# US 9,040,550 B2 · 2,4-pyrimidinediamine compounds and their uses

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- Number: US 9,040,550 B2
- Document ID: US9040550B2
- Status: Granted
- Kind: B2
- Application number: 14/333,163
- Filed: 2014-07-16
- Published: 2014-11-06
- Granted: 2015-05-26
- Earliest claimed: 2002-02-01
- Assignees: Rigel Pharmaceuticals, Inc.
- Applicants: Rigel Pharmaceuticals, Inc
- Inventors: Rajinder Singh; Ankush Argade; Donald G. Payan; Susan Molineaux; Sacha J. Holland; Jeffrey Clough; Holger Keim; Somasekhar Bhamidipati; Catherine Sylvain; Hui Li; Alexander B. Rossi
- Web page: https://patentgrep.com/patent/US9040550B2

## CPC

- A61K 31/505: Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/538: ortho- or peri-condensed with carbocyclic ring systems
- A61K 31/5383: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/5395: having two or more nitrogen atoms in the same ring, e.g. oxadiazines
- A61K 31/551: having two nitrogen atoms, e.g. dilazep
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- 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 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/06: Antimigraine agents
- A61P 27/02: Ophthalmic agents
- A61P 27/14: Decongestants or antiallergics
- A61P 27/16: Otologicals
- 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
- C07D 239/48: Two nitrogen atoms
- C07D 265/36: condensed with one six-membered ring
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 403/14: containing three or more hetero rings
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 407/14: containing three or more hetero rings
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 409/14: containing three or more hetero rings
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D 413/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- C07D 495/04: Ortho-condensed systems
- C07D 498/04: Ortho-condensed systems
- C07D 498/14: Ortho-condensed systems
- C07F 5/027: {Organoboranes and organoborohydrides}
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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 invention provides 2,4-pyrimidinediamine compounds that inhibit the IgE and/or IgG receptor signaling cascades that lead to the release of chemical mediators, intermediates and methods of synthesizing the compounds and methods of using the compounds in a variety of contexts, including in the treatment and prevention of diseases characterized by, caused by or associated with the release of chemical mediators via degranulation and other processes effected by activation of the IgE and/or IgG receptor signaling cascades.

## Claims

### Claim 1

A compound according to Formula (I):
or a salt thereof, wherein:
R2 and R4 independently are each phenyl substituted with one or more of the same or different R8 groups;
R5 is fluoro or (C1-C6) alkyl optionally substituted with one or more of the same or different R8 groups;
R8 is selected from Ra, Rb, Ra substituted with one or more of the same or different Ra or Rb, —(CH2)m—Rb, —(CHRa)m—Rb, —O—(CH2)m—Rb, —S—(CH2)m—Rb, —O—CHRaRb, —O—CRa(Rb)2, —O—(CHRa)m—Rb, —S—(CHRa)m—Rb, —C(O)NH—(CH2)m—Rb, —C(O)NH— (CHRa)m—Rb, —O— (CH2)m—C(O)NH— (CH2)m—Rb, —S—(CH2)m—C(O)NH—(CH2)m—Rb, —O—(CHRa)m—C(O)NH—(CHRa)m—Rb, —S—(CHRa)mC(O)NH—(CHRa)m—Rb, —NH—(CH2)m—Rb, —NH— (CHRa)m—Rb, —NH[(CH2)mRb], —N[(CH2)mRb]2, —NH—C(O)—NH—(CH2)m—Rb, —NH—C(O)—(CH2)m—CHRbRb, or —NH—(CH2)m—C(O)—NH—(CH2)m—Rb;
each Ra is independently selected from hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl, or 6-16 membered heteroarylalkyl;
each Rb is independently selected from —ORd, (C1-C3) haloalkyloxy, —OCF3, —NRcRc, halogen, —CF3, —CN, —NO2, —S(O)2Rd, —S(O)2ORd, —S(O)NRcRc, —S(O)2NRcRc, —OS(O)Rd, —OS(O)2Rd, —OS(O)2ORd, —OS(O)2NRcRc, —C(O)Rd, —C(O)ORd, —C(O)NRcRc, —C(NH)NRcRc, —C(NRa)NRcRc, —C(NOH)Ra, —C(NOH)NRcRc, —OC(O)Rd, —OC(O)ORd, —OC(O)NRcRc, —OC(NH)NRcRc, —OC(NRa)NRcRc, —[NHC(O)]nRd, —[NRaC(O)]nRd, —[NHC(O)]nORd, —[NRaC(O)]nORd, —[NHC(O)]nNRcRc, —[NRaC(O)]nNRcRc, —[NHC(NH)]nNRcRc, or —[NRaC(NRa)]nNRcRc;
each Rc is independently Ra, or, alternatively, each Rc is taken together with the nitrogen atom to which it is bonded to form a 5 to 8-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which is optionally substituted with one or more of the same or different Ra or suitable Rb groups;
each Rd is independently Ra;
at least one R8 is Rb;
each m is independently an integer from 1 to 3; and
each n is independently an integer from 0 to 3.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R2 is monosubstituted with an R8 group.

### Claim 3 (depends on 2)

The compound of claim 2, wherein the R8 group is at the para position of R2.

### Claim 4 (depends on 2)

The compound of claim 2, wherein the R8 group on R2 is (C1-C10) alkyl, (C1-C10) branched alkyl, —O—C(O)ORa, —O—(CH2)m—C(O)ORa, —C(O)ORa, —O—(CH2)m—NRcRc, —O—C(O)NRcRc, —O—(CH2)m—C(O)NRcRc, —O—C(NH)NRcRc, —O—(CH2)m—C(NH)NRcRc, or —NH—(CH2)m—NRcRc.

### Claim 5 (depends on 3)

The compound of claim 3, wherein the R8 group on R2 is —O—(CH2)m—Rb.

### Claim 6 (depends on 1)

The compound of claim 1, wherein R4 is substituted with at least one Rb group.

### Claim 7 (depends on 6)

The compound of claim 6, wherein the at least one Rb group is —OC(O)Rd, —OC(O)ORd, —OC(O)NRcRc, —OC(NH)NRcRc, —OC(NRa)NRcRc, —[NHC(O)]nRd, —[NRaC(O)]nRd, —[NHC(O)]nORd, —[NRaC(O)]nORd, —[NHC(O)]nNRcRc, —[NRaC(O)]nNRcRc, —[NHC(NH)]nNRcRc, or —[NRaC(NRa)]nNRcRc.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the R4 phenyl is monosubstituted.

### Claim 9 (depends on 8)

The compound of claim 8, wherein the R4 phenyl is monosubstituted at the meta or para position.

### Claim 10 (depends on 2)

The compound of claim 2, wherein R2 is monosubstituted with —O—(CH2)m—Rb.

### Claim 11 (depends on 10)

The compound of claim 10, wherein Rb is ORd.

### Claim 12 (depends on 11)

The compound of claim 11, wherein Rd is (C1-C6) alkyl.

### Claim 13 (depends on 12)

The compound of claim 12, wherein Rd is methyl.

### Claim 14 (depends on 10)

The compound of claim 10, wherein m is two.

### Claim 15 (depends on 1)

The compound of claim 1, wherein R2 is monosubstituted at the para position with —O—(CH2)2—OMe; and R4 is monosubstituted with Rb.

### Claim 16 (depends on 1)

The compound of claim 1 in the form of a benzene sulfonic acid salt.