# US 7,465,725 B2 · Pyrimidine compounds

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- Number: US 7,465,725 B2
- Document ID: US7465725B2
- Status: Granted
- Kind: B2
- Application number: 11/193,001
- Filed: 2005-07-29
- Published: 2006-02-02
- Granted: 2008-12-16
- Earliest claimed: 2001-11-30
- Assignees: Synta Pharmaceuticals Corp.
- Inventors: Mitsunori Ono; Lijun Sun; Teresa Przewloka; Shijie Zhang; Elena Kostik; Weiwen Ying; Yumiko Wada; Keizo Koya
- Web page: https://patentgrep.com/patent/US7465725B2

## CPC

- C07D 239/48: Two nitrogen atoms
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/53: having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine (melarsoprol A61K31/555 {; with four nitrogen atoms A61K31/495})
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 31/541: Non-condensed thiazines containing further heterocyclic rings
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- 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: 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

This invention features pyrimidine compounds of formula (I): R1 is aryl, or heteroaryl; each of R2 and R4, independently, is Rc, halogen, nitro, cyano, isothionitro, SRc, or ORc; or R2 and R4, taken together, is carbonyl; R3 is Rc, alkenyl, alkynyl, ORc, OC(O)Rc, SO2Rc, S(O)Rc, S(O2)NRcRd, SRc, NRcRd, NRcCORd, NRcC(O)ORd, NRcC(O)NRcRd, NRcSO2Rd, CORc, C(O)ORc, or C(O)NRcRd; R5 is H or alkyl; n is 0, 1, 2, 3, 4, 5, or 6; X is O, S, S(O), S(O2), or NRc; Y is a covalent bond, CH2, C(O), C═N—Rc, C═N—ORc, C═N—SRc, O, S, S(O), S(O2), or NRc; Z is N or CH; one of U and V is N, and the other is CRc; and W is O, S, S(O), S(O2), NRc, or NC(O)Rc; in which each of Ra and Rb, independently, is H, alkyl, aryl, heteroaryl; and each of Rc and Rd, independently, is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl.

## Claims

### Claim 1

A method for treating an interleukin-12 overproduction-related disorder selected from rheumatoid arthritis, sepsis, Crohn's disease, multiple sclerosis, psoriasis, or insulin-dependent diabetes mellitus, comprising administering to a subject in need thereof an effective amount of the compound of formula (I):
wherein
R1 is
aryl, or heteroaryl;
each of R2 and R4, independently, is Rc, halogen, nitro, cyano, isothionitro, SRc, or ORc; or R2 and R4, taken together, is carbonyl;
R3 is Rc, alkenyl, alkynyl, ORc, OC(O)Rc, SO2Rc, S(O)Rc, S(O2)NRcRd, SRc, NRcRd, NRcCORd, NRcC(O)ORd, NRcC(O)NRcRd, NRcSO2Rd, CORc, C(O)ORc, or C(O)NRcRd;
R5 is H or alkyl;
n is 0, 1, 2, 3, 4, 5, or 6;
X is O, S, S(O), S(O2), or NRc;
Y is a covalent bond, CH2, C(O), C═N—Rc, C═N—ORc, C═N—SRc, O, S, S(O), S(O2), or NRc;
Z is N or CH;
one of U and V is N, and the other is CRc; and
W is O, S, S(O), S(O2), NRc, or NC(O)Rc
in which each of Ra and Rb, independently, is H, alkyl, aryl, or heteroaryl; and each of Rc and Rd, independently, is H, alkyl, aryl, heteroaryl, cyclyl, heterocyclyl, or alkylcarbonyl; or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein R1 is

### Claim 3 (depends on 2)

The method of claim 2, wherein U is N and V is CH.

### Claim 4 (depends on 2)

The method of claim 2, wherein Z is N and W is O.

### Claim 5 (depends on 2)

The method of claim 2, wherein X is NRc.

### Claim 6 (depends on 5)

The method of claim 5, wherein Rc is H, methyl, ethyl, or acetyl.

### Claim 7 (depends on 2)

The method of claim 2, wherein Y is O or CH2, and n is 0, 1, 2, 3, or 4.

### Claim 8 (depends on 7)

The method of claim 7, wherein R3 is aryl or heteroaryl.

### Claim 9 (depends on 8)

The method of claim 8, wherein R3 is pyridinyl.

### Claim 10 (depends on 7)

The method of claim 7, wherein R3 is ORc, SRc, C(O)ORc, or C(O)NRcRd.

### Claim 11 (depends on 7)

The method of claim 7, wherein R3 is
in which
each of A and A′, independently, is O, S, or NH;
each of Re and Rf, independently is H, alkyl, aryl, or heteroaryl; and
m is 1 or 2.

### Claim 12 (depends on 2)

The method of claim 2, wherein one of Ra and Rb is
in which
B is NRi, O, or S;
B′ is N or CRi;
Rg is H, alkyl, or alkoxyl;
Rh is halogen, NO2, CN, alkyl, aryl, heteroaryl, ORc, OC(O)Rc, SO2Rc, S(O)Rc
S(O2)NRcRd, SRc, NRcRd, NRcCORd, NRcC(O)ORd, NRcC(O)NRcRd, NRcSO2Rd, CORc,
C(O)ORc, or C(O)NRcRd;
Ri is H, alkyl, or alkylcarbonyl;
p is 0, 1, or 2; and
q is 0, 1, 2, 3, or 4.

### Claim 13 (depends on 12)

The method of claim 12, wherein one of Ra and Rb is
the other of Ra and Rb is H or alkyl.

### Claim 14 (depends on 13)

The method of claim 13, wherein Rg is H, methyl, ethyl, propyl, cyclopropyl, methoxy, or ethoxy; Rh is F, Cl, CN, methyl, methoxy, ethoxy, OC(O)CH3, OC(O)C2H5, C(O)OH, C(O)OC2H5, C(O)NH2, NHC(O)CH3 or S(O2)NH2; Ri is H, methyl, ethyl, or acetyl, and q is 0, 1, or 2.

### Claim 15 (depends on 14)

The method of claim 14, wherein Rg is methyl or methoxy; Ri is H; and q is 0.

### Claim 16 (depends on 14)

The method of claim 14, wherein U is N and V is CH.

### Claim 17 (depends on 16)

The method of claim 16, wherein Z is N and W is O.

### Claim 18 (depends on 17)

The method of claim 17, wherein X is NRc; and Rc is H, methyl, ethyl, or acetyl.

### Claim 19 (depends on 18)

The method of claim 18, wherein Y is O or CH2; and n is 0, 1, 2, 3, or 4.

### Claim 20 (depends on 19)

The method of claim 19, wherein R3 is aryl or heteroaryl.

### Claim 21 (depends on 20)

The method of claim 20, wherein R3 is pyridinyl.

### Claim 22 (depends on 14)

The method of claim 14, wherein Y is O or CH2, and n is 0, 1, 2, 3, or 4.

### Claim 23 (depends on 22)

The method of claim 22, wherein R3 is aryl or heteroaryl.

### Claim 24 (depends on 22)

The method of claim 22, wherein R3 is pyridinyl.

### Claim 25 (depends on 1)

The method of claim 1, wherein R1 is aryl or heteroaryl.

### Claim 26 (depends on 25)

The method of claim 25, wherein R1 is
in which
D is O, S, or NRm;
Rj is benzo, halogen, CN, hydroxyl, alkyl, aryl, heteroaryl, alkoxyl, aryloxyl, or heteroaryloxyl;
Rm is H, alkyl, or alkylcarbonyl; and
r is 0, 1, or 2.

### Claim 27 (depends on 26)

The method of claim 26, wherein X is NRc; and Rc is H, methyl, ethyl, or acetyl.

### Claim 28 (depends on 27)

The method of claim 27, wherein U is N and V is CH.

### Claim 29 (depends on 28)

The method of claim 28, wherein Z is N and W is O.

### Claim 30 (depends on 29)

The method of claim 29, wherein Y is O or CH2; and n is 0, 1, 2, 3, or 4.

### Claim 31 (depends on 26)

The method of claim 26, wherein Y is O or CH2; and n is 0, 1, 2, 3, or 4.

### Claim 32 (depends on 31)

The method of claim 31, wherein R3 is aryl or heteroaryl.

### Claim 33 (depends on 32)

The method of claim 32, wherein R3 is pyridinyl.

### Claim 34 (depends on 31)

The method of claim 31, wherein R3 is ORc, SRc, C(O)ORc or C(O)NRcRd.

### Claim 35 (depends on 31)

The method of claim 31, wherein R3 is
in which
each of A and A′, independently, is O, S, or NH;
each of Re and Rf, independently is H, alkyl, aryl, or heteroaryl; and m is 1 or 2.

### Claim 36 (depends on 31)

The method of claim 31, wherein R1 is

### Claim 37 (depends on 36)

The method of claim 36, wherein Rj is methyl, ethyl, propyl, or benzo; and r is 1 or 2.