# US 7,745,451 B2 · Tetrahydronaphthyridine and tetrahydropyrido[4,3-d]pyrimidine compounds and compositions thereof useful in the treatment of conditions associated with neurological and inflammatory disorders and dysfunctions

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- Number: US 7,745,451 B2
- Document ID: US7745451B2
- Status: Granted
- Kind: B2
- Application number: 11/429,026
- Filed: 2006-05-04
- Published: 2006-11-16
- Granted: 2010-06-29
- Earliest claimed: 2005-05-04
- Assignees: Renovis, Inc.
- Inventors: Michael G. Kelly; John Kincaid; Carl J. Kaub
- Web page: https://patentgrep.com/patent/US7745451B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/06: Antihyperlipidemics
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/02: of urine or of the urinary tract, e.g. urine acidifiers
- A61P 13/08: of the prostate
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/26: Psychostimulants, e.g. nicotine, cocaine
- 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 27/16: Otologicals
- 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 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Fused heterocyclic compounds are disclosed that have formula 1: where A, B, L, N, R1, R3, R4′, Y and Z are as defined herein. The compounds and pharmaceutical compositions thereof are useful for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, cognitive disorders, anxiety, depression, and others.

## Claims

### Claim 1

A compound having a formula 1:
wherein
A and B are independently CR2′R2′, CO, or CS;
Y is CR2′R2′;
W is N;
Z is O or NR2;
L is substituted or unsubstituted C1-C9 alkylene or substituted or unsubstituted C1-C9 heteroalkylene;
R1 is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
R2 is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl;
each R2′ is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, or aralkyl;
R3 is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl; and
R4′ is R4 or —Z-L′-R4, wherein Z′ is a single bond, NR2′, O, S, SO, SO2, COO, or CONR2′, and L′ is (C1-C6)alkylene; and wherein R4 is selected from the group consisting of H, alkyl, —C(O)R20, —NR21C(O)R22, alkylamino, alkylthio, alkoxy, alkoxycarbonyl, alkylarylamino, arylalkyloxy, amino, aryl, arylalkyl, —SO2R23, substituted sulfanyl, aminosulfonyl, arylsulfonyl, dihydroxyphosphoryl, azido, carbamoyl, carboxyl, cyano, cycloalkyl, cycloheteroalkyl, dialkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxy, nitro, and —SH; wherein
R20 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl;
R21 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl;
R22 is alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl; and
R23 is alkyl, aryl, or heteroaryl;
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer or an isotopic variant thereof.

### Claim 2

A compound having a formula 1:
wherein
A and B are independently CR2′R2′, CO, or CS;
Y is CR2′R2′;
W is N;
Z is O or NR2;
L is a single bond;
R1 is a substituted or unsubstituted carbocyclic group or a substituted or unsubstituted heterocyclic group;
R2 is hydrogen, C1-C6 alkyl, or C3-C8 cycloalkyl;
each R2 is independently hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, aryl, or aralkyl;
R3 is a carbocyclic group or a heterocyclic group; and
R4′ is R4 or —Z′-L′-R4, wherein Z′ is a single bond, NR2′, O, S, SO, SO2, COO, or CONR2′, and L′ is (C1-C6)alkylene; and wherein R4 is selected from the group consisting of H, alkyl, —C(O)R20, —NR21C(O)R22, alkylamino, alkylthio, alkoxy, alkoxycarbonyl, alkylarylamino, arylalkyloxy, amino, aryl, arylalkyl, —SO2R23, substituted sulfanyl, aminosulfonyl, arylsulfonyl, dihydroxyphosphoryl, azido, carbamoyl, carboxyl, cyano, cycloalkyl, cycloheteroalkyl, dialkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxy, nitro, and —SH; wherein
R20 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl;
R21 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl;
R22 is alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl; and
R23 is alkyl, aryl, or heteroaryl;
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer or an isotopic variant thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein L is branched C1-C9 alkylene or substituted C1-C9 alkylene.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein L is unsubstituted C1-C9 alkylene.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein Z is O.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein Z is NR2.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein Z is NH.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R4′ is H.

### Claim 9 (depends on 3)

The compound according to claim 3, having a formula 2:

### Claim 10 (depends on 9)

The compound according to claim 9, wherein
W is N;
Z is NH; and
R4′ is H.

### Claim 11 (depends on 10)

The compound according to claim 10, wherein L is selected from the group consisting of —CH2—, —CHMe-, —CMe2-, —(CH2)2—, —CMe2-CH2—, and —(CH2)3—.

### Claim 12 (depends on 10)

The compound according to claim 10, wherein R1 is aryl, heteroaryl, bicycloaryl, bicycloalkyl, or bicycloheteroaryl.

### Claim 13 (depends on 10)

The compound according to claim 10, wherein R1 is substituted or unsubstituted cycloalkyl.

### Claim 14 (depends on 10)

The compound according to claim 10, wherein R1 is substituted or unsubstituted quinoline, isoquinoline, methylenedioxyphenyl, or indole.

### Claim 15 (depends on 10)

The compound according to claim 10, wherein R1 is
and wherein the subscript n′ is 1, 2, 3, 4, or 5, and each R5 is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, —C(O)R20, —NR21C(O)R22, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, —S(O)R24, —SO2R23, —SO2CF3, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted dihydroxyphosphoryl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and —SH; wherein
R20 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl;
R21 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl;
R22 is alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl;
R23 is alkyl, aryl, or heteroaryl; and
R24 is alkyl, aryl, or heteroaryl.

### Claim 16 (depends on 15)

The compound according to claim 15, wherein the subscript n′ is 1, 2 or 3.

### Claim 17 (depends on 15)

The compound according to claim 15, wherein the subscript n′ is 1 or 2.

### Claim 18 (depends on 15)

The compound according to claim 15, wherein each R5 is independently selected from the group consisting of Me, Et, Pr, iso-Pr, Ph, Cl, F, Br, CN, OH, OMe, OEt, OPh, COPh, CO2Me, CH2—N-morpholino, CH2—N-(4-Me-piperidino), CONH2, CF3, CHF2, OCF3, OCHF2, t-Bu, SMe, SOMe, SO2Me, SO2CF3, SO2NH2, and pyridyl.

### Claim 19 (depends on 10)

The compound according to claim 10, wherein R3 is
and wherein the subscript n′ is 1, 2, 3, 4, or 5, and each of R5 is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, —C(O)R20, —NR21C(O)R22, substituted or unsubstituted alkylamino, substituted or unsubstituted alkylthio, substituted or unsubstituted alkoxy, aryloxy, alkoxycarbonyl, substituted alkoxycarbonyl, substituted or unsubstituted alkylarylamino, arylalkyloxy, substituted arylalkyloxy, amino, aryl, substituted aryl, arylalkyl, —S(O)R24, —SO2R23, —SO2CF3, substituted sulfanyl, substituted or unsubstituted aminosulfonyl, substituted or unsubstituted arylsulfonyl, substituted or unsubstituted dihydroxyphosphoryl, azido, substituted or unsubstituted carbamoyl, carboxyl, cyano, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloheteroalkyl, substituted or unsubstituted dialkylamino, halo, heteroaryloxy, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalkyl, hydroxy, nitro, and —SH; wherein
R20 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl;
R21 is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl;
R22 is alkyl, alkoxy, cycloalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroalkyl, heteroaryl, or heteroarylalkyl;
R23 is alkyl, aryl, or heteroaryl; and
R24 is alkyl, aryl, or heteroaryl.

### Claim 20 (depends on 19)

The compound according to claim 19, wherein R3 is

### Claim 21 (depends on 19, 20)

The compound according to claim 19 or 20, wherein the subscript n′ is 1, 2 or 3.

### Claim 22 (depends on 19, 20)

The compound according to claim 19 or 20, wherein the subscript n′ is 1 or 2.

### Claim 23 (depends on 19, 20)

The compound according to claim 19 or 20, wherein each R5 is independently selected from the group consisting of Me, Et, Pr, iso-Pr, Ph, Cl, F, CN, OH, OMe, OEt, OPh, CF3, CHF2, OCF3, OCHF2, t-Bu, SO2Me, and SO2CF3.

### Claim 24 (depends on 10)

The compound according to claim 10, wherein R3 is

### Claim 25 (depends on 24)

The compound according to claim 24, wherein R3 is

### Claim 26 (depends on 1)

The compound according to claim 1, selected from the group consisting of:
(2,3-Difluoro-benzyl)-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
(4-Fluoro-3-methyl-benzyl)-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine; and
(2-Fluoro-4-trifluoromethyl-benzyl)-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer or an isotopic variant thereof.

### Claim 27 (depends on 1)

The compound according to claim 1, selected from the group consisting of:
(2-Methyl-benzyl)-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
(4-Chloro-benzyl)-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
Cyclohexylmethyl-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
(2-Methoxy-benzyl)-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
(3-Methoxy-benzyl)-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
(2-Chloro-benzyl)-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
[2-(2-Chloro-phenyl)-ethyl]-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
[2-(4-Methoxy-phenyl)-ethyl]-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
Benzo[1,3]dioxol-5-ylmethyl-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
[6-(5-Methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(2-trifluoromethoxy-benzyl)-amine;
[6-(5-Methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-phenethyl-amine;
[2-(3-Methoxy-phenyl)-ethyl]-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
[2-(4-Chloro-phenyl)-ethyl]-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
[6-(5-Methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(2-p-tolyl-ethyl)-amine;
[6-(5-Methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-(4-trifluoromethyl-benzyl)-amine;
(2-Difluoromethoxy-benzyl)-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
(4-Methoxy-benzyl)-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
(3-Chloro-benzyl)-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
(4-Methyl-benzyl)-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
(3-Fluoro-benzyl)-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
[6-(5-Methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine;
(3,4-Difluoro-benzyl)-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine; and
[1-(4-Fluoro-phenyl)-ethyl]-[6-(5-methyl-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[4,3-d]pyrimidin-4-yl]-amine;
or a pharmaceutically acceptable salt, a stereoisomer, a tautomer or an isotopic variant thereof.

### Claim 28 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of the compound of claim 1.

### Claim 29 (depends on 28)

The pharmaceutical composition of claim 28, wherein the carrier is a parenteral carrier.

### Claim 30 (depends on 28)

The pharmaceutical composition of claim 28, wherein the carrier is an oral carrier.

### Claim 31 (depends on 28)

The pharmaceutical composition of claim 28, wherein the carrier is a topical carrier.