# US 2010/0168170 A1 · Piperidinones Useful in the Treatment of Inflammation

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- Number: US 2010/0168170 A1
- Document ID: US20100168170A1
- Status: Published application
- Kind: A1
- Application number: 12/530,592
- Filed: 2008-03-12
- Published: 2010-07-01
- Earliest claimed: 2007-03-12
- Inventors: Benjamin Pelcman; Christian Krog-Jensen; Yaping Shen; James Gee Kan Yee; Lloyd F. Mackenzie; Yuanlin Zhou; Kang Han; Jeffery R. Raymond
- Web page: https://patentgrep.com/patent/US20100168170A1

## CPC

- C07D 211/08: with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- 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 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 11/08: Bronchodilators
- A61P 13/12: of the kidneys
- A61P 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 19/06: Antigout agents, e.g. antihyperuricemic or uricosuric agents
- A61P 19/08: for bone diseases, e.g. rachitism, Paget's disease
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/24: Antidepressants
- 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 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- 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: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

There is provided compounds of formula (I), wherein R1, R2, R3, R4, R5, R6, R7, R8, m, n, q and r have meanings given in the description, and pharmaceutically acceptable derivatives thereof, which compounds are useful in the treatment of diseases and conditions associated with inflammation.

## Claims

### Claim 1

A compound of formula (I),
wherein:
m and q each independently represent 0, 1, 2, 3, 4 or 5;
n represents 0, 1, 2 or 3;
r represents 1, 2, 3, 4, 5 or 6;
R1 represents C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, halo, -A1-B1, —R12—CN, —R12—NO2, —R12—N(R10)R11, —R12—OR10, —R12—OC(O)R10, —R12—C(O)R13, —R12—C(O)OR10, —R12—C(O)N(R10)R11, —R12—N(R10)C(O)N(R10)R11, —R12—O—R9—C(O)OR10, —R12—O—R9—C(O)N(R10)R11, —R12—S(O)pxR10, —R12—OS(O)2R10, —R12—S(O)txN(R10)R11, —R12—N(R10)S(O)txN(R10)R11, —R12—C(═NR10)N(R10)R11, —R12—C(═NOH)N(R10)R11, —R12—B(OR10)2, —R12—P(R10)R11, —R12—P(O)(OR10)2 or —R12—OP(O)(OR10)2, wherein C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl are optionally substituted by one or more substituents selected from X1;
tx represents 1 or 2;
px represents 0, 1, 2 or 3;
R2 represents hydrogen, —OR4, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or -A2-B2, wherein C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl are optionally substituted by one or more substituents selected from X2;
R3 represents hydrogen, —OR4, —R12—O—R9—C(O)OR10, —R12—O—R9—C(O)N(R10)R11, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or -A3-B3, wherein C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl are optionally substituted by one or more substituents selected from X2;
provided that when r represents 1 and q is other than 0, then either:
R1 represents -A1-B1, —R12—CN, —R12—NO2, —R12—N(R10)R11, —R12—OC(O)R10, —R12—C(O)R13, —R12—C(O)OR10, —R12—C(O)N(R10)R11, —R12—N(R10)C(O)N(R10)R11, —R12—O—R9—C(O)OR10, —R12—O—R9—C(O)N(R10)R11, —R12—S(O)pxR10, —R12—OS(O)2R10, —R12—S(O)txN(R10)R11, —R12—N(R10)S(O)txN(R10)R11, —R12—C(═NR10)N(R10)R11, —R12—C(═NOH)N(R10)R11, —R12—B(OR10)2, —R12—P(R10)R11, —R12—P(O)(OR10)2 or —R12—OP(O)(OR10)2; or
R3 represents —R12—O—R9—C(O)OR10 or —R12—O—R9—C(O)N(R10)R11;
R4 represents hydrogen, —R9—OR10, —R9—C(O)OR10, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from X3) or -A4-B4;
R5 represents hydrogen, -A5-B5, —R12—C(O)R10, —R12—C(O)OR10, —R12—C(O)N(R10)R11, C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl, which latter three groups are optionally substituted by one or more substituents selected from X4;
each R6 independently represents halo, —R12—OR10, —R12—CN, —R12—NO2, —R12—C(O)OR10, —R12—N(R10)R11, —R12—C(O)N(R10)R11, —R12—N(Rw3)C(O)R10, —R12—N(Rw3)C(O)N(R10)R11, —R12—N(Rw3)S(O)tR10x, —R12—N(Rw3)S(O)tOR10x, —R12—OC(O)R10, —R12—OC(O)N(R10)R11, —R12—OS(O)tR10x, —R12—S(O)pR10, —R12—S(O)tN(Rw3)R10, —R12—S(O)tOR10; —R12—Si(R16)3, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C3-15 cycloalkyl and/or heterocyclyl which latter five groups are optionally substituted by one or more substituents selected from X5; or
any two R6 groups, or R2 and any R6 group, may be linked together to form a further ring, which is formed either by the two relevant groups being linked together by a direct bond or C1-5 alkylene;
R7 represents halo, —R12—OR10, —R12—CN, —R12—NO2, —R12—C(O)OR10, —R12—N(R10)R11, —R12—C(O)N(R10)R11, —R12—N(Rw3)C(O)R10, —R12—N(Rw3)C(O)N(R10)R11, —R12—N(Rw3)S(O)tR10x, —R12—N(Rw3)S(O)tOR10x, —R12—OC(O)R10, —R12—OC(O)N(R10)R11, —R12—OS(O)tR10x, —R12—S(O)pR10, —R12—S(O)tN(Rw3)R10, —R12—S(O)tOR10; —R12—Si(R16)3, C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl, C3-15 cycloalkyl or heterocyclyl which latter five groups are optionally substituted by one or more substituents selected from X6;
R8 represents hydrogen, —R12—O—R10, -A6-B6, C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl, which latter three groups are optionally substituted by one or more substituents selected from X7;
R10x represents C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, -A7-O-A8 or -A9-B9, wherein C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl are optionally substituted by one or more substituents selected from X8;
Rw3, R10 and R11 each independently represent hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, -A7-O-A8 and/or -A9-B9, wherein C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl are optionally substituted by one or more substituents selected from X8;
or R10 and R11, together with the nitrogen atom to which they are both attached, may be linked together to form a heterocyclyl group optionally substituted by one or more substituents selected from Z2a or a heteroaryl group optionally substituted by one or more substituents selected from Z1a; or
in the case of —R12—B(OR10)2, the two R10 groups may be linked together to form, along with the relevant boron and oxygen atoms, a heterocyclyl group;
R12 represents a direct bond or R9;
R13 represents hydrogen, halo, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl (which latter three groups are optionally substituted by one or more substituents selected from X9), -A10-O-A11 or -A12-B12;
R9 represents C1-12 alkylene, C2-12 alkenylene or C2-12 alkynylene, all of which are optionally substituted by one or more substituents selected from X10;
A1, A3, A4, A9 and A12 each independently represent a direct bond, C1-12 alkylene, C2-12 alkenylene or C2-12 alkynylene, which latter three groups are optionally substituted by one or more substituents selected from X11;
A2, A5, A6, A7 and A10 each independently represent C1-12 alkylene, C2-12 alkenylene or C2-12 alkynylene, all of which are optionally substituted by one or more substituents selected from X12;
A8 and A11 each independently represent C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl, all of which are optionally substituted by one or more substituents selected from X13;
B1, B3, B4, B9 and B12 each independently represent aryl optionally substituted by one or more substituents selected from Y1, heteroaryl optionally substituted by one or more substituents selected from Z1, heterocyclyl optionally substituted by one or more substituents selected from Z2 or cycloalkyl optionally substituted by one or more substituents selected from Z3;
B2, B5 and B6 each independently represent aryl optionally substituted by one or more substituents selected from Y2;
X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12 and X13 each independently represent G1, aryl optionally substituted by one or more T1 substituents, C3-15 cycloalkyl optionally substituted by one or more T2 substituents, heterocyclyl optionally substituted by one or more T3 substituents, heteroaryl optionally substituted by one or more T4 substituents, ═O, —Si(R16)3, —OR14, —OC(O)—R14, —N(R14)2, —C(O)R14, —C(O)OR14, —C(O)N(R14)2, —N(R14)C(O)OR16, —N(R14)C(O)R16, —N(R14)S(O)tR16, —S(O)tOR16, —S(O)pR16, —S(O)tN(R14)2, —N(R14)C(O)N(R14)2, —N(R14)S(O)tOR16, —OC(O)N(R14)2 or —OS(O)tR9x;
Y1 and Y2 each independently represent -Ax-By, G1, G2, —R15—OR17—N(R14)2 or —R15—O—R17—N(R14)S(O)tR16;
Z1a, Z1, Z2a, Z2 and Z3 each independently represent G1, ═O, ═S, -Ax-By or G2;
G1 represents C1-12 alkyl optionally substituted by one or more substituents selected from T5 or C2-12 alkenyl optionally substituted by one or more substituents selected from T6, halo, —CN, —NO2 or ═O;
G2 represents -Ax-Bx, —R15—OR14, —R15—OC(O)—R14, —R15—N(R14)2, —R15—C(O)R14, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—N(R14)C(O)OR16, —R15—N(R14)C(O)R16, —R15—N(R14)S(O)tR16, —R15—S(O)tOR16, —R15—S(O)pR16 or —R15—S(O)tN(R14)2;
Ax represents a direct bond or C1-12 alkylene optionally substituted by one or more halo or ═O substituents;
Bx represents aryl or heteroaryl, which groups are optionally substituted by one or more substituents selected from T7 and T8, respectively;
By represents cycloalkyl or heterocyclyl, both of which are optionally substituted by one or more substituents selected from halo, C1-6 alkyl, —OCH3, —OCHF2, —OCF3 and/or ═O, wherein C1-12 alkyl, is optionally substituted by one or more halo substituents;
T1, T4, T5, T6, T7 and T8 each independently represent halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl which latter three groups are optionally substituted by one or more substituents selected from Qx1, —OH, —O—C1-6 alkyl, —OC2-6 alkenyl, —OC2-6 alkynyl which latter three groups are optionally substituted by one or more substituents selected from Qx2, —N(Rw)2, —NO2 and/or —CN; or
T5 and T6 may alternatively or additionally represent ═O;
T2 and T3 each independently represent halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —OCH3, —OCHF2, —OCF3 and/or ═O, wherein C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl are optionally substituted by halo;
Qx1 and Qx2 each independently represent halo, —OCH3, —OCHF2, —OCF3, —N(Rw)2 or ═O;
Rw represents hydrogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, which latter three groups are optionally substituted by one or more substituents selected from halo, —OCH3, —OCHF2, —OCF3 or ═O; or
two Rw groups, when attached to the same nitrogen atom, may be linked together to form, together with the nitrogen atom to which they are necessarily attached, a 5- or 6-membered ring, optionally containing a further heteroatom and optionally substituted by one or more substituents selected from fluoro, —CH3 or ═O;
t represents 1 to 2;
p represents 0, 1 or 2;
R14 represents hydrogen, -Ax1-Bx1, C1-12 alkyl, C2-6 alkenyl or C2-6 alkynyl, which latter three groups are optionally substituted by one or more substituents selected from E1;
R15 represents a direct bond, C1-12 alkylene or C2-12 alkenylene, which latter two groups are optionally substituted by one or more substituents selected from halo, —OCH3, —OCHF2, —OCF3 or ═O;
R16 represents C1-12 alkyl, C2-6 alkenyl, C2-6 alkynyl or -Ay1-By1, wherein C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl are optionally substituted by one or more halo and/or ═O groups;
R17 represents C1-12 alkylene or C2-12 alkenylene, both of which are optionally substituted by one or more substituents selected from halo and ═O;
Ax1 and Ay1 each independently represent a direct bond or C1-12 alkylene optionally substituted by one or more halo or ═O groups;
Bx1 and By1 each independently represent cycloalkyl optionally substituted by one or more substituents selected from halo and ═O, heterocyclyl optionally substituted by one or more substituents selected from halo and ═O, aryl optionally substituted by one or more halo atoms or heteroaryl optionally substituted by one or more halo atoms;
E1 represents halo, —CN, —NO2, ═O, —OR18, —OC(O)—R18, —N(R18)2, —C(O)R18, —C(O)OR18, —C(O)N(R18)2, —N(R18)C(O)OR19, —N(R18)C(O)R19, —N(R18)S(O)t1R19, —S(O)t1OR19, —S(O)p1R19, —S(O)t1N(R18)2, —N(R18)C(O)N(R18)2, —N(R18)S(O)t1OR19x, —OC(O)N(R18)2, —OS(O)t1R19x or —Si(R19x)3;
R18 and R19 each independently represents hydrogen, C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl, which latter three groups are optionally substituted by one or more halo atoms;
R19x represents C1-3 alkyl, C2-3 alkenyl or C2-3 alkynyl, which latter three groups are optionally substituted by one or more halo atoms;
t1 represents 1 or 2;
p1 represents 0, 1 or 2,
or a pharmaceutically acceptable salt, solvate, prodrug or polymorph thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein when r represents 1, then either:
R1 represents -A1-B1, —R12—O—R9—C(O)N(R10)R11, —R12—OS(O)2R10, —R12—N(R10)S(O)txN(R10)R11, —R12—C(═NR10)N(R10)R11, —R12—C(═NOH)N(R10)R11, —R12—N(R10)C(O)N(R10)R11 or —R12—O—R9—C(O)OR10; or
R3 represents —R12—O—R9—C(O)OR10 or —R12—O—R9—C(O)N(R10)R11.

### Claim 3 (depends on 2)

The compound according to claim 2, wherein when r represents 1, then either R1 or R3 represents —R12—N(R10)C(O)N(R10)R11 or —R12—O—R9—C(O)OR10.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein m, n and q each independently represent 0, 1, or 2.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R2 represents -A2-B2, C1-4 alkyl or hydrogen.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R3 represents -A3-B3, hydrogen, —OR4, —R12—O—R9—C(O)R10 or —R12—O—R9—C(O)N(R10)R11.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R4 represents hydrogen, —R9—OR10, —R9—C(O)OR10, C1-12 alkyl optionally substituted by one or more substituents selected from X3 or -A4-B4.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein A3 and A4 each independently represent C1-3 alkylene or a direct bond.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein B4 represents C3-15 cycloalkyl optionally substituted by one or more substituents selected from Z3 or a 3- to 18-membered heterocyclyl group optionally substituted by one or more substituents selected from Z2.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein R5 represents -A5-B5, hydrogen, —R12C(O)R10 or —R12—C(O)N(R10)R11.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein R6 and R7 each independently represent halo, —R12—OR10, —R12—CN, —R12—NO2, —R12—C(O)OR10, —R12—N(R10)R11, —R12—C(O)N(R10)R11 or C1-12 alkyl optionally substituted by one or more substituents selected from X5 or X6.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein R8 represents hydrogen or C1-6 alkyl optionally substituted by or more substituents selected from X7.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein R9 represents C1-12 alkylene optionally substituted by one or more substituents selected from X10.

### Claim 14 (depends on 1)

The compound according to claim 1, wherein R10 and R11 each independently represent hydrogen, C1-12 alkyl optionally substituted by one or more substituents selected from X8, C1-12 alkenyl optionally substituted by one or more substituents selected from, -A7-O-A8 or -A9-B9; or R10 and R11 are linked together to form, together with the nitrogen atom to which they are necessarily attached, a 5- or 6-membered heterocyclyl group, which is optionally substituted by one or more substituent selected from Z2a.

### Claim 15 (depends on 1)

The compound according to claim 1, wherein R13 represents hydrogen or C1-6 alkyl optionally substituted by one or more substituents selected from X9.

### Claim 16 (depends on 1)

The compound according to claim 1, wherein A1, A3, A4, A9 and A12 each independently represent C1-6 alkylene optionally substituted by one or more X11 substituents.

### Claim 17 (depends on 1)

The compound according to claim 1, wherein A8 and A11 each independently represent C1-6 alkyl optionally substituted by one or more X13 substituents.

### Claim 18 (depends on 1)

The compound according to claim 1, wherein A2, A5, A6, A7 and A10 each independently represent a direct bond or C1-6 alkylene optionally substituted by one or more X12 substituents.

### Claim 19 (depends on 1)

The compound according to claim 1, wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, X11, X12 and X13 each independently represent a 5- or 6-membered heterocyclyl group, —OR14, N(R14)2, —C(O)OR14, —C(O)N(R14)2, —S(O)tN(R14)2 or G1.

### Claim 20 (depends on 1)

The compound according to claim 1, wherein Z1a, Z1, Z2a, Z2, Z3, Y1 and Y2 each independently represent G2 or G1.

### Claim 21 (depends on 20)

The compound according to claim 20, wherein G1 represents —CN, —NO2, halo or C1-6 alkyl optionally substituted by one or more T5 substituents.

### Claim 22 (depends on 20)

The compound according to claim 20, wherein G2 represents —R15—N(R14)2, —R15—C(O)OR14, —R15—C(O)N(R14)2, —R15—S(O)tN(R14)2 or —R15—O—R14.

### Claim 23 (depends on 1)

The compound according to claim 1, wherein R15 represents a direct bond; R14 represents C1-6 alkyl optionally substituted by one or more substituents selected from E1; each R16 independently represents
C1-3 alkyl; R17 represents C1-6 alkylene; or R18 and R19 independently represent hydrogen.

### Claim 24 (depends on 1)

The compound according to Claim 1, wherein:
(A) when r represents 1, each R8 represents hydrogen, R2 represents hydrogen, m and n both represent 0, R4 represents methyl:
(I) when R3 represents —OR4 in which R4 represents cyclopentyl:
(i) R5 represents hydrogen, then q does not represent 0;
(ii) R5 represents hydrogen, q represents 1, then R1 does not represent: methyl substituted in either the 2-, 3- or 4-position; isopropyl substituted in the 4-position; chloro substituted in the 2- or 3-position; methoxy, ethoxy, propoxy, butoxy, pentyloxy, each hexyloxy, heptyloxy, phenoxy, benzyloxy, trifluoromethyl or 4-chlorophenoxy, each of which are substituted in the 3-position; butoxy, fluoro, trifluoromethyl, trifluoromethoxy or phenoxy, each of which are substituted in the 4-position;
(iii) R5 represents hydrogen, q represents 2, then the two R1 substituents do not represent 3-methoxy and 4-hydroxy; 3-methoxy and 4-benzyloxy; or 2-chloro and 5-trifluoromethyl;
(iv) R5 represents —R12C(O)OR10, in which R12 represents a direct bond and R10 represents tert-butyl, q represents 2, then the two R1 substituents do not represent 3-methoxy and 4-benzyloxy;
(v) R5 represents isobutyl or —R12C(O)R9, in which R12 represents a direct bond and R9 represents methyl or unsubstituted phenyl, q represents 1, then R1 does not represent methyl substituted in the 3-position;
(II) when R3 represents —OR4 in which R4 represents methyl:
(i) R5 represents hydrogen or benzyl, q represents 2, then the two R1 substituents do not represent 3-methoxy and 4-benzyloxy; or 3-methoxy and 4-hydroxy;
(ii) R5 represents —R12C(O)OR10, in which R12 represents a direct bond and R10 represents tert-butyl, q represents 2, then the two R1 substituents do not represent 3-methoxy and 4-benzyloxy;
(III) when R3 represents —OR4 in which R4 represents isopropyl:
(i) R5 represents hydrogen, then q does not represent 0;
(ii) R5 represents hydrogen, q represents 1, then R1 does not represent 4-trifluoromethyl or 3-benzyloxy;
(IV) when R3 represents —OR4 in which R4 represents ethyl:
(i) R5 represents hydrogen, then q does not represent 0;
(ii) R5 represents hydrogen, q represents 1, then R1 does not represent 4-fluoro or 3-benzyloxy.

### Claim 25 (depends on 24)

The compound according to claim 24, wherein when r represents 1, then R2 represents —OR4, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or -A2-B2; wherein C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl are optionally substituted by one or more substituents selected from X2.

### Claim 26 (depends on 24, 25)

The compound according to claim 24 or claim 25, wherein when r represents 1, then at least one R8 group represents —R12—O—R10, -A6-B6 or C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl, which latter three groups are optionally substituted by one or more substituents selected from X7.

### Claim 27 (depends on 1)

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

### Claim 28 (depends on 1)

A pharmaceutical formulation including a compound according to claim 1, or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, carrier or excipient.

### Claim 29 (depends on 1)

A compound according to claim 1, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disorder selected from: i) an inflammatory disorder; ii) a disorder in which the modulation of intracellular cyclic adenosine 5′-monophosphate levels within a mammal is desired and/or required, which disorder may be an inflammatory disorder; iii) a disorder associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers; iv) transplant rejection in a mammal; v) uncontrolled cellular proliferation; or vi) a disorder associated with the central nervous system.

### Claim 30 (depends on 1)

Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder selected from i) an inflammatory disorder; ii) a disorder in which the modulation of intracellular cyclic adenosine 5′-monophosphate levels within a mammal is desired and/or required, which disorder may be an inflammatory disorder; iii) a disorder associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers; iv) transplant rejection in a mammal; v) uncontrolled cellular proliferation; or vi) a disorder associated with the central nervous system.

### Claim 31 (depends on 29, 30)

The compound according to claim 29 or a use according to claim 30, wherein the disorder is inflammation, a proliferative disorder a disease or pathological condition of the central nervous system, ankylosing spondylitis, arthritis, asthma, chronic obstructive pulmonary disease, chronic bronchitis, respiratory distress syndrome, rhinitis, allergic rhinitis, Crohn's disease, nephritis, eczema, atopic dermatitis, urticaria, conjunctivitis, ulcerative colitis, rheumatoid arthritis, osteoarthritis, eosinophilic gastrointestinal disorders, vascular disease and diabetes mellitus fibromyalgia syndrome, gout, inflammations of the brain, emphysema, inflammatory bowel disease, irritable bowel syndrome, ischemia-reperfusion injury juvenile erythematosus pulmonary sarcoidosis, Kawasaki disease, osteoarthritis, pelvic inflammatory disease, psoriatic arthritis (psoriasis), rheumatoid arthritis, psoriasis, tissue/organ transplant, scleroderma, spondyloarthropathies, systemic lupus erythematosus, pulmonary sarcoidosis, ulcerative colitis, cancer, leukemia, a solid tumor, cognitive function, Alzheimer's disease, a learning and memory disorder, cerebrovascular disease, depression, schizophrenia, Parkinson's disease and/or multiple sclerosis.

### Claim 32

(canceled)

### Claim 33 (depends on 1)

A method of treatment of a disorder selected from: i) an inflammatory disorder; ii) a disorder in which the modulation of intracellular cyclic adenosine 5′-monophosphate levels within a mammal is desired and/or required, which disorder may be an inflammatory disorder; iii) a disorder associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers; iv) transplant rejection in a mammal; v) uncontrolled cellular proliferation; or vi) a disorder associated with the central nervous system, said method comprising administration of a therapeutically effective amount of a compound according to claim 1, or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, such a disorder.

### Claim 34 (depends on 1)

A combination product comprising:
(A) a compound according to claim 1, or a pharmaceutically-acceptable salt thereof; and
(B) another therapeutic agent that is useful in the treatment of a disorder selected from: i) an inflammatory disorder; ii) a disorder in which the modulation of intracellular cyclic adenosine 5′-monophosphate levels within a mammal is desired and/or required, which disorder may be an inflammatory disorder; iii) a disorder associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers; iv) transplant rejection in a mammal; v) uncontrolled cellular proliferation; or vi) a disorder associated with the central nervous system,
wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent, carrier or excipient.

### Claim 35 (depends on 1)

A combination product comprising a pharmaceutical formulation including a compound according to claim 1, or a pharmaceutically-acceptable salt thereof, another therapeutic agent that is useful in the treatment of a disorder selected from: i) an inflammatory disorder; ii) a disorder in which the modulation of intracellular cyclic adenosine 5′-monophosphate levels within a mammal is desired and/or required, which disorder may be an inflammatory disorder; iii) a disorder associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers; iv) transplant rejection in a mammal; v) uncontrolled cellular proliferation; or vi) a disorder associated with the central nervous system, and a pharmaceutically-acceptable adjuvant, diluent, carrier or excipient.

### Claim 36 (depends on 1)

A kit of parts comprising:
(a) a pharmaceutical formulation including a compound according to claim 1, or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent, carrier or excipient; and
(b) a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of a disorder selected from: i) an inflammatory disorder; ii) a disorder in which the modulation of intracellular cyclic adenosine 5′-monophosphate levels within a mammal is desired and/or required, which disorder may be an inflammatory disorder; iii) a disorder associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers; iv) transplant rejection in a mammal; v) uncontrolled cellular proliferation; or vi) a disorder associated with the central nervous system in admixture with a pharmaceutically-acceptable adjuvant, diluent, carrier or excipient, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

### Claim 37 (depends on 1)

A process for the preparation of a compound according to claim 1, said process comprises:
(i) reaction of a compound of formula II:
or protected derivatives thereof, wherein R2, R3, R4, R5, R6, R7, m and n are as defined in claim 1, with a compound of formula III,
wherein L1 represents a suitable leaving group, and R1, q, r and R8 are as defined in claim 1;
(ii) for compounds of formula I in which either at least one R1 represents —R12—O—R9—C(O)N(R10)R11, —R12—O—R9—C(O)OR10 or —R12—OS(O)2R10 wherein q is other than 0, or R3 represents —R12—O—R9—C(O)N(R10)R11 or —R12—O—R9—C(O)OR10, reaction of a corresponding compound of formula I in which either R1 represents —R12—OR10 in which R10 represents hydrogen, or, R3 represents —OR4 in which R4 represents hydrogen, with a compound of formula IV,
Za-L1a IV
wherein L1a represents a suitable leaving group, Za represents —R9—C(O)N(R10)R11, R9—C(O)OR10 or —OS(O)2R10, in which R10 and R11 are as defined in claim 1;
(iii) for compounds of formula I in which there is an R1 substituent present that represents —R12—O—R9—C(O)N(R10)R11, reaction of a corresponding compound of formula I in which R1 represents —R12—O—R9—C(O)OR10 with a compound of formula V,
HN(R10)R11 V
wherein R10 and R11 are as defined in claim 1;
(iv) for compounds of formula I in which R2 represents C1-12 alkyl optionally substituted by one or more substituents selected from X2, C2-12 alkenyl optionally substituted by one or more substituents selected from X2, C2-12 alkynyl optionally substituted by one or more substituents selected from X2 or -A2-B2 in which A2 represents optionally substituted C1-12 alkylene, reaction of a corresponding compound of formula I in which R2 represents hydrogen, with a compound of formula VI,
Zb-L1b VI
wherein Zb represents C1-12 alkyl optionally substituted by one or more substituents selected from X2, C2-12 alkenyl optionally substituted by one or more substituents selected from X2, C2-12 alkynyl optionally substituted by one or more substituents selected from X2 or -A2a-B2, in which A2a represents A2 provided that it does not represent a direct bond, and L1b represents a suitable leaving group;
(v) for compounds of formula I in which there is an R1 substituent present that represents —R12—C(═NR10)N(R10)R11 or —R12—C(═NOH)N(R10)R11, in which R10 and R11 represent hydrogen, reaction of a corresponding compound of formula I in which R1 represents —R12—CN, in the presence of a suitable amidating or hydroxyamidating reagent;
(vi) for compounds of formula I in which q is other than 0, and R1 represents -A1-B1 (and A1 represents a direct bond), —R12—N(R10)R11, —R12—OR10, —R12—OC(O)R10, —R12—C(O)OR10, —R12—N(R10)C(O)N(R10)R11, —R12—O—R9—C(O)OR10, —R12—O—R9—C(O)N(R10)R11, —R12—S(O)pxR10 (in which px represents 0), —R12—OS(O)2R10, —R12—N(R10)S(O)txN(R10)R11, —R12—B(OR10)2, —R12—P(R10)R11 or —R12—P(O)(OR10)2, and R12 represents a direct bond, reaction of a compound of formula VII,
wherein L1c represents a suitable leaving group, q1 represent q, provided that it does not represent 0, and R2, R3, R4, R5, R6, R7, R8, m, n and r are as defined in claim 1, either:
(A) with a compound of formula VIII,
Zd-H VIII
wherein Zd represents -A1-B1 (in which A1 represents a direct bond), —R12—N(R10)R11, —R12—OR10, —R12—OC(O)R10, —R12—N(R10)C(O)N(R10)R11, —R12—O—R9—C(O)OR10, —R12—O—R9—C(O)N(R10)R11, —R12—S(O)pxR10 (in which px represents 0), —R12—OS(O)2R10 or —R12—N(R10)S(O)txN(R10)R11, R12 represents a direct bond and R9, R10 and R11 are as defined in claim 1;
(B) for the compounds of formula I in which R1 represents —R12—B(OR10)2 and R12 represents a direct bond), with an appropriate borane or boronic acid;
(C) for the compounds of formula I in which R1 represents —R12—P(R10)R11 or —R12—P(O)(OR10)2 and R12 represents a direct bond), with a phosphonic acid diethyl ester or diphenylphosphane;
(D) for the compounds of formula I in which R1 represents —R12—C(O)OR10, under carbonylation conditions;
(vii) for compounds of formula I in which q is other than 0, and R1 represents —S(O)2 N(R10)R11, reaction of a compound of formula IX,
wherein q1, R2, R3, R4, R5, R6, R7, R8, m, n and r are as defined in claim 1, with a compound of formula V as defined above.
(viii) intramolecular cyclisation of a compound of formula X,
or a protected derivative thereof, wherein R1, R2, R3, R4, R6, R7, R8, m, n, q and r are as defined in claim 1;
(ix) reaction of a compound of formula XI,
wherein L2 represents a suitable leaving group, and R3, R4, R7 and n are as defined in claim 1, with a compound of formula XII,
or a tautomer thereof or derivative thereof, wherein L3 represents a suitable leaving group, and R1, R2, R5, R6, R8, L3 m and r are as defined in claim 1;
(x) for compounds of formula I in which R2 represents hydrogen, and there is a maximum of two R6 substituents present at the 4- or 6-position, reduction of a compound of formula XIII,
or a tautomer or protected derivative thereof, wherein m1 represents 0, 1 or 2, and R1, R3, R4, R5, R6, R7, R8, q, r and n are as defined in claim 1;
(xi) for compounds of formula I in which R3 represents —OR4 in which R4 is other than hydrogen, or for compounds of formula I in which R4 is other than hydrogen, reaction of a corresponding compound of formula I in which R3 represents —OH or, R4 represents hydrogen, with a compound of formula XIV,
R4a-L2x XIV
wherein R4a represents —R9—OR10, —R9—C(O)OR10, C1-12 alkyl optionally substituted by one or more substituents selected from X3, C2-12 alkenyl optionally substituted by one or more substituents selected from X3, C2-12 alkynyl optionally substituted by one or more substituents selected from X3 or -A4-B4, L2x represents a suitable leaving group, and R9, R10, X3, A4 and B4 are as defined in claim 1;
(xii) for compounds of formula I in which R3 represents —OR4 in which R4 is other than hydrogen, or for compounds of formula I in which R4 at the position para to the point of attachment of the piperidin-2-one ring is other than hydrogen, reaction of a compound of formula XV,
wherein L2x1 represents L2x or R3, L2x2 represents L2x or —OR4, provided that at least one of R2x1 and R2x2 represents L2x, in which L2x is as defined above, and R1, R2, R5R6, R7, m and n are as defined in claim 1, with a compound of formula XVI,
R4—OH XVI
wherein R4 is as defined in claim 1;
(xiii) compounds of formula I in which R2 represents —OR4 in which R4 represents hydrogen, may be prepared by reaction of a corresponding compound of formula I in which R2 represents hydrogen, with a base, followed by quenching with oxygen or a suitable equivalent thereof under standard conditions.

### Claim 38 (depends on 28)

A process for the preparation of a pharmaceutical formulation according to claim 28, said process comprises bringing into association a compound with a pharmaceutically-acceptable adjuvant, diluent, carrier or excipient.

### Claim 39 (depends on 34)

A process for the preparation of a combination product according to Claim 34, which process comprises bringing into association a compound, or a pharmaceutically acceptable salt thereof with the other therapeutic agent that is useful in the treatment of a disorder selected from: i) an inflammatory disorder; ii) a disorder in which the modulation of intracellular cyclic adenosine 5′-monophosphate levels within a mammal is desired and/or required, which disorder may be an inflammatory disorder; iii) a disorder associated with pathological conditions that are modulated by inhibiting enzymes associated with secondary cellular messengers; iv) transplant rejection in a mammal; v) uncontrolled cellular proliferation: or vi) a disorder associated with the central nervous system, and at least one pharmaceutically-acceptable adjuvant, diluent, carrier or excipient.