# US 8,785,437 B2 · Prodrugs of 2,4-pyrimidinediamine compounds and their uses

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- Number: US 8,785,437 B2
- Document ID: US8785437B2
- Status: Granted
- Kind: B2
- Application number: 13/909,858
- Filed: 2013-06-04
- Published: 2013-12-19
- Granted: 2014-07-22
- Earliest claimed: 2005-01-19
- Assignees: Rigel Pharmaceuticals, Inc.
- Applicants: Rigel Pharmaceuticals, Inc.
- Inventors: Rajinder Singh; Somasekhar Bhamidipati; Esteban Masuda; Thomas Sun; Valentino J. Stella
- Web page: https://patentgrep.com/patent/US8785437B2

## CPC

- C07D 498/04: Ortho-condensed systems
- A61K 31/5383: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- 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 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- 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 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/10: Anti-acne agents
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 21/04: for myasthenia gravis
- A61P 25/00: Drugs for disorders of the nervous system
- 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 37/00: Drugs for immunological or allergic disorders
- 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
- C07F 9/65583: {each of the hetero rings containing nitrogen as ring hetero atom}
- C07F 9/6561: containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- C07F 9/65742: {non-condensed with carbocyclic rings or heterocyclic rings or ring systems}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

The present disclosure provides prodrugs of biologically active 2,4-pyrimidinediamine compounds, compositions comprising the prodrugs, intermediates and methods for synthesizing the prodrugs and methods of using the prodrugs in a variety of applications.

## Claims

### Claim 1

A method of treating systemic lupus erythematosus comprising administering to a subject in need thereof an effective amount of a compound according to structural formula (I):
or a salt, solvate, hydrate or N-oxide thereof, wherein:
Y is CH2, NR24, O, S, S(O) or S(O)2;
Z1 and Z2 are each, independently of one another, CH or N;
R2 is an optionally substituted lower alkyl, lower cycloalkyl, lower heteroalkyl, lower cycloheteroalkyl, aryl, phenyl, or heteroaryl group;
R5 is an electronegative group;
R17 is hydrogen, halogen, fluoro, or lower alkyl or, alternatively, R17 taken together with R18 are an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms;
R18 is hydrogen, halogen, fluoro, or lower alkyl, or, alternatively, R18 taken together with R17 are an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms;
R19 hydrogen or lower alkyl, or, alternatively, R19 taken together with R20 are an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms;
R20 is hydrogen or lower alkyl, or, alternatively, R20 taken together with R19 are an oxo (═O) group or, together with the carbon atom to which they are attached, a spirocycle containing from 3 to 7 carbon atoms;
R21, R22 and R23 are each, independently of one another, hydrogen or RP;
R24 is hydrogen, lower alkyl or RP, with the proviso that at least one of R21, R22, R23 and R24 is RP; and
each RP is, independently of the others, —(CRdRd)y—O—P(O)(OR1)(OR1), —(CRdRd)y—O—P(O)(OR1)(OH), —(CRdRd)y—O—P(OR1)(OR1) or —(CRdRd)y—O—P(OR1)(OH), where each Ri is, independently of the others, lower unsubstituted alkanyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl;
each Rd is, independently of the other, hydrogen, cyano, optionally substituted (C1-C20) alkyl, (C1-C20) perfluoroalkyl, optionally substituted (C7-C30) arylalkyl or optionally substituted 6-30 membered heteroarylalkyl, where each optional substituent is, independently of the others, selected from hydrogen, alkyl, aryl, arylalkyl, heteroaryl and heteroalkyl, or, alternatively, two Rd taken together with the carbon atom to which they are bonded are a (C3-C8) cycloalkyl; and
y is 1, 2, or 3.

### Claim 2 (depends on 1)

The method according to claim 1 wherein the method reduces or ameliorates a symptom of systemic lupus erythematosus.

### Claim 3 (depends on 2)

The method according to claim 2 wherein the symptom is fever.

### Claim 4 (depends on 2)

The method according to claim 2 wherein the symptom is arthralgias.

### Claim 5 (depends on 2)

The method according to claim 2 wherein the symptom is arthritis.

### Claim 6 (depends on 2)

The method according to claim 2 wherein the symptom is serositis.

### Claim 7 (depends on 6)

The method according to claim 6 wherein the serositis manifests as pleurisy.

### Claim 8 (depends on 6)

The method according to claim 6 wherein the serositis manifests as pericarditis.