# US 9,751,893 B2 · Methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds

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- Number: US 9,751,893 B2
- Document ID: US9751893B2
- Status: Granted
- Kind: B2
- Application number: 12/487,486
- Filed: 2009-06-18
- Published: 2009-12-24
- Granted: 2017-09-05
- Earliest claimed: 2003-07-30
- Assignees: Rigel Pharmaceuticals, Inc.
- Applicants: Rajinder Singh; Ankush Argade; Hui Li; Somasekhar Bhamidipati; David Carroll; Catherine Sylvain; Jeffrey Clough; Holger Keim
- Inventors: Rajinder Singh; Ankush Argade; Hui Li; Somasekhar Bhamidipati; David Carroll; Catherine Sylvain; Jeffrey Clough; Holger Keim
- Web page: https://patentgrep.com/patent/US9751893B2

## CPC

- C07D 498/04: Ortho-condensed systems
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/538: ortho- or peri-condensed with carbocyclic ring systems
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- 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 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 498/02: in which the condensed system contains two hetero rings
- C07D 498/06: Peri-condensed 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

## Abstract

The present invention provides methods of treating or preventing autoimmune diseases with 2,4-pyrimidinediamine compounds, as well as methods of treating, preventing or ameliorating symptoms associated with such diseases. Specific examples of autoimmune diseases that can be treated or prevented with the compounds include rheumatoid arthritis and/or its associated symptoms, systemic lups erythematosis and/or its associated symptoms and multiple sclerosis and/or its associated symptoms.

## Claims

### Claim 1

A 2,4 pyrimidinediamine compound of the structural formula
or in the form of a salt or N-oxide thereof, in which
R4 is
Y is selected from the group consisting of S, SO and SO2;
Z is selected from the group consisting of NH and NR35;
R2 is
a)
in which each R31 is, independently of the others, methyl or (C1-C6) alkyl,
b)
in which each R31 is, independently of the others, methyl or (C1-C6) alkyl and yy is 1-6, or
c)
R5 is selected from the group consisting of R6, (C1-C6) alkyl optionally substituted with one or more of the same or different R8 groups, (C1-C4) alkanyl optionally substituted with one or more of the same or different R8 groups, (C2-C4) alkenyl optionally substituted with one or more of the same or different R8 groups and (C2-C4) alkynyl optionally substituted with one or more of the same or different R8 groups;
each R6 independently is selected from the group consisting of hydrogen, —ORd, —SRd, (C1-C3) haloalkyloxy, (C1-C3) perhaloalkyloxy, —NRcRc, halogen, (C1-C3) haloalkyl, (C1-C3) perhaloalkyl, —CF3, —CH2CF3, —CF2CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, —N3, —S(O)Rd, —S(O)2Rd, —S(O)2ORd, —S(O)NRcRc; —S(O)2NRcRc, —OS(O)Rd, —OS(O)2Rd, —OS(O)2ORd, —OS(O)NRcRc, —OS(O)2NRcRc, —C(O)Rd, —C(O)ORd, —C(O)NRcRc, —C(NH)NRcRc, —OC(O)Rd, —SC(O)Rd, —OC(O)ORd, —SC(O)ORd, —OC(O)NRcRc, —SC(O)NRcRc, —OC(NH)NRcRc, —SC(NH)NRcRc, —[NHC(O)]nRd, —[NHC(O)]nORd, —[NHC(O)]nNRcRc and —[NHC(NH)]nNRcRc, (C5-C10) aryl optionally substituted with one or more of the same or different R8 groups, phenyl optionally substituted with one or more of the same or different R8 groups, (C6-C16) arylalkyl optionally substituted with one or more of the same or different R8 groups, 5-10 membered heteroaryl optionally substituted with one or more of the same or different R8 groups and 6-16 membered heteroarylalkyl optionally substituted with one or more of the same or different R8 groups;
R8 is selected from the group consisting of Ra, Rb, Ra substituted with one or more of the same or different Ra or Rb, —ORa substituted with one or more of the same or different Ra or Rb, —B(ORa)2, —B(NRcRc)2, —(CH2)m—Rb, —(CHRa)m—Rb, —O—(CH2)m—Rb, —S—(CH2)m—Rb, —O—CHRaRb, —O—CRa(Rb)2, —O—(CHRa)m—Rb, —O—(CH2)m—CH[(CH2)mRb]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)m—C(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 and —NH—(CH2)m—C(O)—NH—(CH2)m—Rb;
each R35 is, independently of the others, selected from the group consisting of hydrogen and R8, or, alternatively, two R35 bonded to the same carbon atom are taken together to form an oxo (═O), NH or NR38 group and the other two R35 are each, independently of one another, selected from the group consisting of hydrogen and R8;
R38 is selected from the group consisting of (C1-C6) alkyl and (C5-C14) aryl;
each Ra is independently selected from the group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl, cyclohexyl, (C4-C11) cycloalkylalkyl, (C5-C10) aryl, phenyl, (C6-C16) arylalkyl, benzyl, 2-6 membered heteroalkyl, 3-8 membered cycloheteroalkyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, 4-11 membered cycloheteroalkylalkyl, 5-10 membered heteroaryl and 6-16 membered heteroarylalkyl;
each Rb is a suitable group independently selected from the group consisting of ═O, —ORd, (C1-C3) haloalkyloxy, —OCF3, ═S, —SRd, ═NRd, ═NORd, —NRcRc, halogen, —CF3, —CN, —NC, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)Rd, —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 and —[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 may optionally be substituted with one or more of the same or different Ra or suitable Rb groups;
each Rd is independently Ra;
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)

A compound according to claim 1, wherein R4 is
in which each R35 is H or CH3.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein R4 is
in which each R35 is H or CH3.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein R4 is

### Claim 5 (depends on 1)

A compound according to claim 1, wherein R2 is
in which each R31 is, independently of the others, methyl or (C1-C6) alkyl.

### Claim 6 (depends on 1)

A compound according to claim 1, wherein R2 is
in which each R31 is, independently of the others, methyl or (C1-C6) alkyl, and yy is 1 to 6.

### Claim 7 (depends on 1)

A compound according to claim 1, wherein R5 is fluoro.

### Claim 8 (depends on 1)

A compound according to claim 1, wherein R6 is hydrogen.

### Claim 9 (depends on 1)

A compound according to claim 1, wherein R5 is fluoro and R6 is hydrogen.

### Claim 10

A compound, or salt or N-oxide thereof, that is
5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3,5-dimethoxyphenyl)-5-fluoro-N4-(3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-(3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-(3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-(3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N4-(3,4-dihydro-2H,4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine;
5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(4-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3,5-dimethoxyphenyl)-5-fluoro-N4-(4-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3,5-dimethylphenyl)-5-fluoro-N4-(2-methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
5-fluoro-N2-(indazol-6-yl)-N4-(2-methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
5-fluoro-N4-(2-methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;
N2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;
N2-(3,5-dimethylphenyl)-N4-(2,2-dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;
N4-(2,2-dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;
N2-(3,5-dimethoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3,5-dimethylphenyl)-5-fluoro-N4-(2-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
5-fluoro-N4-(2-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;
N4-(2,2-dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-(indazol-6-yl)-2,4-pyrimidinediamine;
N4-(2,2-dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-(indazol-5-yl)-2,4-pyrimidinediamine;
N4-(2,2-dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine;
N2-(3-chloro-4-methoxyphenyl)-N4-(2,2-dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;
5-fluoro-N4-(2-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-N2-(indazol-6-yl)-2,4-pyrimidinediamine;
5-fluoro-N4-(2-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-N2-(indazol-5-yl)-2,4-pyrimidinediamine;
5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(2-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;
5-fluoro-N2-(3-hydroxyphenyl)-N4-(3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
racemic 5-fluoro-N2-(3-hydroxyphenyl)-N4-(2-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
racemic N4-(2,2-dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine;
racemic 5-fluoro-N2-(3-hydroxyphenyl)-N4-(2-methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
racemic 5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(2-methyl-1,1,3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
racemic N2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-(2-methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
5-fluoro-N4-(3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;
5-fluoro-N2-(indazol-5-yl)-N4-(3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-chloro-4-methoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;
N2-(3,5-dimethoxyphenyl)-N4-(2,2-dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine;
N4-(2,2-dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-N2-(3,5-dimethylphenyl)-5-fluoro-2,4-pyrimidinediamine;
N4-(2,2-dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)-2,4-pyrimidinediamine;
N4-(2,2-dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine;
N4-(2,2-dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-2,4-pyrimidinediamine;
N4-(2,2-dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-(indazol-6-yl)-2,4-pyrimidinediamine;
racemic 5-fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4-(2-methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N4-(2,2-dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-(3-fluoro-4-methoxyphenyl)-2,4-pyrimidinediamine;
racemic 5-fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4-(2-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N4-(2,2-dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-(3-fluoro-4-methoxyphenyl)-2,4-pyrimidinediamine;
5-fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4-(3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3,5-dimethylphenyl)-5-fluoro-N4-(3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3,5-dimethylphenyl)-5-fluoro-N4-(1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3,5-dimethoxyphenyl)-5-fluoro-N4-(1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(3-chloro-4-methoxyphenyl)-5-fluoro-N4-(1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
5-fluoro-N2-[3-(N-methylamino)carbonylmethyleneoxyphenyl]-N4-(1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
5-fluoro-N2-(3,4,5-trimethoxyphenyl)-N4-(1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
5-fluoro-N2-(indazol-6-yl)-N4-(1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
5-fluoro-N2-(3-hydroxyphenyl)-N4-(1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
5-fluoro-N2-(3-fluoro-4-methoxyphenyl)-N4-(1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
5-fluoro-N2-(indazol-5-yl)-N4-(1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N4-(2,2-dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-(1-methylindazol-6-yl)-2,4-pyrimidinediamine;
N4-(2,2-dimethyl-3-oxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-N2-(indazol-6-yl)-2,4-pyrimidinediamine trifluoroacetate salt;
5-fluoro-N2-(2-methyl-3H-benzimidazol-5-yl)-N4-(2-methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
5-fluoro-N4-(2-methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-N2-(2-trifluoromethyl-1H-benzimidazol-5-yl)-2,4-pyrimidinediamine;
racemic N2-(1,2-benzisoxazol-5-yl)-5-fluoro-N4-(2-methyl-1,1,3-trioxo-2H,4H-benzo[1,4]thiazin-6-yl)-2,4-pyrimidinediamine;
N2-(1,2-benzisoxazol-5-yl)-N4-(2,2-dimethyl-1,1,3-trioxo-4H-benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine; or
racemic N2-(1,2-benzisoxazol-5-yl)-5-fluoro-N4-(2-methyl-3-oxo-2H,4H-benzo[1,4]thiazin-6-yl)-5-fluoro-2,4-pyrimidinediamine.

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.

### Claim 12 (depends on 1)

A method of treating an autoimmune disease and/or one or more symptoms associated therewith, comprising administering to a subject suffering from an autoimmune disease or at risk of developing an autoimmune disease an effective amount of a compound according to claim 1, wherein the disease is rheumatoid arthritis.