# US 2010/0168167 A1 · Piperidinones Useful in the Treatment of Inflammation

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- Number: US 2010/0168167 A1
- Document ID: US20100168167A1
- Status: Published application
- Kind: A1
- Application number: 12/530,578
- 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/US20100168167A1

## CPC

- C07D 211/22: by oxygen atoms
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 7/12: Antidiuretics, e.g. drugs for diabetes insipidus (ADH A61P5/10)
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- 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 35/04: specific for metastasis
- A61P 37/02: Immunomodulators
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 407/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 409/06: linked by a carbon chain containing only aliphatic carbon atoms
- 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, m and n 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 represents 0, 1, 2, 3, 4 or 5;
n represents 0, 1, 2 or 3;
R1 represents hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, -A1-Tz-B1, -A1a-N(R9)R10, -A1b-OR9, -A1c-C(O)R9, -A1d-C(O)OR9 or -A1e-C(O)N(R9)R10, wherein C1-12 alkyl, C2-12 alkenyl, and C2-12 alkynyl are optionally substituted by one or more substituents selected from X1;
R2 represents hydrogen, —OR4, C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl, which latter three groups are optionally substituted by one or more substituents selected from X1; or
R1 and R2 together form ═C(R9)R10;
R3 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;
represents hydrogen, —R8—OR9, —R8—C(O)OR9, 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 X3;
R5 represents hydrogen, -A4-B4, —C(O)R9, —C(O)OR10, 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;
R6 represents halo, —R11—OR9, —R11—CN, —R11—NO2, —R11—C(O)OR9, —R11—N(R9)R10, —R11—C(O)N(R9)R10, —R11—N(Rw3)C(O)R9, —R11—N(Rw3)C(O)N(R9)R10, —R11—N(Rw3)S(O)tR9x, —R11—N(Rw3)S(O)tOR9x, —R11—OC(O)R9, —R11—OC(O)N(R)R10, —R11—OS(O)tR9x, —R11—S(O)pR9, —R11—S(O)tN(Rw3)R9, —R11—S(O)tOR9; —R11—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 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, —R11—OR9, —R11—CN, —R11—NO2, —R11—C(O)OR9, —R11—N(R9)R10, —R11—C(O)N(R9)R10, —R11—N(Rw3)C(O)R9, —R11—N(Rw3)C(O)N(R9)R10, —R11—N(Rw3)S(O)tR9x, —R11—N(Rw3)S(O)tOR9x, —R11—OC(O)R9, —R11—OC(O)N(R)R10, —R11—OS(O)tR9x, —R11—S(O)pR9, —R11—S(O)tN(Rw3)R9, —R11—S(O)tOR9, —R11—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 X5;
Tz represents a direct bond, —N(Rw1)— or —C(O)N(Rw2)—;
R9x represents C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, -A5-O-A6 and/or -A7-B7, wherein C1-12 alkyl, C2-12 alkenyl C2-12 alkynyl are optionally substituted by one or more substituents selected from X6;
R9, R10, Rw1, Rw2 and Rw3 each independently represent hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl -A5-O-A6 and/or -A7-B7, wherein C1-12 alkyl, C2-12 alkynyl are optionally substituted by one or more substituents selected from X6;
or R9 and R10, together with the carbon or nitrogen atom to which they are both attached, may be linked together to form a cycloalkyl or heterocyclyl group both of which are optionally substituted by one or more substituents selected from Z1a or an aryl or heteroaryl group (both of which are optionally substituted by one or more substituents selected from Z1b; and
R11 represents a direct bond or R8;
A1, A1a, A1b, A1c, A1d, A1e, A4 and A5 each independently represent C1-12 alkylene, C2-12 alkenylene or C2-12 alkynylene, which latter three groups are optionally substituted by one or more substituents selected from X7;
A2, A3 and A7 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 X8;
A6 represents C1-12 alkyl, C2-12 alkenyl or C2-12 alkynyl, all of which are optionally substituted by one or more substituents selected from X9;
R8 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;
B1 represents heteroaryl Optionally substituted by one or more substituents selected from Z2a or a heterocyclyl Optionally substituted by one or more substituents selected from Z2b, wherein when B1 represents a polycyclic heteroaryl group, then the point of attachment of B1 to the Tz is via a heterocyclyl or heteroaromatic ring of the polycycle;
B2, B3 and B7 each independently represent aryl Optionally substituted by one or more substituents selected from Y1), cycloalkyl, which cycloalkyl group is optionally substituted by one or more substituents selected from Z3, heterocyclyl Optionally substituted by one or more substituents selected from Z4a or heteroaryl Optionally substituted by one or more substituents selected from Z4b;
B4 represents aryl optionally substituted by one or more substituents selected from Y2;
X1 represents G1, 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;
X2, X3, X4, X5, X6, X7, X8, X9 and X10 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, —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, Z1b, Z2a, Z2b, Z3, Z4a and Z4b 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, C2-12 alkenyl, C2-12 alkynyl, halo, —CN, —NO2 or ═O, wherein C2-12 alkenyl, and C2-12 alkynyl are optionally substituted by one or more substituents selected from T6;
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 and/or —R15—S(O)tN(R14)2;
Ax represents a direct bond or O1-12 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, C2-6 alkenyl, C2-6 alkynyl, —OCH3, —OCHF2, —OCF3 or ═O, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are 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, C2-6 alkynyl —OH, —O—C1-6 alkyl, —OC2-6 alkenyl, —OC2-6 alkynyl, —N(Rw)2, —NO2 and/or —CN; or
T5 and T6 may alternatively or additionally represent ═O, wherein C1-6 alkyl, C2-6 alkenyl and C2-6 alkynyl are optionally substituted by one or more substituents selected from Qx1 and —O—C1-6 alkyl, —OC2-6 alkenyl, and —OC2-6 alkynyl are optionally substituted by one or more substituents selected from Qx2;
T2 and T3 each independently represent halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl —OCH3, —OCHF2, —OCF3 or ═O, wherein C1-6 alkyl, C2-6 alkenyl, and C2-6 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 and ═O;
t represents 1 or 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 and ═O;
R16 represents C1-12 alkyl, C2-6 alkenyl, C2-6 alkynyl (which latter three groups are optionally substituted by one or more halo and/or ═O groups) or Ay1-By1;
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, heterocyclyl, aryl or heteroaryl, wherein cycloalkyl, heterocyclyl are optionally substituted by one or more substituents selected from halo and ═O and aryl or heteroaryl are 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)ti R19, —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 and/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,
provided that:
(B) when R4 represents methyl, R2, R3 and R5 all represent hydrogen, n represents 0, m represents 1, and R6 represents methyl substituted α to the —N(R5)— moiety, then R1 does not represent unsubstituted methyl;
(C) when R2 represents hydrogen, m and n both represent O, R4 represents methyl, then R1 does not represent hydrogen when R3 represents —OR4 in which wherein R4 represents cyclopentyl or methyl and R5 represents hydrogen, benzyl or —C(O)OR10, wherein R10 represents tert-butyl;
(D) when R2 represents hydrogen, m and n both represent O, R3 represents hydrogen, R5 represents methyl, then R1 does not represent hydrogen when R4 represents methyl substituted by X3, wherein X3—C(O)N(R14)2 and R14 represents isopropyl.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein R1 represents hydrogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, -A1-Tz-B1, -A1a-N(R9)R16, -A1b-OR9, -A1c-C(O)R9, -A1d-C(O)OR9 or -A1e-C(O)N(R)R16; wherein C1-12 alkyl, C1-12 alkenyl, C1-12 alkynyl are optionally substituted by one or more substituents selected from halo and OH.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R1 and R2 are not hydrogen.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R2 represents hydrogen, C1-12 alkyl or C1-12 alkenyl, wherein C1-12 alkyl or C1-12 alkenyl are optionally substituted by one or more substituents selected from hydroxy or halo.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein R3 represents -A2-B2, hydrogen or —OR4.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein each R4 represents hydrogen, —R8—OR9, —R8—C(O)OR9, C1-12 alkyl Optionally substituted by one or more substituents selected from X3—) or -A3-B3.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein A2 and A3 each independently represent C1-3 alkylene or a direct bond.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein B3 represents C3-15 cycloalkyl Optionally substituted by one or more substituents selected from Z3— or a 5- to 10-membered heterocyclyl group Optionally substituted by one or more substituents selected from Z4a).

### Claim 10 (depends on 1)

The compound according to claim 1, wherein R5 represents -A4-B4, hydrogen or —C(O)R9.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein R6 and R7 each independently represent halo, —R11—OR9, —R11—CN, —R11—NO2, —R11—C(O)OR9, —R11—N(R9)R10, —R11—C(O)N(R9)R10 or C1-12 alkyl optionally substituted by one or more substituents selected from X5.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein R8 represents C1-12 alkylene optionally substituted by one or more substituents selected from X10.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein R9 and R10 each independently represent hydrogen, C1-12 alkyl, C1-12 alkenyl (optionally substituted with X6, -A5-O-A6 or -A7-B7; or R9 and R10 are linked together to form, together with the nitrogen atom, a 5- or 6-membered heterocyclyl group, which is optionally substituted by one or more substituents selected from halo, —CH3 and ═O.

### Claim 14 (depends on 1)

The compound according to claim 1, wherein A1, A1a, A1b, A1c, A1d, A1e, A4 and A5 each independently represent C1-6 alkylene.

### Claim 15 (depends on 1)

The compound according to claim 1, wherein A6 represents C1-6 alkyl.

### Claim 16 (depends on 1)

The compound according to claim 1, wherein A2, A3 and A7 each independently represent a direct bond or C1-6 alkylene.

### Claim 17 (depends on 1)

The compound according to claim 1, wherein X1, X2, X3, X4, X5, X6, X7, X8, X9, X10, Y1 and Y2 each independently represent G1.

### Claim 18 (depends on 1)

The compound according to claim 1, wherein Z1a, Z1b, Z2a, Z2b, Z3, Z4a and Z4b each independently represent G2 or G1.

### Claim 19 (depends on 1)

The compound according to claim 1, wherein G1 represents halo or C1-6 alkyl optionally substituted by one or more halo atoms.

### Claim 20 (depends on 1)

The compound according to claim 1, wherein G2 represents —R15—O—R14.

### Claim 21 (depends on 20)

The compound according to claim 20, wherein R15 represents a direct bond.

### Claim 22 (depends on 1)

The compound according to claim 1, wherein R14 represents C1-6 alkyl optionally substituted by one or more substituents selected from —C(O)N(R18)2 and halo.

### Claim 23 (depends on 22)

The compound according to claim 22, wherein R18 represents hydrogen.

### Claim 24 (depends on 1)

The compound according to claim 1, wherein Rw1 and Rw2 each independently represent hydrogen or C1-3 alkyl optionally substituted by one or more halo atoms.

### Claim 25 (depends on 1)

The compound according to claim 1, wherein when B1 represents a monocyclic heteroaryl group selected from imidazolyl, triazolyl, pyridyl, thienyl or furanyl.

### Claim 26 (depends on 1)

The compound according to claim 1, wherein when B1 represents a polycyclic heteroaryl group selected from 1,3-dihydroindol-2-one-yl, 2,3-dihydrobenzo[1,4]dioxinyl, benzo[1,4]oxazinyl, pyrrolopyridinyl, imidazopyridyl, thiazolopyridyl, benzoxazolyl, benzimidazolyl, benzofuranyl, indolyl, benzothienyl, benzothiazolyl, benzotriazolyl or oxazolopyridinyl.

### Claim 27 (depends on 1)

The compound according to claim 1, wherein:
X1, X2, X3, X4, X5, X6, X7, X8, X9 and X10 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 and/or —OS(O)tR9x;
provided that:
(A) when R1 represents methyl substituted by X1, R2 represents hydrogen, m and n both represent O, R4 represents methyl:
(I) when R3 represents —OR4 in which R4 represents cyclopentyl:
(i) R5 represents hydrogen, then X1 does not represent unsubstituted phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 4-isopropylphenyl, 2-chlorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 3-ethoxyphenyl, 3-propoxyphenyl, 3-butoxyphenyl, 4-butoxyphenyl, 3-pentyloxyphenyl, 3-hexyloxyphenyl, 3-heptyloxyphenyl, 3-phenoxyphenyl, 4-fluorophenyl, 3-benzyloxyphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 3-methoxy-4-hydroxyphenyl, 3-methoxy-4-benzyloxyphenyl, 3-(4-chloro-phenoxy)phenyl, 4-phenoxyphenyl, 2-chloro-5-trifluoromethyl-phenyl, or benzodioxol-5-yl (especially when the compound is in the (3R,5R) orientation);
(ii) R5 represents —C(O)OR10, in which R10 represents tert-butyl, then X1 does not represent 3-methoxy-4-benzyloxyphenyl;
(iii) R5 represents isobutyl or —C(O)R9, in which R9 represents methyl or unsubstituted phenyl, then X1 does not represent 3-methylphenyl;
(II) when R3 represents —OR4 in which R4 represents methyl:
(i) R5 represents hydrogen or benzyl, then X1 does not represent 3-methoxy-4-benzyloxyphenyl or 3-methoxy-4-hydroxyphenyl;
(ii) R5 represents —C(O)OR16, in which R10 represents tert-butyl, then X1 does not represent 3-methoxy-4-benzyloxyphenyl;
(III) when R3 represents —OR4 in which R4 represents isopropyl:
(i) R5 represents hydrogen, then X1 does not represent unsubstituted phenyl, 4-trifluoromethylphenyl or 3-benzyloxyphenyl;
(IV) when R3 represents —OR4 in which R4 represents ethyl:
(i) R5 represents hydrogen, then X1 does not represent unsubstituted phenyl, 4-fluorophenyl or 3-benzyloxyphenyl;
(B) when R4 represents methyl, R2, R3 and R5 all represent hydrogen, n represents 0, m represents 1, and the R6 substituent represents methyl substituted α to the —N(R5)— moiety, then R1 does not represent unsubstituted methyl;
(C) when R2 represents hydrogen, m and n both represent O, R4 represents methyl, then R1 does not represent hydrogen when R3 represents —OR4 in which R4 represents cyclopentyl or methyl and R5 represents hydrogen, benzyl or —C(O)OR10, in which R10 represents tert-butyl; and
(D) when R2 represents hydrogen, m and n both represent 0, R3 represents hydrogen, R5 represents methyl, then R1 does not represent hydrogen when R4 represents methyl substituted by X3, in which X3—C(O)N(R14)2 and each R14 represents isopropyl.

### Claim 28 (depends on 27)

The compound according to claim 27, wherein when R2 represents hydrogen, then R1 does not represent optionally substituted benzyl.

### Claim 29 (depends on 28)

The compound according to claim 28 without provisos (C) and (D), or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical.

### Claim 30 (depends on 27)

A pharmaceutical formulation including a compound of formula I, as defined in claim 27, without provisos (C) and (D), or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent, carrier or excipient.

### Claim 31 (depends on 1)

The compound according to claim 1 without the provisos, or a pharmaceutically acceptable salt thereof, for use in the treatment of: i) an inflammatory disorder; ii) a disorder in which the modulation of intracellular cyclic adenosine 5′-monophosphate levels within a mammal is desired, 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 32 (depends on 1)

Use of a compound of formula I according to claim 1 without the provisos, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a disorder.

### Claim 33 (depends on 32)

The Use according to claim 32, wherein the disorder is inflammation, a proliferative disorder or a disease or pathological condition of the central nervous system.

### Claim 34 (depends on 32)

The Use according to claim 32, wherein the disorder is 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 or multiple sclerosis.

### Claim 35 (depends on 1)

A method of treatment of a disorder, said method comprising administering a therapeutically effective amount of a compound of claim 1 without the provisos, or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, 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, 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 36 (depends on 1)

A combination product comprising:
(A) a compound of formula I as defined in claim 1 without the provisos, 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, 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 resection in a mammal; v) uncontrolled cellular proliferation; or yl) 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 37 (depends on 36)

The combination product according to claim 36 wherein components (A) and (B) are formulated in a single composition with pharmaceutically-acceptable adjuvant, diluent, carrier or excipient.

### Claim 38 (depends on 1)

A kit comprising:
(a) a pharmaceutical formulation including a compound of claim 1 without the provisos, 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, 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 as 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 39 (depends on 1, 27)

A process for the preparation of a compound of the formula I as defined in claim 1 or claim 27, said process comprising:
(i) for compounds of formula I in which R1 represents -A1-Tz-B1, 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,
L1-A1-Tz-B1 III
wherein L1 represents a suitable leaving group, and Tz, A1 and B1 are as defined in claim 1;
(ii) for compounds of formula I in which R1 represents -A1-Tz-B1 and Tz represents —N(Rw1)—, or R1 represents -A1a-N(R9)R10 or -A1b-OR9, reaction of a compound of formula IV,
wherein L1x represents a suitable leaving group, A1x represents A1, A1a or A1b for the preparation of compounds of formula I in which R1 represents -A1-N(Rw1)-B1, -A1a-N(R9)R10 or -A1b-OR9, and R2, R3, R4, R5, R6, R7, m and n are as defined in claim 1, with a compound of formula V,
H—Za V
wherein Za represents —N(R9)R10 or —OR9 (for the preparation of compounds of formula I in which R′ represents -A1-N(Rw1)-B1, -A1a-N(R9)R10 or -A1b-OR9, respectively), and Rw1, B1, R9 and R10 are as defined in claim 1;
(iii) for compounds of formula I in which R1 represents -A1-Tz-B1 and Tz represents —C(O)—N(Rw2)—, or R1 represents -A1e-C(O)N(R9)R10, reaction of a compound of formula VI,
or a protected derivative thereof, wherein A1y represents A1 or A1e for the preparation of compounds of formula I in which R1 represents -A1-C(O)N(Rw2)—B1 or -A1e-C(O)N(R9)R10, and R2, R3, R4, R5, R6, R7, R9, R10, Rw2, B1, A1, A1e, m and n are as defined in claim 1, with a compound of formula VII,
H—Zb VII
wherein Zb represents —N(Rw2)—B1 or —N(R9)R10 (for the preparation of compounds of formula I in which R1 represents -A1-C(O)—N(Rw2)—B1 or -A1e-C(O)N(R9)R10, and Rw2, B1, R9 and R10 are as defined in claim 1;
(iv) for compounds of formula I in which R1 represents C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, -A1a-N(R9)R10, -A1b-OR9, -A1c-C(O)R9, -A1d-C(O)OR9 or -A1e-C(O)N(R9)R10, and R9 and R10 do not represent hydrogen, reaction of a compound of formula II as defined above, with a compound of formula VIIA,
L1b-Zc VIIA
wherein L1b represents a suitable leaving group, Zc represents C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl, -A1a-N(R9)R10, -A1b-OR9, -A1c-C(O)R9, -A1d-C(O)OR9 or -A1e-C(O)N(R9)R10, but in which R9 and R10 represent a group other than hydrogen;
(v) for compounds of formula I in which R1 and R2 together form ═C(R9)R10, dehydration of a compound of formula VIIB,
wherein R3, R4, R5, R6, R7, R9, R10, m and n are as defined in claim 1;
(vi) intramolecular cyclisation of a compound of formula VIIC,
or a protected derivative thereof, wherein R1, R2, R3, R4, R5, R6, R7, m and n are as defined in claim 1;
(vii) compounds of formula I in which R1 represents hydrogen and 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;
(viii) compounds of formula I in which R1 represents hydrogen and R2 represents —OR4 in which R4 represents hydrogen may be prepared by reaction of a compound of formula VIID,
or a protected derivative thereof, wherein each Rz independently represents C1-6 alkyl, and R3, R4, R5, R6, R7, m and n are as defined in claim 1, under double bond epoxidation reaction conditions;
(ix) compounds of formula I in which R1 represents hydrogen and R2 represents —OR4 in which R4 represents hydrogen may be prepared by reaction of a compound of formula VIIE,
or a protected derivative thereof, wherein Rz is as defined above, and R3, R4, R5, R6, R7, m and n are as defined in claim 1, in the presence of a suitable oxidising agent;
(x) compounds of formula I may be prepared by reaction of a compound of formula VIII,
wherein L2 represents a suitable leaving group, and R3, R4, R7 and n are as defined in claim 1, with a compound of formula IX,
or a tautomer thereof or derivative thereof, wherein L3 represents a suitable leaving group, and R2, R5, R6, L3 and m are as defined in claim 1;
(xi) for compounds of formula I in which R2 represents hydrogen, and there is a maximum of two R6 substituents present at the 4- and/or 6-position, reduction of a compound of formula IXA,
or a tautomer or protected derivative thereof, wherein m1 represents 0, 1 or 2, and R1, R3, R4, R5, R6, R7 and n 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 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 IXB,
R4a-L2x IXB
wherein R4a represents —R8—OR9, —R8—C(O)OR9, C1-12 alkyl, C2-12 alkenyl, C2-12 alkyneyl (which latter three groups are optionally substituted by one or more substituents selected from X3) or -A3-B3, L2x represents a suitable leaving group, and R8, R9, X3, A3 and B3 are as defined in claim 1;
(xiii) 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 compound of formula IXC,
wherein L2x1 represents L2x or R3, L2x2 represents L2x or —OR4, provided that at least one of R2x1 and R2x2 represents L2x, L2x is as defined above, and R1, R2, R5, R6, R7, m and n are as defined in claim 1, with a compound of formula IXD,
R4—OH IXD
wherein R4 is as defined in claim 1.

### Claim 40 (depends on 30)

A process for the preparation of a pharmaceutical formulation as defined in claim 30, which process comprises bringing into association a compound of formula I, without provisos (C) and (D), or a pharmaceutically acceptable salt thereof with a pharmaceutically-acceptable adjuvant, diluent, carrier or excipient.

### Claim 41 (depends on 1)

A process for the preparation of a combination product comprising bringing into association a compound of formula I, as defined in claim 1 without the provisos, or a pharmaceutically acceptable salt thereof with the other therapeutic agent that is useful in the treatment of i) an inflammatory disorder; ii) a disorder in which the modulation of intracellular cyclic adenosine 5′-monophosphate levels within a mammal is desired, 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; vi) a disorder associated with the central nervous system a and at least one pharmaceutically-acceptable adjuvant, diluent, carrier or excipient.