IP Library › Granted Patent US 8,039,470

Granted Patent B2

US 8,039,470 · App. 12/657,887 · Granted Oct 18, 2011

Kinase inhibitor compounds

Assignee: Tyrogenex, Inc.

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Quick Facts

Patent No.: US 8,039,470
App. No.: 12/657,887
Granted: Oct 18, 2011
Kind: B2

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Abstract

The invention relates to compounds, compositions comprising the compounds, and methods of using the compounds and compound compositions. The compounds, compositions, and methods described herein can be used for the therapeutic modulation of kinase-mediated processes, and treatment of disease and disease symptoms, particularly those mediated by certain kinase enzymes.

Claims (237)

1. A method of treating a disease or disease symptom modulated by any one or any combination of the kinases selected from VEGFR, PDGFR, KIT, and Flt-3, in a subject in need thereof comprising administering to the subject an effective amount of a compound of formula (I),

wherein Cy is a cyclic structure that can be cycloalkyl or heterocyclic, each optionally substituted with Z 1 , Z 2 and Z 3 ;

R 1 , R 2 , R 3 , R 4 , and R 5 are each independently:

(1) hydrogen or R 6 , where R 6 , is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heteroaryl, aralkyl, heteroarylalkyl, heterocyclo, or heterocycloalkyl, each of which is unsubstituted or substituted with Z 1 , Z 2 and one or more groups Z 3 ;

(2) —OH or —OR 6 ;

(3) —SH or —SR 6 ;

(4) —C(O) 2 H, —C(O) q R 8 , —C(O)NR 7 R 8 , —C(O)C(O)NR 7 R 8 , or —O—C(O) q R 6 , where q is 1 or 2;

(5) —SO 3 H or —S(O) q NR 7 R 8 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NR 7 R 8 ;

(10) —Z 4 —N(R 9 )—Z 5 —NR 10 R 11 ;

(11) —Z 4 —N(R 12 )—Z 5 —R 6 ;

(12) —P(O)(OR 6 ) 2 ;

R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently:

(1) hydrogen or R 6 ;

(2) R 7 and R 8 together with the nitrogen atom to which they are attached may be a heterocycle which is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ; or

(3) any two of R 9 , R 10 and R 11 together with the nitrogen atoms to which they are attached may be a 3- to 12-membered saturated or unsaturated mono-, bi-, or tri-heterocyclic ring which is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ;

Z 1 , Z 2 and Z 3 are each independently:

(1) hydrogen or Z 6 , where Z 6 is (i) alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; (ii) a group (i) which is itself substituted by one or more of the same or different groups (i); or (iii) a group (i) or (ii) which is substituted by one or more of the following groups (2) to (13);

(2) —OH or —OZ 16 ;

(3) —SH or —SZ 16 ;

(4) —C(O) 2 H, C(O) q Z 16 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 16 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 16 , or —S(O) q NZ 17 Z 18 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 17 Z 18 ;

(10) —Z 4 —N(Z 18 ) —Z 5 —NZ 19 Z 20 ;

(11) oxo;

(12) —O—C(O)—Z 16 ;

(13) any two of Z 1 , Z 2 , and Z 3 may together be alkylene, alkenylene, aryl, heteroaryl, or heterocyclo completing a 3- to 8-membered saturated or unsaturated ring together with the atoms to which they are attached;

Z 4 and Z 5 are each independently

(1) a single bond;

(2) —Z 11 —S(O) q —Z 12 —;

(3) —Z 11 —C(O)—Z 12 —;

(4) —Z 11 —O—Z 12 —;

(5) —Z 11 —S—Z 12 —;

(6) —Z 11 —O—C(O)—Z 12 —; or

(7) —Z 11 —C(O)—O—Z 12 ;

Z 11 and Z 12 are each independently

(1) a single bond;

(2) alkylene;

(3) alkenylene; or

(4) alkynylene;

each Z 16 is independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl, each optionally substituted with one or more of the following groups:

(2) —OH or —OZ 21 ;

(3) —SH or —SZ 21 ;

(4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 21 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 21 , or —S(O) q NZ 17 Z 18 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 -NZ 17 Z 18 ;

(10) —Z 4 —N(Z 18 ) —Z 5 —NZ 19 Z 20 ;

(11) oxo;

(12) —O—C(O)—Z 21 ;

each Z 17 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

each Z 18 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

each Z 19 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

each Z 20 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

each Z 21 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl; each Z 22 is independently is,

(2) —OH or —OZ 21 ;

(3) —SH or —SZ 21 ;

(4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 21 Z 21 , —C(O)C(O)NZ 21 Z 21 , or —O—C(O) q Z 21 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 21 , or —S(O) q NZ 21 Z 21 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 21 Z 21 ;

(10) —Z 4 —N(Z 21 )—Z 5 —NZ 21 Z 21 ;

(11) oxo;

(12) —O—C(O)—Z 21 ;

where Z 17 and Z 18 , or Z 19 and Z 20 , together with the nitrogen atom to which they are attached may be a heterocycle which is unsubstituted or substituted with 1, 2, or 3 independent Z 22 ; and

where any two of Z 18 , Z 19 or Z 20 together with the nitrogen atoms to which they are attached may be a 3- to 12-membered saturated or unsaturatedmono-, bi-, or tri-heterocyclic ring which is unsubstituted or substituted with 1, 2, or 3 independent Z 22 ;

provided said compound is other than a compound of formula IIa or IIb

or pharmaceutical salt thereof;

wherein the disease or disease symptom is renal cell carcinoma or GI stroma tumor.

2. A method of making a compound of formula I

wherein Cy is a cyclic structure that can be cycloalkyl or heterocyclic, each optionally substituted with Z 1 , Z 2 and Z 3 ;

R 1 , R 2 , R 3 , R 4 , and R 5 are each independently:

(2) —OH or —OR 6 ;

(3) —SH or —SR 6 ;

(4) —C(O) 2 H, —C(O) q R 8 , —C(O)NR 7 R 8 , —C(O)C(O)NR 7 R 8 , or —O—C(O) q R 8 , where q is 1 or 2;

(5) —SO 3 H or —S(O) q NR 7 R 8 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NR 7 R 8 ;

(10) —Z 4 —N(R 9 )—Z 5 —NR 10 R 11 ;

(11) —Z 4 —N(R 12 )—Z 5 —R 6 ;

(12) —P(O)(OR 6 ) 2 ;

R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently:

(1) hydrogen or R 6 ;

(2) R 7 and R 8 together with the nitrogen atom to which they are attached may be a heterocycle which is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ; or

Z 1 , Z 2 and Z 3 are each independently:

(2) —OH or —OZ 16 ;

(3) —SH or —SZ 16 ;

(4) —C(O) 2 H, C(O) q Z 16 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 16 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 16 , or —S(O) q NZ 17 Z 18 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 -NZ 17 Z 18 ;

(10) —Z 4 —N(Z 18 )—Z 5 —NZ 19 Z 20 ;

(11) oxo;

(12) —O—C(O)—Z 16 ;

Z 4 and Z 5 are each independently

(1) a single bond;

(2) —Z 11 —S(O) q —Z 12 —;

(3) —Z 11 —C(O)—Z 12 —;

(4) —Z 11 —O—Z 12 —;

(5) —Z 11 —S—Z 12 —;

(6) —Z 11 —O—C(O)—Z 12 —; or

(7) —Z 11 —C(O)—O—Z 12 ;

Z 11 and Z 12 are each independently

(1) a single bond;

(2) alkylene;

(3) alkenylene; or

(4) alkynylene;

(2) —OH or —OZ 21 ;

(3) —SH or —SZ 21 ;

(4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 21 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 21 , or —S(O) q NZ 17 Z 18 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 -NZ 17 Z 18 ;

(10) —Z 4 —N(Z 18 )—Z 5 —NZ 19 Z 20 ;

(11) oxo;

(12) —O—C(O)—Z 21 ;

(2) —OH or —OZ 21 ;

(3) —SH or —SZ 21 ;

(4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 21 Z 21 , —C(O)C(O)NZ 21 Z 21 , or —O—C(O) q Z 21 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 21 , or —S(O) q NZ 21 Z 21 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 21 Z 21 ;

(10) —Z 4 —N(Z 21 )—Z 5 —NZ 21 Z 21 ;

(11) oxo;

(12) —O—C(O)—Z 21 ;

where Z 17 and Z 18 , or Z 19 and Z 20 , together with the nitrogen atom to which they are attached may be a heterocycle which is unsubstituted or substituted with 1, 2, or 3 independent Z 22 ; and

provided said compound is other than a compound of formula IIa or IIb

comprising reacting an intermediate delineated herein with a reagent to provide a compound of formula I as defined herein.

3. A method of identifying a kinase inhibitor that selectively inhibits a kinase target preferentially over inhibition of AMPK comprising: (i) assaying a compound of formula I for inhibition of a kinase enzyme; (ii) assaying the compound of formula I for inhibition of AMPK; (iii) assessing whether the compound of formula I inhibits a kinase target preferentially over inhibition of AMPK; wherein the compound of formula I is

wherein Cy is a cyclic structure that can be cycloalkyl or heterocyclic, each optionally substituted with Z 1 , Z 2 and Z 3 ;

R 1 , R 2 , R 3 , R 4 , and R 5 are each independently:

(2) —OH or —OR 6 ;

(3) —SH or —SR 6 ;

(4) —C(O) 2 H, —C(O) q R 6 , —C(O)NR 7 R 8 , —C(O)C(O)NR 7 R 8 , or —O—C(O) q R 6 , where q is 1 or 2;

(5) —SO 3 H or —S(O) q NR 7 R 8 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NR 7 R 8 ;

(10) —Z 4 —N(R 9 )—Z 5 —NR 10 R 11 ;

(11) —Z 4 —N(R 12 )—Z 5 —R 6 ;

(12) —P(O)(OR 6 ) 2 ;

R 7 , R 8 , R 9 , R 10 , R 11 and R 12 are each independently:

(1) hydrogen or R 6 ;

(2) R 7 and R 8 together with the nitrogen atom to which they are attached may be a heterocycle which is unsubstituted or substituted with Z 1 , Z 2 and Z 3 ; or

Z 1 , Z 2 and Z 3 are independently:

(2) —OH or —OZ 16 ;

(3) —SH or —SZ 16 ;

(4) —C(O) 2 H, C(O) q Z 16 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 16 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 16 , or —S(O) q NZ 17 Z 18 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 17 Z 18 ;

(10) —Z 4 —N(Z 18 )—Z 5 —NZ 19 Z 20 ;

(11) oxo;

(12) —O—C(O)—Z 16 ;

Z 4 and Z 5 are each independently

(1) a single bond;

(2) —Z 11 —S(O) q —Z 12 —;

(3) —Z 11 —C(O)—Z 12 —;

(4) —Z 11 —O—Z 12 —;

(5) —Z 11 —S—Z 12 —;

(6) —Z 11 —O—C(O)—Z 12 —; or

(7) —Z 11 —C(O)—O—Z 12 ;

Z 11 and Z 12 are each independently

(1) a single bond;

(2) alkylene;

(3) alkenylene; or

(4) alkynylene;

(2) —OH or —OZ 21 ;

(3) —SH or —SZ 21 ;

(4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 17 Z 18 , —C(O)C(O)NZ 17 Z 18 , or —O—C(O) q Z 21 , where q is 1 or 2:

(5) —SO 3 H, —S(O) q Z 21 , or —S(O) q NZ 17 Z 18 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 17 Z 18 ;

(10) —Z 4 —N(Z 18 )—Z 5 —NZ 19 Z 20 ;

(11) oxo;

(12) —O—C(O)—Z 21 ;

each Z 18 is independently hydrogen, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, heteroaryl, aralkyl, heteroarylalkyl, alkylaryl, cycloalkylaryl, heterocyclo, or heterocycloalkyl;

(2) —OH or —OZ 21 ;

(3) —SH or —SZ 21 ;

(4) —C(O) 2 H, C(O) q Z 21 , —C(O)NZ 21 Z 21 , —C(O)C(O)NZ 21 Z 21 , or —O—C(O) q Z 21 , where q is 1 or 2;

(5) —SO 3 H, —S(O) q Z 21 , or —S(O) q NZ 21 Z 21 ;

(6) halo;

(7) cyano;

(8) nitro;

(9) —Z 4 —NZ 21 Z 21 ;

(10) —Z 4 —N(Z 21 )—Z 5 —NZ 21 Z 21 ;

(11) oxo;

(12) —O—C(O)—Z 21 ;

where Z 17 and Z 18 , or Z 19 and Z 20 , together with the nitrogen atom to which they are attached may be a heterocycle which is unsubstituted or substituted with 1, 2, or 3 independent Z 22 ; and

provided said compound is other than a compound of formula IIa or IIb

or pharmaceutical salt thereof.

4. The method of claim 3 , wherein the compound of formula I inhibits a kinase target preferentially over inhibition of AMPK with greater selectivity than 5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide.

5. A method of treating a disease or disease symptom wherein the disease or disease symptom is renal cell carcinoma or GI stroma tumor in a subject in need thereof comprising administering to the subject an effective amount of a compound identified by the method of claim 3 , or pharmaceutical salt thereof.

Assignments (5)

RELEASE OF SECURITY INTEREST Recorded Apr 6, 2020

From: HORIZON FUNDING TRUST 2013-1, AS ASSIGNEE OF HORIZON TECHNOLOGY FINANCE CORPORATION / COMPASS HORIZON FUNDING COMPANY LLC

To: TYROGENEX, INC.; XCOVERY HOLDING COMPANY, LLC

Reel/Frame 052315/0553 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 29, 2018

From: TYROGENEX, INC.

To: EQUINOX SCIENCES, LLC

Reel/Frame 046235/0922 →

CHANGE OF NAME Recorded Apr 14, 2014

From: XCOVERY, INC.

To: TYROGENEX, INC.