# US 7,608,603 B2 · Substituted pyrazolo[3,4-D]pyrimidines as p38 MAP kinase inhibitors

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- Number: US 7,608,603 B2
- Document ID: US7608603B2
- Status: Granted
- Kind: B2
- Application number: 11/509,121
- Filed: 2006-08-23
- Published: 2007-03-01
- Granted: 2009-10-27
- Earliest claimed: 2005-08-25
- Assignees: Roche Palo Alto LLC
- Inventors: Nolan James Dewdney; Tobias Gabriel; Kristen Lynn McCaleb
- Web page: https://patentgrep.com/patent/US7608603B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 11/16: Central respiratory analeptics
- A61P 13/12: of the kidneys
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 19/10: for osteoporosis
- 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 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 31/16: for influenza or rhinoviruses
- A61P 31/18: for HIV
- A61P 31/22: for herpes viruses
- A61P 33/06: Antimalarials
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- 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: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of formula Ia, Ib, Ic, Id, Ie, If, Ig or Ih: wherein X and Y are nitrogen or one of X and Y is nitrogen and the other is CRg, and W, D, E, R4, R5, R6 and Rg are as defined herein. Also disclosed are methods of making the subject compounds and methods of using the compounds in the treatment of p38 MAP kinase-mediated diseases.

## Claims

### Claim 1

A compound of formula Ia:
or a pharmaceutically acceptable salt thereof,
wherein:
R1 is optionally substituted phenyl;
R2 is optionally substituted phenyl
R4 is hydroxyalkyl, alkoxyalkyl or alkylsulfonylalkyl
R5 is hydrogen, —C(═O)—Rc, —(O═)P(ORd)2, —S(═O)2ORd, or a mono-, di- or tri-peptide;
wherein
Rc is —(CH2)p—C(═O)—Re;
wherein
Re is hydrogen, hydroxy, alkoxy or amine;
p is 2 or 3;
Rd is hydrogen, alkyl, an alkali metal ion or an alkaline earth metal ion;
X and Y are nitrogen;
D is —(CR 7R8)n—;
wherein
n is from 1 to 3;
R7 and R8 each independently is hydrogen or alkyl;
W is a bond or NRi;
Ri is hydrogen;
A is O; and
k is 0.

### Claim 2 (depends on 1)

The compound of claim 1, wherein n is 1.

### Claim 3

The compound of claim2, wherein R7 and R8 are hydrogen.

### Claim 4 (depends on 3)

The compound of claim 3, wherein R5 is hydrogen.

### Claim 5 (depends on 3)

The compound of claim 3, wherein R5 is —C(═O)—Rc.

### Claim 6 (depends on 5)

The compound of claim 5, wherein p is 2.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R5 is —(O═)P(ORd)2— and Rd is hydrogen.

### Claim 8 (depends on 1)

The compound of claim 1, wherein said compound is of the formula IVa
wherein
u is 1 or 2;
v is 1 or 2;
each R9 is independently halo;
each R10 is independently halo or alkylsulfonyl and
W, D, R4 and R5 are as recited in claim 1.

### Claim 9 (depends on 1)

A composition comprising:
(a) a pharmaceutically acceptable excipient; and
(b) a compound of claim 1.

### Claim 10

A compound selected from the group consisting of:
Succinic acid mono-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2-hydroxyl-propylamino)-pyrazolo[3,4-d]pyrimidin-1-ylmethyl] ester;
Succinic acid mono-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2-hydroxyl-2-methyl-propylamino)-pyrazolo[3,4-d]pyrimidin-1-ylmethyl] ester;
Succinic acid mono-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2-methanesulfonyl-ethylamino)-pyrazolo[3,4-d]pyrimidin-1-ylmethyl] ester;
[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2-methanesulfonyl-ethylamino)-pyrazolo[3,4-d]pyrirnidin-1-yl]-methanol;
Phosphoric acid mono-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2-methanesulfonyl-ethylamino)-pyrazolo[3,4-d]pyrimidin-1-ylmethyl] ester;
Succinic acid mono-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-ylmethyl] ester;
[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-methanol;
1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1-hydroxymethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol;
1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1-hydroxymethyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylarmino]-2-methyl-propan-2-ol;
Phosphoric acid mono-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2-hydroxy-propylamino)-pyrazolo[3,4-d]pyrimidin-1-ylmethyl] ester;
2-Amino-3-methyl-butyric acid 3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-4-(2-methanesulfonyl-ethylamino)-pyrazolo[3,4-d]pyrimidin-1-ylmethyl ester;
Phosphoric acid mono-{2-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-1-methyl-ethyl} ester;
Phosphoric acid mono-{2-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylarnino]-1-methyl-ethyl } ester; and
2-Amino-3-methyl-butyric acid 2-[3-(2-chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-1-methyl-ethyl ester.