# US 8,772,288 B2 · Substituted spiro[cycloalkyl-1,3′-indo]-2′(1′H)-one derivatives and their use as P38 mitogen-activated kinase inhibitors

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- Number: US 8,772,288 B2
- Document ID: US8772288B2
- Status: Granted
- Kind: B2
- Application number: 12/936,784
- Filed: 2009-04-03
- Published: 2011-03-03
- Granted: 2014-07-08
- Earliest claimed: 2008-04-11
- Assignees: Almirall, S.A.
- Applicants: Paul Robert Eastwood; Jacob Gonzalez Rodriguez; Bernet Vidal Juan; Nuria Aguilar Izquierdo
- Inventors: Paul Robert Eastwood; Jacob Gonzalez Rodriguez; Bernet Vidal Juan; Nuria Aguilar Izquierdo
- Web page: https://patentgrep.com/patent/US8772288B2

## CPC

- C07D 209/34: in position 2
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 17/06: Antipsoriatics
- A61P 19/10: for osteoporosis
- 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 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 209/96: Spiro-condensed ring systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure is directed to new inhibitors of the p38 mitogen-activated protein kinase having the general formula (I), processes for preparation thereof, pharmaceutical compositions thereof, and methods of use thereof.

## Claims

### Claim 1

A compound of formula (I)
wherein:
R1 represents
a 5-membered heteroaromatic ring having 1, 2, or 3 heteroatoms chosen from nitrogen, oxygen and sulphur atoms, wherein the heteroaromatic ring is optionally substituted by one or two groups chosen from linear and branched C1-4 alkyl groups, and —(CH2)p—C3-6 cycloalkyl groups; wherein each of the C1-4 alkyl and —(CH2)p—C3-6 cycloalkyl groups is optionally substituted by one, two, or three groups chosen from fluorine atoms, —OR groups, and —NRR′ groups, wherein R and R′ each independently is chosen from a hydrogen atom, linear and branched C1-4 alkyl, and C3-6 cycloalkyl groups, wherein p is an integer ranging from 0 to 3,
or R1 represents a group of formula —CO—NHR6, wherein R6 is chosen from a hydrogen atom, linear and branched C1-4 alkyl groups, C3-6 cycloalkyl groups, C3-6 cycloalkyl-C1-2 alkylene groups, and 5 to 6 membered heteroaromatic groups having 1, 2, or 3 heteroatoms chosen from nitrogen, oxygen and sulphur atoms, wherein the heteroaromatic group is optionally substituted by 1 or 2 groups chosen from linear and branched C1-4 alkyl groups and C3-6 cycloalkyl groups;
R2 is chosen from a hydrogen atom, a chlorine atom, and a methyl group;
R3 is chosen from a hydrogen atom and C1-4 alkyl groups;
R4 and R5 each independently is chosen from C1-3 alkyl groups optionally substituted by a hydroxy group, or, R4 and R5 form together with the carbon atom to which they are attached a cyclic group of formula
wherein n and m each independently is an integer chosen from 1 and 2, and G5 is chosen from —O—, —S—, —SO—, —SO2—, —C(R7R8)— and —N(LR9)—, wherein:
R7 is chosen from a hydrogen atom, halogen atoms, a hydroxyl group, C1-4 alkyl groups, morpholine groups, and morpholino-ethoxy groups;
R8 is chosen from a hydrogen atom, halogen atoms, and C1-4 alkyl groups;
L is chosen from a direct bond, —SO2—, —CO—, —(CO)O—, —(CO)NH—, and —(SO2)NH—; and
R9 is chosen from a hydrogen atom, linear and branched C1-4 alkyl groups, —(CH2)q—C3-6 cycloalkyl groups, C5-C10 aryl groups, and 5 to 10-membered heteroaryl groups containing at least one heteroatom chosen from N, S, and O, wherein each of the C1-4 alkyl and —(CH2)q—C3-6 cycloalkyl groups is optionally substituted by one or two groups chosen from halogen atoms, —OR″ groups, and —NR″R′″ groups, and wherein each of the C5-C10 aryl and 5 to 10-membered heteroaryl groups is optionally substituted by one or two groups chosen from linear and branched C1-C4 alkyl groups, halogen atoms, —OR″ groups, and —NR″R′″ groups, wherein R″ and R′″ each is independently chosen from a hydrogen atom, C1-4 alkyl groups, and C3-6 cycloalkyl groups, or R″ and R′″ together with the nitrogen atom to which they are attached form a 5 or 6-membered saturated heterocyclic ring optionally containing one further heteroatom chosen from N, O, and S, and q is an integer ranging from 0 to 3;
G1 is chosen from a nitrogen atom, —CH═, and —CF═;
G2 is chosen from a nitrogen atom, —CH═, and —CF═;
G3 is chosen from a nitrogen atom, —CH═, —CCl═, and —CF═; and
G4 is chosen from a nitrogen atom, —CH═, and —CF═;
or a pharmaceutically acceptable salt or an N-oxide thereof.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein R1 is chosen from triazolyl, oxadiazolyl, and imidazolyl groups wherein each of the triazolyl, oxadiazolyl, and imidazolyl groups is optionally substituted by one group chosen from linear and branched C1-4 alkyl groups, C3-6 cycloalkyl groups, and —CF3;
or R1 represents a group of formula —CO—NHR6, wherein R6 is chosen from a hydrogen atom, linear and branched C1-4 alkyl groups, C3-6 cycloalkyl groups, C3-6 cycloalkyl-C1-2 alkylene groups, isoxazolyl groups, triazolyl groups, and pyridyl groups.

### Claim 3 (depends on 2)

The compound according to claim 2, wherein R1 is chosen from triazolyl groups optionally substituted by one methyl group, or R1 represents a group of formula —CO—NHR6, wherein R6 is chosen from a hydrogen atom, a methyl group, a cyclopropyl group, cyclopropylmethyl groups, a cyclobutyl group, and isoxazolyl groups.

### Claim 4 (depends on 3)

The compound according to claim 3, wherein R1 is chosen from triazolyl groups optionally substituted by one methyl group, or R1 represents a group of formula —CO—NHR6, wherein R6 is chosen from a cyclopropyl group and isoxazolyl groups.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R2 is chosen from a chlorine atom and a methyl group.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein R2 is a methyl group.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R3 is chosen from a hydrogen atom and a methyl group.

### Claim 8 (depends on 7)

The compound according to claim 7, wherein R3 is a hydrogen atom.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R4 and R5 each independently is chosen from a methyl group and a 2-hydroxyethyl group, or R4 and R5 form together with the carbon atom to which they are attached a cyclic group of formula
wherein
n and m each independently is an integer chosen from 1 and 2, and G5 is chosen from —O—, —S—, —SO—, SO2—, —C(R7R8)— and —N(LR9)—, wherein:
R7 is chosen from a hydrogen atom, a fluorine atom, a hydroxyl group, a methyl group, morpholine groups, and morpholino-ethoxy groups;
R8 is chosen from a hydrogen atom, a fluorine atom, and a methyl group;
L is chosen from a direct bond, —SO2—, —O—, —(CO)O— and —C(O)NH—; and
R9 is chosen from linear and branched C1-4 alkyl groups, C3-6 cycloalkyl groups, phenyl groups, and pyridyl groups, wherein each of the C1-4 alkyl and C3-6 cycloalkyl groups is optionally substituted with one group chosen from a chlorine atom, piperazine groups attached at nitrogen, and morpholine groups attached at nitrogen, and wherein each of the phenyl and pyridyl groups is optionally substituted with one group chosen from a chlorine atom, a methyl group, piperazine groups, and morpholine groups.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein R4 and R5 form together with the carbon atom to which they are attached a cyclic group of formula
wherein n and m each independently is an integer chosen from 1 and 2, and G5 is chosen from —O—, —S—, —SO—, SO2—, —C(R7R8)— and —N(LR9)—, wherein:
R7 is chosen from a hydrogen atom, a fluorine atom, a hydroxyl group, a methyl group, morpholine groups, and morpholino-ethoxy groups;
R8 is chosen from a hydrogen atom, a fluorine atom, and a methyl group;
L is chosen from a direct bond, —SO2—, —CO—, —(CO)O— and —C(O)NH—; and
R9 is chosen from linear and branched C1-4 alkyl groups, C3-6 cycloalkyl groups, phenyl groups, and pyridyl groups, wherein each of the C1-4 alkyl and C3-6 cycloalkyl groups is optionally substituted with one group chosen from a chlorine atom, piperazine groups attached at nitrogen, and morpholine groups attached at nitrogen, and wherein each of the phenyl and pyridyl groups is optionally substituted with one group chosen from a chlorine atom, a methyl group, piperazine groups, and morpholine groups.

### Claim 11 (depends on 9)

The compound according to claim 9, wherein G5 is chosen from —O—, —S—, —C(R7R8)— and —N(LR9)—, wherein:
R7 is chosen from a hydrogen atom, a fluorine atom, a hydroxyl group, morpholine groups, and morpholino-ethoxy groups;
R8 is chosen from a hydrogen atom, a fluorine atom, and a methyl group;
L is chosen from a direct bond, —SO2—(CO)O— and —C(O)NH—; and
R9 is chosen from a methyl group, a tert-butyl group, a cyclopropyl group, and phenyl groups optionally substituted by a chlorine atom, piperazine groups, and morpholine groups.

### Claim 12 (depends on 11)

The compound according to claim 11, wherein L is chosen from a direct bond and —SO2—, and R9 is a methyl group.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein G1 is is chosen from —CH═ and —CF═.

### Claim 14 (depends on 1)

The compound according to claim 1, wherein G2 is chosen from a nitrogen atom and —CH═.

### Claim 15 (depends on 1)

The compound according to claim 1, wherein G3 is chosen from a nitrogen atom, —CH═, and —CCl═.

### Claim 16 (depends on 15)

The compound according to claim 15, wherein G3 is chosen from a nitrogen atom and —CH═.

### Claim 17 (depends on 1)

The compound according to claim 1, wherein G4 is chosen from a nitrogen atom and —CH═.

### Claim 18 (depends on 1)

The compound according to claim 1, wherein:
R1 is chosen from triazolyl groups optionally substituted by one methyl group, or R1 represents a group of formula —CO—NHR6, wherein R6 is chosen from a cyclopropyl group and isoxazolyl groups;
R2 is a methyl group;
R3 is a hydrogen atom;
R4 and R5 form together with the carbon atom to which they are attached a cyclic group of formula
wherein n and m each independently is an integer chosen from 1 and 2, and G5 is chosen from —O—, —S—, —C(R7R8)—, and —N(LR9)—, wherein:
R7 is chosen from a hydrogen atom, a fluorine atom, a hydroxyl group, morpholine groups, and morpholino-ethoxy groups;
R8 is chosen from a hydrogen atom, a fluorine atom, and a methyl group;
L is chosen from a direct bond and —SO2—;
R9 is a methyl group;
G1 is chosen from —CH═ and —CF═; and
G2, G3 and G4 each independently is chosen from a nitrogen atom and —CH═.

### Claim 19 (depends on 1)

The compound according to claim 1 chosen from:
N-Cyclopropyl-4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzamide;
N-cyclopropyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzamide;
N-Cyclopropyl-4-methyl-3-(2′-oxo-1′,2′-dihydrospiro[cyclobutane-1,3′-indol]-6′-yl)benzamide;
N-Isopropyl-4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzamide;
N-4-Dimethyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzamide;
4-Methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzamide;
3-(3,3-dimethyl-2-oxoindolin-6-yl)-4-methylbenzamide;
N-Cyclobutyl-4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzamide;
N-(Cyclopropylmethyl)-4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzamide;
N-tert-Butyl-4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzamide;
4-Methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)-N-(pyridin-2yl)benzamide;
N-(Isoxazol-3-yl)-4-methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzamide;
4-Methyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)-N-(1H-1,2,4-triazol-3-yl)benzamide;
4-Chloro-N-cyclopropyl-3-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzamide;
N-Cyclopropyl-3-fluoro-4-methyl-5-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)benzamide;
N-Cyclopropyl-6-methyl-5-(2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)nicotinamide;
N-Cyclopropyl-3-(3,3-dimethyl-2-oxoindolin-6-yl)-4-methylbenzamide;
N-(Cyclopropylmethyl)-3-(3,3-dimethyl-2-oxoindolin-6-yl)-4-methylbenzamide;
3-(3,3-Dimethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-N-isoxazol-3-yl-4-methylbenzamide;
N-Cyclopropyl-4-methyl-3-(1,3,3-trimethyl-2-oxoindolin-6-yl)benzamide;
N-Cyclopropyl-4-methyl-3-(2′-oxospiro[cyclohexane-1,3′-indoline]-6′-yl)benzamide;
N-Cyclopropyl-4-methyl-3-(2-oxo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-6-yl)benzamide;
N-Isoxazol-3-yl-4-methyl-3-(2-oxo-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-pyran]-6-yl)benzamide;
3-(3,3-bis(2-Hydroxyethyl)-2-oxoindolin-6-yl)-N-cyclopropyl-4-methylbenzamide;
N-Cyclopropyl-4-methyl-3-(2-oxo-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-thiopyran]-6-yl)benzamide;
N-Cyclopropyl-3-(2-oxo-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran-1-oxide]-6-yl)-4-methylbenzamide;
N-Cyclopropyl-3-(1′,1′-dioxido-2-oxo-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran]-6-yl)-4-methylbenzamide;
N-(Cyclopropylmethyl)-3-(1′,1′-dioxido-2-oxo-1,2,2′,3′,5′,6′-hexahydrospiro[indole-3,4′-thiopyran]-6-yl)-5-fluoro-4-methylbenzamide;
N-Cyclopropyl-4-methyl-3-(1′-methyl-2-oxospiro[indoline-3,4′-piperidine]-6-yl)benzamide;
tert-Butyl6-(5-(cyclopropylcarbamoyl)-2-methylphenyl)-2-oxospiro[indoline-3,4′-piperidine]-1′-carboxylate;
N-cyclopropyl-3-fluoro-4-methyl-5-(1′-(methylsulfonyl)-2-oxospiro[indoline-3,4′-piperidine]-6-yl)benzamide;
N-Cyclopropyl-3-(4,4-difluoro-2′-oxospiro[cyclohexane-1,3′-indoline]-6′-yl)-4-methylbenzamide;
3-(4,4-Difluoro-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-indol]-6′-yl)-N-isoxazol-3-yl-4-methylbenzamide;
N-cyclopropyl-3-(4-hydroxy-2′-oxospiro[cyclohexane-1,3′-indoline]-6′-yl)-4-methylbenzamide (Major Isomer);
N-cyclopropyl-3-(4-hydroxy-2′-oxospiro[cyclohexane-1,3′-indoline]-6′-yl)-4-methylbenzamide (Minor isomer);
N-cyclopropyl-3-(4-hydroxy-4-methyl-2′-oxospiro[cyclohexane-1,3′-indoline]-6′-yl)-4-methylbenzamide (major isomer);
N-cyclopropyl-3-(4-hydroxy-4-methyl-2′-oxospiro[cyclohexane-1,3′-indoline]-6′-yl)-4-methylbenzamide (minor isomer);
N-(cyclopropylmethyl)-3-(4-hydroxy-2′-oxospiro[cyclohexane-1,3′-indoline]-6′-yl)-4-methylbenzamide;
N-cyclopropyl-4-methyl-3-(4-(2-morpholinoethoxy)-2′-oxospiro[cyclohexane-1,3′-indoline]-6-yl)benzamide;
N-cyclopropyl-4-methyl-3-(4-morpholino-2′-oxospiro[cyclohexane-1,3′-indoline]-6′-yl)benzamide (major isomer);
N-cyclopropyl-4-methyl-3-(4-morpholino-2′-oxospiro[cyclohexane-1,3′-indoline]-6′-yl)benzamide (minor isomer);
N-cyclopropyl-3-fluoro-4-methyl-5-(4-morpholino-2′-oxospiro[cyclohexane-1,3′-indoline]-6′-yl)benzamide (Major isomer);
N-Cyclopropyl-4-methyl-3-(2′-oxo-1′,2′-dihydrospiro[cyclopentane-1,3′-pyrrolo[2,3-b]pyridine]-6′-yl)benzamide;
3-(5′-Chloro-2′-oxospiro[cyclopentane-1,3′-indoline]-6′-yl)-N-cyclopropyl-benzamide;
N-Cyclopropyl-3-(3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)-4-methylbenzamide;
N-Cyclopropyl-4-methyl-3-(2′-oxo-1′,2′-dihydrospiro[cyclopentane-1,3′-pyrrolo-[3,2-b]pyridin]-6′-yl)benzamide;
N-Cyclopropyl-4-methyl-3-(2′-oxo-1′,2,2′,3,5,6-hexahydrospiro[pyran-4,3′-pyrrolo-[3,2-b]pyridin]-6′-yl)benzamide;
N-cyclopropyl-3-(4,4-difluoro-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridine]-6′-yl)-4-methylbenzamide hydrochloride;
N-cyclopropyl-4-methyl-3-(4-morpholino-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridine]-6′-yl)benzamide (major isomer);
N-cyclopropyl-4-methyl-3-(4-morpholino-2′-oxo-1′,2′-dihydrospiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridine]-6′-yl)benzamide (minor isomer);
N-Cyclopropyl-4-methyl-3-(2′-oxo-1′,2′-dihydrospiro[cyclopentane-1,3′-pyrrolo[3,2-c]pyridin]-6′-yl)benzamide;
N-Cyclopropyl-4-methyl-3-(6′-oxo-6′,7′-dihydrospiro[cyclopentane-1,5′-pyrrolo[2,3-d]pyrimidin]-2′-yl)benzamide;
6′-(2-Methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)spiro[cyclopentane-1,3′-indolin]-2′-one;
6′-[2-Methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]spiro[cyclobutane-1,3′-indol]-2′(1′H)-one;
6′-(2-Methyl-5-(4H-1,2,4-triazol-3-yl)phenyl)spiro[cyclopentane-1,3′-indolin]-2′-one;
6′-(5-(5-Cyclopropyl-4H-1,2,4-triazol-3-yl)-2-methylphenyl)spiro[cyclopentane-1,3′-indolin]-2′-one;
6′-(2-Methyl-5-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)phenyl)spiro[cyclopentane-1,3′-indolin]-2′-one;
3,3-Dimethyl-6-(2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)indolin-2-one;
6-(2-Methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)-2′,3′,5′,6′-tetrahydrospiro[indoline-3,4′-pyran]-2-one;
1′-(4-chlorophenyl)-6-(2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)spiro[indoline-3,4′-piperidin]-2-one;
6-[3-Fluoro-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-2′,3′,5′,6′-tetrahydro-spiro[indole-3,4′-pyran]-2(1H)-one;
6′-[2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl]-2,3,5,6-tetrahydrospiro[pyran-4,3′-pyrrolo[3,2-b]pyridin]-2′(1′H)-one hydrogen chloride;
4,4-Difluoro-6′-(2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)spiro[cyclohexane-1,3′-indolin]-2′-one;
4-hydroxy-6′-(2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)spiro[cyclohexane-1,3′-indolin]-2′-one;
6′-(3-fluoro-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)-4-hydroxy-4-methylspiro[cyclohexane-1,3′-indolin]-2′-one;
6′-(2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)-4-(2-morpholinoethoxy)spiro[cyclohexane-1,3′-indolin]-2′-one;
6-(2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)-1′-(methylsulfonyl)spiro[indoline-3,4′-piperidin]-2-one;
6-(2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)-1′-tosylspiro[indoline-3,4′-piperidin]-2-one;
6′-(2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)phenyl)-4-morpholinospiro[cyclohexane-1,3′-indolin]-2′-one;
6′-(2-Methyl-5-(5-methyl-1,4-oxadiazol-2-yl)phenyl)spiro[cyclopentane-1,3′-indolin]-2′-one;
6′-(2-Methyl-5-(1,3,4-oxadiazol-2-yl)phenyl)spiro[cyclopentane-1,3′-indolin]-2′-one;
4,4-Difluoro-6′-(2-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)spiro-[cyclohexane-1,3′-indolin]-2′-one;
4-hydroxy-6′-(2-methyl-5-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)spiro[cyclohexane-1,3′-indolin]-2′-one;
6′-(5-(5-cyclopropyl-1,3,4-oxadiazol-2-yl)-2-methylphenyl)-4-hydroxyspiro[cyclohexane-1,3′-indolin]-2′-one;
6′-(2-Methyl-5-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)spiro[cyclopentane-1,3′-indolin]-2′-one;
6′-(2-Methyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)spiro[cyclopentane-1,3′-indolin]-2′-one;
6-[2-Methyl-5-(2-methyl-1H-imidazol-5-yl)phenyl]-2′,3′,5′,6′-tetrahydrospiro[indole-3,4′-pyran]-2(1H)-one; and
6-(2-methyl-5-(5-methyl-1H-imidazol-2-yl)phenyl)-2′,3′,5′,6′-tetrahydrospiro-[indoline-3,4′-pyran]-2-one.

### Claim 20 (depends on 1)

A pharmaceutical composition comprising the compound according to claim 1 and a pharmaceutically acceptable diluent or carrier.

### Claim 21 (depends on 1)

A composition comprising:
(i) the compound according to claim 1; and
(ii) another compound chosen from (1) antagonists of M3 muscarinic receptors, (2) β2-agonists, (3) PDE4 inhibitors, (4) corticosteroids, (5) leukotriene D4 antagonists, (6) inhibitors of egfr-kinase, (7) antagonists of the A2B adenosine receptor, (8) NK1 receptor agonists, (9) CRTh2 antagonists, (10) syk kinase inhibitors, (11) CCR3 antagonists, (12) VLA-4 antagonists, (13) methotrexate, (14) JAK3 inhibitors, (15) DHODH inhibitors and (16) a disease modifying antirheumatic drug (DMARD).