IP Library › Granted Patent US 8,524,709

Granted Patent B2

US 8,524,709 · App. 13/349,222 · Granted Sep 3, 2013

Kinase inhibitor compounds

Inventors: Congxin Liang (Palm Beach Gardens, FL); Ming Qi (Shanghai, CN); Shu Gao (Shanghai, CN); Zhigang Li (Shanghai, CN)

Assignee: Tyrogenex, Inc.

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Quick Facts

Patent No.: US 8,524,709
App. No.: 13/349,222
Granted: Sep 3, 2013
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 (429)

1. A method of treating a disease or disease symptom that is modulated by a kinase enzyme in a subject in need thereof comprising administering to the subject an effective amount of a compound of formula (I), or pharmaceutical salt thereof,

wherein

the disease or disease symptom is selected from the group consisting of renal cell carcinoma, GI stromal tumor, pancreatic neuroendocrine tumor, lung cancer, colorectal cancer, age-related macular degeneracy (AMD), glioblastoma, ovarian cancer, and hepatocellular carcinoma;

Cy is a cyclic structure that can be cycloalkyl, heterocyclic, or heteroaryl, each optionally substituted with Z 1 , Z 2 and Z 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, aryl, 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 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, —S(O) q R 6 , 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 6 —NR 10 R 11 ;

(11) —Z 4 —N(R 12 )—Z 5 —R 6 ;

(12) —P(O)(OR 6 ) 2 ;

R 1 , R 2 , and R 3 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 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, —S(O) q R″ 6 , or —S(O) q NR 7 R 8 ,

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

(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 unsaturated mono-, 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:

2. The method of claim 1 , wherein the disease or disease symptom is modulated by any one or any combination of the kinases selected from VEGFR, PDGFR, KIT, Flt-1, Flt-3, Flt-4, and RET.

3. The method of claim 2 , wherein the disease or disease symptom is modulated by RET.

4. The method of claim 1 , wherein Cy in formula (I) is a non-aromatic cycloalkyl or heterocyclic structure that is optionally substituted with Z 1 , Z 2 and Z 3 .

5. The method of claim 1 , wherein any of R 1 , R 2 or R 3 in the 4-indolinone position in formula (I) is not a heterocycle or heteroaryl group.

6. The method of claim 1 , wherein said compound of formula (I) is selected from:

5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1-acetyl-piperidin-4-yl)-amide,

5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1-methanesulfonyl-piperidin-4-yl)-amide,

N-(2H-3,4,5,6-tetrahydropyran-4-yl){5-[(5-fluoro-2-oxo(1H-benzo[d]azolin-3-ylidene))methyl]-2,4-dimethylpyrrol-3-yl}carboxamide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid piperidin-4-ylamide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((S)-1-acetyl-pyrrolidin-3-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((S)-1-methanesulfonyl-pyrrolidin-3-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1,1-dioxo-tetrahydro-thiophen-3-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1-pyrimidin-2-yl-piperidin-4-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-hydroxy-1,1-dioxo-tetrahydro-thiophen-3-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1,1-dioxo-hexahydro-thiopyran-4-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((S)-6-oxo-piperidin-3-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((2S,3S,4R,5S,6S)-3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1-(2-hydroxy-acetyl)-piperidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(S)-1-(2-hydroxy-acetyl)-pyrrolidin-3-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-hydroxy-tetrahydro-furan-3-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((S)-2-oxo-pyrrolidin-3-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1-benzyl-4-hydroxy-pyrrolidin-3-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1-acetyl-4-hydroxy-pyrrolidin-3-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (1-dimethylaminooxalyl-piperidin-4-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((S)-1-dimethylaminooxalyl-pyrrolidin-3-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((2S,3S,4R,5S)-3,4-dihydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((S)-1-carbamoylmethyl-2-oxo-pyrrolidin-3-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(S)-1-(2-hydroxy-ethyl)-2-oxo-pyrrolidin-3-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(R)-2-(2-hydroxy-ethyl)-3-oxo-isoxazolidin-4-yl]amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((R)-2-dimethylcarbamoylmethyl-3-oxo-isoxazolidin-4-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((R)-2-ethyl-3-oxo-isoxazolidin-4-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((R)-2-carbamoylmethyl-3-oxo-isoxazolidin-4-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(R)-2-(2-methoxy-ethyl)-3-oxo-isoxazolidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((R)-3-oxo-2-pyridin-3-ylmethyl-isoxazolidin-4-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(R)-3-oxo-2-(tetrahydro-pyran-4-yl)-isoxazolidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(R)-3-oxo-2-(tetrahydro-furan-3-yl)-isoxazolidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1-(morpholine-4-carbonyl)-piperidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(S)-1-(morpholine-4-carbonyl)-pyrrolidin-3-yl]-amide,

4-({5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carbonyl}-amino)-piperidine-1-carboxylic acid dimethylamide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((S)-1-dimethylcarbamoyl-pyrrolidin-3-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1-(2-methoxy-acetyl)-piperidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(S)-1-(2-methoxy-acetyl)-pyrrolidin-3-yl]-amide,

N-((3R)oxolan-3-yl){5-[(5-fluoro-2-oxo(1H-benzo[id]azolin-3-ylidene))methyl]-2,4-dimethylpyrrol-3-yl}carboxamide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(R)-2-(2-morpholin-4-yl-ethyl)-3-oxo-isoxazolidin-4-yl]amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(S)-1-(2-methoxy-ethyl)-2-oxo-pyrrolidin-3-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((S)-2-oxo-1-pyridin-4-ylmethyl-pyrrolidin-3-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(R)-3-oxo-2-(tetrahydro-pyran-4-ylmethyl)-isoxazolidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(S)-1-(2-methoxy-ethyl)-pyrrolidin-3-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1-(2-methoxy-ethyl)-piperidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1-(2-dimethylamino-acetyl)-piperidin-4-A-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(8)-1-(2-dimethylamino-acetyl)-pyrrolidin-3-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1-(2-hydroxy-ethyl)-piperidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(S)-1-(2-hydroxy-ethyl)-pyrrolidin-3-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (6′-methyl-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(S)-1-(6-methyl-pyridin-3-yl)-pyrrolidin-3-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(S)-2-oxo-1-(tetrahydro-pyran-4-ylmethyl)-pyrrolidin-3-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [1-(2-methanesulfonyl-ethyl)-piperidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(S)-1-(2-methanesulfonyl-ethyl)-pyrrolidin-3-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(R)-2-(2-methanesulfonyl-ethyl)-3-oxo-isoxazolidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(S)-2-(2-methoxy-ethyl)-3-oxo-isoxazolidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(R)-2-(2-ethoxy-ethyl)-3-oxo-isoxazolidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(S)-1-(2-methoxy-ethyl)-2,5-dioxo-pyrrolidin-3-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(R)-3-oxo-2-(tetrahydro-furan-3-ylmethyl)-isoxazolidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(R)-3-oxo-2-(tetrahydro-furan-2-ylmethyl)-isoxazolidin-4-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(S)-2,5-dioxo-1-(tetrahydro-pyran-4-ylmethyl)-pyrrolidin-3-yl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(S)-2,5-dioxo-1-(tetrahydro-pyran-4-yl)-pyrrolidin-3-yl]-amide, and

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((S)-1-dimethylcarbamoyl-2-oxo-pyrrolidin-3-yl)-amide.

7. The method of claim 1 , wherein said compound of formula (I) is selected from the group of:

5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-hydroxy-cyclohexyl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-amino-cyclohexyl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-oxo-cyclohexyl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((1S,2S)-2-hydroxy-cyclopentyl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((1S,2R)-2-hydroxy-cyclopentyl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-acetylamino-cyclohexyl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (4-methanesulfonylamino-cyclohexyl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid ((1S,2S)-2-hydroxy-cyclohexyl)-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [4-(morpholine-4-carbonyl)-cyclohexyl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [4-(pyrrolidine-1-carbonyl)-cyclohexyl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [4-(aziridine-1-carbonyl)-cyclohexyl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(1R,3S)-3-(pyrrolidine-1-carbonyl)-cyclopentyl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(1R,3S)-3-(morpholine-4-carbonyl)-cyclopentyl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(1R,3S)-3-(aziridine-1-carbonyl)-cyclopentyl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(1R,2S)-2-(pyrrolidine-1-carbonyl)-cyclopentyl]-amide,

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(1R,2S)-2-(morpholine-4-carbonyl)-cyclopentyl]-amide, and

5-[5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid [(1R,2S)-2-(aziridine-1-carbonyl)-cyclopentyl]-amide.

8. The method of claim 1 , wherein the Cy in formula (I) is optionally substituted cycloalkyl.

9. The method of claim 1 , wherein the compound of formula (I) is a compound delineated in Table 1, or pharmaceutical salt thereof:

10. The method of claim 1 , wherein the Cy in formula (I) is optionally substituted 5-membered ring heterocyclic.

11. The method of claim 1 , wherein the Cy is optionally substituted 6-membered ring heterocyclic.

12. A method of treating a disease or disease symptom that is modulated by a kinase enzyme in a subject in need thereof comprising administering to the subject an effective amount of a compound of formula III, or pharmaceutical salt thereof:

wherein

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

R 1 , R 2 , and R 3 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, —S(O) q R″ 6 , 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 ;

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 13 , 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

13. The method of claim 12 , wherein R 3 in formula (III) is halo.

14. The method of claim 13 , wherein R 3 in formula (III) is fluoro.

15. The method of claim 12 , wherein R 1 and R 2 in formula (III) are H, and R 3 is fluoro.

16. A method of treating a disease or disease symptom that is modulated by a kinase enzyme in a subject in need thereof comprising administering to the subject an effective amount of a compound of formula (I), or pharmaceutical salt thereof,

wherein

Cy is aryl optionally substituted with Z 1 , Z 2 and Z 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, —S(O) q R 6 , 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 1 , R 2 , and R 3 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, —S(O) q R″ 16 , or —S(O) q NR 7 R 6 ,

(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 2 o;

(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 17 is independently alkyl, 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.

17. A method of treating a disease or disease symptom that is modulated by a kinase enzyme in a subject in need thereof comprising administering to the subject an effective amount of a compound of formula III, or pharmaceutical salt thereof:

wherein

Cy is aryl optionally substituted with Z 1 , Z 2 and Z 3 ;

R 1 , R 2 , and R 3 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, —S(O) q R″ 6 , 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 ;

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 ;

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

Assignments (4)

RELEASE OF SECURITY INTEREST Recorded Aug 23, 2022

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 060865/0885 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 29, 2018

From: TYROGENEX, INC.

To: EQUINOX SCIENCES, LLC

Reel/Frame 046235/0922 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jul 30, 2013

From: LIANG, CONGXIN; QI, MING; GAO, SHU; LI, ZHIGANG

To: XCOVERY, INC.