# US 7,608,634 B2 · Substituted pyrrolines as kinase inhibitors

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- Number: US 7,608,634 B2
- Document ID: US7608634B2
- Status: Granted
- Kind: B2
- Application number: 11/800,912
- Filed: 2007-05-08
- Published: 2007-09-13
- Granted: 2009-10-27
- Earliest claimed: 2002-06-05
- Assignees: Janssen Pharmaceutica NV
- Inventors: Han-Cheng Zhang; Bruce E. Maryanoff; David F. McComsey; Kimberly White; Hong Ye; Leonard R. Hecker; Bruce Conway; Keith Demarest
- Web page: https://patentgrep.com/patent/US7608634B2

## CPC

- C07D 409/14: containing three or more hetero rings
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/04: Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 17/14: for baldness or alopecia
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/14: containing three or more hetero rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/14: containing three or more hetero rings
- C07D 405/14: containing three or more hetero rings
- C07D 417/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is directed to novel substituted pyrroline compounds useful as kinase or dual-kinase inhibitors, methods for producing such compounds and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.

## Claims

### Claim 1

A method for treating or ameliorating diabetes and diabetes-associated disorders comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):
wherein
R is selected from phenyl and naphthyl;
R1 is -heteroaryl-R6; wherein a heteroaryl ring carbon atom forms the point of attachment to the indole nitrogen atom;
R5 is 1 to 2 substituents independently selected from hydrogen, —O—(C1-8)alkyl, —O—(C1-8)alkyl-OH, —O—(C1-8)alkyl-O—(C1-8)alkyl, —O—(C1-8)alkyl-NH2, —O—(C1-8)alkyl-NH(C1-8alkyl), —O—(C1-8)alkyl-N(C1-8alkyl)2, —O—(C1-8)alkyl-S—(C1-8)alkyl, —O—(C1-8)alkyl-SO2—(C1-8)alkyl, —O—(C1-8)alkyl-SO2—NH2, —O—(C1-8)alkyl-SO2—NH(C1-8alkyl), —O—(C1-8)alkyl-SO2—N(C1-8alkyl)2, —O—C(O)H, —O—C(O)—(C1-8)alkyl, —O—C(O)—NH2, —O—C(O)—NH(C1-8alkyl), —O—C(O)—N(C1-8alkyl)2, —O—(C1-8)alkyl-C(O)H, —O—(C1-8)alkyl-C(O)—(C1-8)alkyl, —O—(C1-8)alkyl-CO2H, —O—(C1-8)alkyl-C(O)—O—(C1-8)alkyl, —O—(C1-8)alkyl-C(O)—NH2, —O—(C1-8)alkyl-C(O)—NH(C1-8alkyl), —O—(C1-8)alkyl-C(O)—N(C1-8alkyl)2, —C(O)H, —C(O)—(C1-8)alkyl, —CO2H, —C(O)—O—(C1-8)alkyl, —C(O)—NH2, —C(NH)—NH2, —C(O)—NH(C1-8alkyl), —C(O)—N(C1-8alkyl)2, —SH, —S—(C1-8)alkyl, —S—(C1-8)alkyl-S—(C1-8)alkyl, —S—(C1-8)alkyl-O—(C1-8)alkyl, —S—(C1-8)alkyl-O—(C1-8)alkyl-OH, —S—(C1-8)alkyl-O—(C1-8)alkyl-NH2, —S—(C1-8)alkyl-O—(C1-8)alkyl-NH(C1-8alkyl), —S—(C1-8)alkyl-O—(C1-8)alkyl-N(C1-8alkyl)2, —S—(C1-8)alkyl-NH(C1-8alkyl), —SO2—(C1-8)alkyl, —SO2—NH2, —SO2—NH(C1-8alkyl), —SO2—N(C1-8alkyl)2, —N—R7, —(C1-4)alkyl-N—R7, cyano, (halo)1-3, hydroxy, nitro, oxo, -cycloalkyl-R6, —(C1-4)alkyl-cycloalkyl-R6, -heterocyclyl-R6, —(C1-4)alkyl-heterocyclyl-R6, -aryl-R6, —(C1-4)alkyl-aryl-R6, -heteroaryl-R6 or —(C1-4)alkyl-heteroaryl-R6;
R6 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from hydrogen, —C1-8alkyl, —(C1-8)alkyl-(halo)1-3 or —(C1-8)alkyl-OH;
with the proviso that, when R6 is attached to a carbon atom, R6 is further selected from —C1-8alkoxy, —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, cyano, halo, —(C1-8)alkoxy-(halo)1-3, hydroxy or nitro;
R7 is 2 substituents independently selected from hydrogen, —C1-8alkyl, —C2-8alkenyl, —C2-8alkynyl, —(C1-8)alkyl-OH, —(C1-8)alkyl-O—(C1-8)alkyl, —(C1-8)alkyl-NH2, —(C1-8)alkyl-NH(C1-8alkyl), —(C1-8)alkyl-N(C1-8alkyl)2, —(C1-8)alkyl-S—(C1-8)alkyl, —C(O)—(C1-8)alkyl, —C(O)—O—(C1-8)alkyl, —C(O)—NH2, —C(O)—NH(C1-8alkyl), —C(O)—N(C1-8alkyl)2, —SO2—(C1-8)alkyl, —SO2—NH2, —SO2—NH(C1-8alkyl), —SO2—N(C1-8alkyl)2, —C(N)—NH2, -cycloalkyl-R8, —(C1-8)alkyl-heterocyclyl-R8, -aryl-R8, —(C1-8)alkyl-aryl-R8 or —(C1-8)alkyl-heteroaryl-R8;
R8 is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from hydrogen, —C1-8alkyl, —(C1-8)alkyl-(halo)1-3 or —(C1-8)alkyl-OH;
with the proviso that, when R8 is attached to a carbon atom, R8 is further selected from —C1-8alkoxy, —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, cyano, halo, —(C1-8)alkoxy-(halo)1-3, hydroxy or nitro;
R2 is one substituent attached to a carbon or nitrogen atom selected from hydrogen, —C1-8alkyl-R5, —C2-8alkenyl-R5, —C2-8alkynyl-R5, —C(O)H, —C(O)—(C1-8)alkyl-R9, —C(O)—NH2, —C(O)—NH(C1-8alkyl-R9), —C(O)—N(C1-8alkyl-R9)2, —C(O)—NH(aryl-R8), —C(O)-cycloalkyl-R8, —C(O)-heterocyclyl-R8, —C(O)-aryl-R8, —C(O)-heteroaryl-R8, —CO2H, —C(O)—O—(C1-8)alkyl-R9, —C(O)—O-aryl-R8, —SO2—(C1-8)alkyl-R9, —SO2-aryl-R8, -cycloalkyl-R6, -aryl-R6 or —(C1-8)alkyl-N—R7;
with the proviso that, when R2 is attached to a carbon atom, R2 is further selected from —C1-8alkoxy-R5, —N—R7, cyano, halogen, hydroxy, nitro, oxo (wherein oxo is attached to a saturated carbon atom), -heterocyclyl-R6 or -heteroaryl-R6;
R9 is 1 to 2 substituents independently selected from hydrogen, —C1-8alkoxy, —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, cyano, (halo)1-3, hydroxy or nitro;
R3 is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen, —C1-8alkyl-R10, —C2-8alkenyl-R10, —C2-8alkynyl-R10, —C1-8alkoxy-R10, —C(O)H, —C(O)—(C1-8)alkyl-R9, —C(O)—NH2, —C(O)—NH(C1-8alkyl-R9), —C(O)—N(C1-8alkyl-R9)2, —C(O)-cycloalkyl-R8, —C(O)-heterocyclyl-R8, —C(O)-aryl-R8, —C(O)-heteroaryl-R8, —C(NH)—NH2, —CO2H, —C(O)—O—(C1-8)alkyl-R9, —C(O)—O-aryl-R8, —SO2—(C1-8)alkyl-R9, —SO2-aryl-R8, —N—R7, —(C1-8)alkyl-N—R7, cyano, halogen, hydroxy, nitro, -cycloalkyl-R8, -heterocyclyl-R8, -aryl-R8 or -heteroaryl-R8;
R4 is 1 to 4 substituents attached to a carbon atom independently selected from hydrogen, —C1-8alkyl-R10, —C2-8alkenyl-R10, —C2-8alkynyl-R10, —C1-8alkoxy-R10, —C(O)H, —C(O)—(C1-8)alkyl-R9, —C(O)—NH2, —C(O)—NH(C1-8alkyl-R9), —C(O)—N(C1-8alkyl-R9)2, —C(O)-cycloalkyl-R8, —C(O)-heterocyclyl-R8, —C(O)-aryl-R8, —C(O)-heteroaryl-R8, —C(NH)—NH2, —CO2H, —C(O)—O—(C1-8)alkyl-R9, —C(O)—O-aryl-R8, —SH, —S—(C1-8)alkyl-R10, —SO2—(C1-8)alkyl-R9, —SO2-aryl-R8, —SO2—NH2, —SO2—NH(C1-8alkyl-R9), —SO2—N(C1-8alkyl-R9)2, —N—R7, —(C1-8)alkyl-N—R7, cyano, halogen, hydroxy, nitro, -cycloalkyl-R8, -heterocyclyl-R8, -aryl-R8 or -heteroaryl-R8;
R10 is 1 to 2 substituents independently selected from hydrogen, —NH2, —NH(C1-8alkyl), —N(C1-8alkyl)2, cyano, (halo)1-3, hydroxy, nitro or oxo;
X is CR11; and,
R11 is selected from hydrogen, —C1-8alkyl-R10, —C2-8alkenyl-R10, —C2-8alkynyl-R10, —C1-8alkoxy-R10, -aryl-R8, -heteroaryl-R8 or halogen.

### Claim 2 (depends on 1)

The method of claim 1 wherein the disorder is mediated by selective inhibition of a kinase selected from protein kinase C or glycogen synthase kinase-3.

### Claim 3 (depends on 2)

The method of claim 2 wherein the kinase is selected from protein kinase C α, protein kinase C β-II, protein kinase C γ or glycogen synthase kinase-3β.

### Claim 4 (depends on 1)

The method of claim 1 wherein the diabetes is mediated by dual inhibition of at least two kinases selected from protein kinase C or glycogen synthase kinase-3.

### Claim 5 (depends on 4)

The method of claim 4 wherein at least two kinases are selected from protein kinase C α, protein kinase C β-II, protein kinase C γ or glycogen synthase kinase-3β.

### Claim 6 (depends on 1)

The method of claim 1 wherein the therapeutically effective amount of the compound is from about 0.001 mg/kg/day to about 300 mg/kg/day.

### Claim 7 (depends on 1)

The method of claim 1 wherein diabetes is selected from insulin dependent diabetes or Type II non-insulin dependent diabetes mellitus.

### Claim 8 (depends on 1)

The method of claim 1 wherein diabetes-associated disorders are selected from impaired glucose tolerance, diabetic retinopathy, proliferative retinopathy, retinal vein occlusion, macular edema, cardiomyopathy, nephropathy or neuropathy.

### Claim 9 (depends on 1)

The method of claim 1 further comprising administering to a subject in need thereof a therapeutically effective amount of a composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 9)

The method of claim 9 wherein the therapeutically effective amount of the composition is from about 0.001 mg/kg/day to about 300 mg/kg/day.