ) 2 ;

each R 3 independently is C 1-6 alkyl, C 1-3 haloalkyl, or halo;

m is 0, 1 or 2;

each R 4 independently is C 1-6 alkyl;

k is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;

A is N or CR h ;

R h is H, R 3 or the

moiety;

R 5 is H, aliphatic, phosphonooxyalkyl, phosphonoalkyl, or acyl;

each of R 6 and R 7 independently is H, aliphatic, or halo;

X is O or NR 9 ;

R 9 is R a , C(O)C 1-6 aliphatic, C(O)N(R c ) 2 , or CO 2 R a ;

Y is N or CH;

Linker is a bond, —(C(R 10 ) 2 ) n —, —(C(R 10 ) 2 ) n —O—, —C(O)—(C(R 10 ) 2 ) p —, or —(C(R 10 ) 2 ) p —N(R a )—;

each R 10 independently is R a or R b ;

n is 1, 2, 3, 4, 5, or 6;

p is 0, 1, or 2;

R a is independently for each occurrence H, D, C 1-6 alkyl, or C 3-6 cycloalkyl;

R b is independently for each occurrence —OH, —OR a , or halo; and

R c is independently for each occurrence R a , or two R c groups together with the nitrogen bound thereto form a C 3-7 heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents selected from C 1-6 alkyl, C 1-3 haloalkyl, —OH, or halo, and optionally interrupted with one or two additional heteroatoms selected from O, —N(R g )—, or S, where R g is R a , —C(O)R a , —C(O)OR a or —C(O)N(R a ) 2 ; or

the compound is selected from

I-39: N-(2-methoxy-5-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-40: N-(2-methoxy-5-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide; or

I-41: N-(2-methoxy-5-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide.

2. The method of claim 1 , wherein Het-1 is pyridinyl, furanyl or thiazolyl.

3. The method of claim 1 , wherein:

R 2 has a formula

Z is a bond, O, —NR a , —NC(O)R a , or C(R 8 ) 2 ; and

each R 8 independently is H, C 1-6 alkyl, C 1-3 haloalkyl, —OH, or halo.

4. The method of claim 3 , wherein R 2 is

5. The method of claim 1 , wherein m is 1 or 2 and each R 3 independently is F, Cl, Br, or I.

6. The method of claim 1 , wherein k is 0.

7. The method of claim 1 , wherein:

each of R 6 and R 7 independently is H, halo, or C 1-6 alkyl;

R 5 is H, C 1-6 alkyl, —CH 2 OP(O)(R d ) 2 , —CH 2 P(O)(R d ) 2 , or acyl, where each R d is independently for each occurrence —OR a , —O − M + where each M + independently is an alkali metal ion or an ammonium ion;

R 6 is H;

R 7 is H;

R 9 is H or C 1-6 alkyl; or

a combination thereof.

8. The method of claim 7 , wherein R 5 is H.

9. The method of claim 1 , wherein the

moiety is

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

or a pharmaceutically acceptable salt, hydrate, N-oxide e, or solvate thereof.

11. The method of claim 1 , wherein m is 1; and

R 3 is para to the amide; or

R 3 is para to R 2 .

12. The method of claim 1 , the compound having a structure according to formula 2

or a pharmaceutically acceptable salt, hydrate, N-oxide e, or solvate thereof, wherein:

Het-1 is pyridinyl, furanyl or thiazolyl;

R 2 is —N(R c ) 2 ;

each R 3 independently is halo;

m is 0 or 1;

each of R 5 , R 6 and R 7 is H;

A is N or CR h ;

R h is H, R 3 or the

moiety;

X is O or NR 9 ;

R 9 is IV;

Y is N or CH;

Linker is a bond, —(C(R 10 ) 2 ) n —, —(C(R 10 ) 2 ) n —O—, —C(O)—(C(R 10 ) 2 ) p —, or —(C(R 10 ) 2 ) p —N(R a )—;

each R 10 independently is R a or R b ;

n is 1 or 2; and

p is 0 or 1.

13. The method of claim 12 , wherein the compound has a general formula selected from

or a pharmaceutically acceptable salt, hydrate, N-oxide e, or solvate thereof.

14. The method of claim 1 , wherein the compound is selected from:

I-1: N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-2: N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-3: N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-4: N-(2-(4-fluoropiperidin-1-yl)-4-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-5: N-(2-(4-fluoropiperidin-1-yl)-4-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-6: N-(2-(4-fluoropiperidin-1-yl)-4-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-7: N-(2-(4-fluoropiperidin-1-yl)-4-(4-methylpiperazin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-8: N-(2-(4-fluoropiperidin-1-yl)-4-(4-methylpiperazin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-9: N-(2-(4-fluoropiperidin-1-yl)-4-(4-methylpiperazin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-10: N-(2-(4-hydroxypiperidin-1-yl)-4-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-11: N-(2-(4-hydroxypiperidin-1-yl)-4-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-12: N-(2-(4-hydroxypiperidin-1-yl)-4-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-13: N-(2,4-dimorpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-14: N-(2,4-dimorpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-15: N-(2,4-dimorpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-16: N-(2-(4-hydroxy-4-methylpiperidin-1-yl)-4-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-17: N-(2-(4-hydroxy-4-methylpiperidin-1-yl)-4-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-18: N-(2-(4-hydroxy-4-methylpiperidin-1-yl)-4-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-19: N-(2-(4,4-difluoropiperidin-1-yl)-4-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-20: N-(2-(4,4-difluoropiperidin-1-yl)-4-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-21: N-(2-(4,4-difluoropiperidin-1-yl)-4-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-22: N-(4-morpholino-2-(pyrrolidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-23: N-(4-morpholino-2-(pyrrolidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-24: N-(4-morpholino-2-(pyrrolidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-25: N-(5-morpholino-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-26: N-(5-morpholino-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-27: N-(5-(2-morpholinoethoxy)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-28: N-(5-(2-morpholinoethoxy)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-29: N-(5-(2-morpholinoethoxy)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-30: N-(4-fluoro-5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-31: N-(4-fluoro-5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-32: N-(4-fluoro-5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-33: N-(5-(1,1-difluoro-2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-34: N-(5-(1,1-difluoro-2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-35: N-(5-(1,1-difluoro-2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-36: N-(4-morpholino-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-37: N-(4-morpholino-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-38: N-(4-morpholino-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-39: N-(2-methoxy-5-morpholinophenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-40: N-(2-methoxy-5-morpholinophenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-41: N-(2-methoxy-5-morpholinophenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-42: N-(6-morpholino-4-(piperidin-1-yl)pyridin-3-yl)-6-(1H-pyrazol-4-yl)picolinamide;

I-43: N-(6-morpholino-4-(piperidin-1-yl)pyridin-3-yl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-44: N-(6-morpholino-4-(piperidin-1-yl)pyridin-3-yl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-45: N-(4-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-46: N-(4-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-47: N-(4-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-48: N-(4-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-49: N-(4-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-50: N-(4-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-51: N-(4-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-52: N-(4-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-53: N-(4-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-54: N-(4-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-55: N-(4-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-56: N-(4-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-57: N-(5-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-58: N-(5-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-59: N-(5-(morpholine-4-carbonyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-60: N-(5-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-61: N-(5-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-62: N-(5-(morpholinomethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-63: N-(5-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-64: N-(5-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-65: N-(5-(2-morpholino-2-oxoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-66: N-(5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-67: N-(5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-68: N-(5-(2-morpholinoethyl)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-69: N-(4-(methyl(2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-70: N-(4-(methyl(2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-71: N-(4-(methyl(2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide;

I-72: N-(4-((2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide;

I-73: N-(4-((2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-5-(1H-pyrazol-4-yl)furan-2-carboxamide;

I-74: N-(4-((2-morpholinoethyl)amino)-2-(piperidin-1-yl)phenyl)-2-(1H-pyrazol-4-yl)thiazole-4-carboxamide; or

I-75: N-(5-morpholino-2-(piperidin-1-yl)phenyl)-6-(1H-pyrazol-4-yl)picolinamide.

15. The method of claim 1 , comprising inhibiting an IRAK protein in vivo.

Assignments (3)

SECURITY INTEREST Recorded May 8, 2026

From: RIGEL PHARMACEUTICALS, INC.

To: MIDCAP FUNDING IV TRUST

Reel/Frame 075576/0880 →

SECURITY INTEREST Recorded Aug 25, 2022

From: RIGEL PHARMACEUTICALS, INC.

To: MIDCAP FINANCIAL TRUST

Reel/Frame 061327/0712 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 13, 2020

From: YEN, ROSE; CHEN, YAN; TAYLOR, VANESSA

To: RIGEL PHARMACEUTICALS, INC.

Reel/Frame 052106/0783 →

Continuity (3)

Continuation 16022323 · Jun 28, 2018

Provisional Application 62526838 · Jun 29, 2017

Related Publication 20200181135A1 · Jun 11, 2020

Cited By (1)

US 12,384,775