# US 10,369,148 B2 · 2,4-pyrimidinediamine compounds and their uses

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- Number: US 10,369,148 B2
- Document ID: US10369148B2
- Status: Granted
- Kind: B2
- Application number: 15/366,931
- Filed: 2016-12-01
- Published: 2017-03-23
- Granted: 2019-08-06
- 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/US10369148B2

## 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 method of inhibiting an Fc receptor signaling cascade, comprising administering to a subject a compound according to Formula (I)
or a salt thereof, wherein:
one of R2 and R4 is a phenyl monosubstituted with (C1-C6) alkyl, —ORa, —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, —NH—(CH2)m—NRcRc or —[NHC(O)]Rd;
the other of R2 and R4 is a phenyl monosubstituted or disubstituted with R8;
R2 and R4 are different;
R5 is fluoro, —CN, or (C1-C3) haloalkyl;
each R8 is independently Ra, Rb, or Ra substituted with one Ra or Rb;
each Ra is (C1-C6) alkyl, or 3-8 membered cycloheteroalkyl;
each Rb is —ORa, —OCF3, —NRcRc, halogen, —CF3, —CN, —NO2, —N3, —SO2NRcRc, —C(O)Ra, —C(O)ORa, —C(O)NRcRc, or —C(NH)NRcRc;
each Rc is independently Ra or, alternatively, two Rc are taken together with the nitrogen atom to which they are bonded to form a 5 or 6-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different Ra or suitable Rb groups;
each Rd is independently Ra; and
each m is independently an integer from 1 to 2.

### Claim 2 (depends on 1)

The method of claim 1, wherein R5 is (C1-C3) haloalkyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein R5 is —CF3.

### Claim 4 (depends on 2)

The method of claim 2, wherein at least one R8 is Rb and each Rb is independently —ORa, —NRcRc, halogen, —CF3, —CN, —SO2NRcRc, —C(O)Ra, or —C(O)NRcRc.

### Claim 5 (depends on 1)

The method of claim 1, wherein R4 is a phenyl monosubstituted with —ORa, —O—C(O)ORa, —O—(CH2)m—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, —NH—(CH2)m—NRcRc or —[NHC(O)]Rd.

### Claim 6 (depends on 5)

The method of claim 5, wherein R4 is a phenyl monosubstituted with —[NHC(O)]Rd.

### Claim 7 (depends on 6)

The method of claim 6, wherein Rd is (C1-C6)alkyl.

### Claim 8 (depends on 1)

The method of claim 1, wherein R2 is a phenyl disubstituted with R8.

### Claim 9 (depends on 8)

The method of claim 8, wherein at least one R8 is Ra substituted with one Ra or Rb.

### Claim 10 (depends on 9)

The method of claim 9, wherein at least one R8 is a 3-8 membered cycloheteroalkyl substituted with one Ra or Rb.

### Claim 11 (depends on 8)

The method of claim 8, wherein at least one R8 is Rb.

### Claim 12 (depends on 11)

The method of claim 11, wherein at least one R8 is NRcRc.

### Claim 13 (depends on 8)

The method of claim 8, wherein at least one R8 is —ORa.

### Claim 14 (depends on 13)

The method of claim 13, wherein Ra is (C1-C6)alkyl.

### Claim 15 (depends on 8)

The method of claim 8, wherein one R8 comprises piperazinyl.

### Claim 16 (depends on 15)

The method of claim 15, wherein the piperazinyl is substituted with one Ra or Rb.

### Claim 17 (depends on 1)

The method according to claim 1, comprising treating a disease selected from osteoarthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, idiopathic inflammatory bowel disease, irritable bowel syndrome, spastic colon, scleroderma, increased fibrosis, keloids, post-surgical scars, pulmonary fibrosis, vascular spasms, migraine, reperfusion injury and post myocardial infarction, anaphylactoid reactions, hay fever, allergic conjunctivitis, allergic rhinitis, allergic asthma, atopic dermatitis, eczema, urticaria, mucosal disorders.

### Claim 18

A method of inhibiting an Fc receptor signaling cascade, comprising administering to a subject a compound having a formula
or a salt thereof, wherein:
R2 is a phenyl disubstituted with R8;
R4 is a phenyl monosubstituted with (C1-C6) alkyl, —ORa, —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, —NH—(CH2)m—NRcRc or —[NHC(O)]Rd;
R5 is (C1-C3) haloalkyl;
one R8 comprises piperazinyl, and the other R8 is independently Ra, Rb, or Ra substituted with one Ra or Rb;
each Ra is (C1-C6) alkyl, or 3-8 membered cycloheteroalkyl;
each Rb is —ORa, —OCF3, —NRcRc, halogen, —CF3, —CN, —NO2, —N3, —SO2NRcRc, —C(O)Ra, —C(O)ORa, —C(O)NRcRc, or —C(NH)NRcRc;
each Rc is independently Ra or, alternatively, two Rc are taken together with the nitrogen atom to which they are bonded to form a 5 or 6-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different Ra or suitable Rb groups;
each Rd is independently Ra; and
each m is independently an integer from 1 to 2.

### Claim 19

A method, comprising contacting a cell that degranulates with a compound according to Formula (I)
or a salt thereof, wherein:
one of R2 and R4 is a phenyl monosubstituted with (C1-C6) alkyl, —ORa, —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, —NH—(CH2)m—NRcRc or —[NHC(O)]Rd;
the other of R2 and R4 is a phenyl monosubstituted or disubstituted with R8;
R2 and R4 are different;
R5 is fluoro, —CN, or (C1-C3) haloalkyl;
each R8 is independently Ra, Rb, or Ra substituted with one Ra or Rb;
each Ra is (C1-C6) alkyl, or 3-8 membered cycloheteroalkyl;
each Rb is —ORa, —OCF3, —NRcRc, halogen, —CF3, —CN, —NO2, —N3, —SO2NRcRc, —C(O)Ra, —C(O)ORa, —C(O)NRcRc, or —C(NH)NRcRc;
each Rc is independently Ra or, alternatively, two Rc are taken together with the nitrogen atom to which they are bonded to form a 5 or 6-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different Ra or suitable Rb groups;
each Rd is independently Ra; and
each m is independently an integer from 1 to 2.

### Claim 20 (depends on 19)

The method according to claim 19 comprising contacting the cell in vitro.

### Claim 21 (depends on 19)

The method according to claim 19 comprising contacting the cell in vivo.

### Claim 22 (depends on 19)

The method according to claim 19 wherein contacting the cell comprises contacting a Syk kinase associated with the cell with the compound.

### Claim 23

A method, comprising administering to a human or animal subject a compound according to Formula (I)
or a salt thereof, wherein:
one of R2 and R4 is a phenyl monosubstituted with (C1-C6) alkyl, —ORa, —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, —NH—(CH2)m—NRcRc or —[NHC(O)]Rd;
the other of R2 and R4 is a phenyl monosubstituted or disubstituted with R8;
R2 and R4 are different;
R5 is fluoro, —CN, or (C1-C3) haloalkyl;
each R8 is independently Ra, Rb, or Ra substituted with one Ra or Rb;
each Ra is (C1-C6) alkyl, or 3-8 membered cycloheteroalkyl;
each Rb is —ORa, —OCF3, —NRcRc, halogen, —CF3, —CN, —NO2, —N3, —SO2NRcRc, —C(O)Ra, —C(O)ORa, —C(O)NRcRc, or —C(NH)NRcRc;
each Rc is independently Ra or, alternatively, two Rc are taken together with the nitrogen atom to which they are bonded to form a 5 or 6-membered cycloheteroalkyl or heteroaryl which may optionally include one or more of the same or different additional heteroatoms and which may optionally be substituted with one or more of the same or different Ra or suitable Rb groups;
each Rd is independently Ra; and
each m is independently an integer from 1 to 2.