US 10,590,121 B2Granted

Kinase inhibitors and methods for making and using

AssigneeRigel Pharmaceuticals, Inc.

InventorsVanessa Taylor, Yan Chen, Rose Yen

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Abstract

Disclosed embodiments concern kinase inhibitors having a structure according to formula 1, such as 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 a kinase-associated disease or condition, particularly an IRAK-associated disease or condition.

Claims37

Dependent claims

A compound, having a formula 1

or a pharmaceutically acceptable salt, hydrate, N-oxide, 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;
R1 is H or alkyl;
R2 is —N(Rc)2;
each R3 independently is C1-6alkyl, C1-3haloalkyl, or halo;
m is 0, 1 or 2;
each R4 independently is C1-6alkyl;
k is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9;
A is N or CRh;
Rh is H, R3 or the
moiety;
R5 is H, aliphatic, phosphonooxyalkyl, phosphonoalkyl, or acyl;
each of R6 and R7 independently is H, aliphatic, or halo;
X is O or NR9;
R9 is Ra, C(O)C1-6aliphatic, C(O)N(Rc)2, or CO2Ra;
Y is N or CH;
Linker is a bond, —(C(R10)2)n—, —(C(R10)2)n—O—, —C(O)—(C(R10)2)p—, or —(C(R10)2)p—N(Ra)—;
each R10 independently is Ra or Rb;
n is 1, 2, 3, 4, 5, or 6;
p is 0, 1, or 2;
Ra is independently for each occurrence H, D, C1-6 alkyl, or C3-6cycloalkyl;
Rb is independently for each occurrence —OH, —ORa, or halo;
and
Rc is independently for each occurrence Ra, or two Rc groups together with the nitrogen bound thereto form a C3-7heterocyclyl optionally substituted with 1, 2, 3 or 4 substituents selected from C1-6 alkyl, C1-3haloalkyl, —OH, or halo, and optionally interrupted with one or two additional heteroatoms selected from O, —N(Rg)—, or S, where Rg is Ra, —C(O)Ra, —C(O)ORa or —C(O)N(Ra)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.

30 more elements

A compound 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-carb oxamide;
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.

148 more elements

Dependencies are inferred from the claim text.

Facts

Application: 16/022,323Filed 28 Jun 2018 · us provisional application
Priority: 29 Jun 2017
Published: US 2019/0002455 A13 Jan 2019
Granted: 17 Mar 2020
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 417/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms,…
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…

Family

Application62/526,838Us provisional application · filed 29 Jun 2017
US 2019/0002455 A1Pre-grant publication · published 3 Jan 2019
US 10,590,121 B2This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

Facts

Application

16/022,323Filed 28 Jun 2018 · us provisional application

Priority

29 Jun 2017

Published

US 2019/0002455 A13 Jan 2019

Granted

17 Mar 2020

Term ends

Not estimatedThe source records don’t support an estimate.

Classification10 codes

C07D 417/14
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms,…
A61P 29/00
Non-central analgesic, antipyretic or antiinflammatory agents
C07D 401/04
Containing two hetero rings: directly linked by a ring-member-to-ring-member bond
C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…