# US 8,541,363 B2 · Pyruvamide compounds as inhibitors of dust mite group 1 peptidase allergen and their use

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- Number: US 8,541,363 B2
- Document ID: US8541363B2
- Status: Granted
- Kind: B2
- Application number: 13/521,067
- Filed: 2011-01-21
- Published: 2012-12-20
- Granted: 2013-09-24
- Earliest claimed: 2010-01-22
- Assignees: St George's Hosptial Medical School; The University of Manchester
- Applicants: Clive Robinson; Jihui Zhang; David Ronald Garrod; Trevor Robert Perrior; Gary Karl Newton; Kerry Jenkins; Rebekah Elisabeth Beevers; Meriel Ruth Major; Mark Richard Stewart
- Inventors: Clive Robinson; Jihui Zhang; David Ronald Garrod; Trevor Robert Perrior; Gary Karl Newton; Kerry Jenkins; Rebekah Elisabeth Beevers; Meriel Ruth Major; Mark Richard Stewart
- Web page: https://patentgrep.com/patent/US8541363B2

## CPC

- C07K 5/0202: {containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids}
- A01N 37/46: N-acyl derivatives
- A01N 43/16: with oxygen as the ring hetero atom
- A01N 43/30: with two oxygen atoms in positions 1,3, condensed with a carbocyclic ring
- A01N 43/36: five-membered rings
- A01N 43/38: condensed with carbocyclic rings
- A01N 43/40: six-membered rings
- A01N 43/42: condensed with carbocyclic rings
- A01N 43/48: having rings with two nitrogen atoms as the only ring hetero atoms
- A01N 43/60: 1,4-Diazines; Hydrogenated 1,4-diazines
- A01N 43/72: having rings with nitrogen atoms and oxygen or sulfur atoms as ring hetero atoms
- A01N 43/84: six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
- A61K 38/06: Tripeptides
- A61K 38/07: Tetrapeptides
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- 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 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 33/14: Ectoparasiticides, e.g. scabicides
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- C07K 5/06008: {with the first amino acid being neutral}
- C07K 5/06034: {the side chain containing 2 to 4 carbon atoms}
- C07K 5/06078: {and aromatic or cycloaliphatic}
- C07K 5/06139: {with the first amino acid being heterocyclic}
- C07K 5/06191: {containing heteroatoms different from O, S, or N}
- C07K 5/0804: {and aliphatic}
- C07K 5/0806: {the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala}
- C07K 5/0808: {the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu}
- C07K 5/0812: {and aromatic or cycloaliphatic}
- C07K 5/0821: {with the first amino acid being heterocyclic, e.g. His, Pro, Trp}
- C07K 5/0827: {containing heteroatoms different from O, S, or N}
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A01N: PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF (preservation of food or foodstuff A23); BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES (preparations for medical, dental or toiletry purposes which kill or prevent the growth or proliferation of unwanted organisms A61K); PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention pertains generally to the field of therapeutic compounds and more specifically to certain pyruvamide compounds of the formula (X) (for convenience, collectively referred to herein as “PVA compounds”), which, inter alia, inhibit a dust mite Group 1 peptidase allergen (e.g., Der p 1, Der f 1, Eur m 1). The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit a dust mite Group 1 peptidase allergen, and in the treatment of diseases and disorders that are mediated by a dust mite Group 1 peptidase allergen; that are ameliorated by the inhibition of a dust mite Group 1 peptidase allergen; asthma; rhinitis; allergic conjunctivitis; atopic dermatitis; an allergic condition which is triggered by dust mites; an allergic condition which is triggered by a dust mite Group 1 peptidase allergen; and canine atopy.

## Claims

### Claim 1

A compound selected from compounds of the following formula, and pharmaceutically acceptable salts thereof:
wherein:
—R1 is independently —H or —R1A;
—R1A is saturated aliphatic C1-6alkyl, and is optionally substituted with one or more substituents —RX1;
—R2 is —H;
—R3 is independently —H or —R3A;
—R3A is saturated aliphatic C1-3alkyl;
—R4 is —R4A;
—R4A is -Me;
—R5 is —H;
—R6 is —H or —R6A;
—R6A is saturated aliphatic C1-3alkyl;
—R7 is —H, —R7A, or —R7B;
—R7A is saturated aliphatic C1-6alkyl;
—R7B is independently -L7B1-R7BB or —R7BB;
-L7B1- is saturated aliphatic C1-3alkylene;
—R7BB is independently —R7BB1, —R7BB2, —R7BB3, or —R7BB4;
—R7BB1 is independently phenyl or naphthyl, and is optionally substituted with one or more substituents —RX3;
—R7BB2 is C5-10heteroaryl, and is optionally substituted with one or more substituents —RX3;
—R7BB3 is C3-7cycloalkyl, and is optionally substituted with one or more substituents —RX2, or is optionally fused to a benzene ring which is optionally substituted with one or more substituents —RX3;
—R7BB4 is saturated bridged C5-10cycloalkyl, and is optionally substituted with one or more substituents —RX2;
—R8 is —H;
—R9 is independently —H or —R9A;
—R9A is saturated aliphatic C1-4alkyl;
—R10 is independently —R10A, —R10B, —R10C, or —R10D;
—R10A is independently phenyl or naphthyl, and is optionally substituted with one or more substituents —RX3;
—R10B is C5-10heteroaryl, and is optionally substituted with one or more substituents —RX3;
—R10C is saturated C3-7cycloalkyl, and is optionally substituted with one or more substituents —RX2;
—R10D is non-aromatic C3-10heterocyclyl, and is optionally substituted with one or more substituents —RX2;
or —R9 and —R10, taken together with the nitrogen atom and carbon atom to which they are respectively attached, form a non-aromatic C5-7heterocyclic lactam ring, which is optionally substituted with one or more substituents —RX2, or which is optionally fused to a benzene ring which is optionally substituted with one or more substituents —RX3;
—R11 is independently —H, —R11A, or —R11B;
—R11A is independently —RZ1, —RZ2, —RZ3, —RZ4, —RZ5, -LZ-RZ2, -LZ-RZ3, -LZ-RZ4, or -LZ-RZ5;
—RZ1 is saturated aliphatic C1-6alkyl, and is optionally substituted with one or more substituents —RX1;
each —RZ2 is saturated C3-7cycloalkyl, and is optionally substituted with one or more substituents —RX2;
each —RZ3 is independently —RZ3A or —RZ3B;
each —RZ3A is non-aromatic C3-7heterocyclyl, and is optionally substituted with one or more substituents —RX2;
each —RZ3B is saturated bridged C5-10heterocyclyl, and is optionally substituted with one or more substituents —RX2;
each —RZ4 is independently phenyl or naphthyl, and is optionally substituted with one or more substituents —RX3;
each —RZ5 is C5-10heteroaryl, and is optionally substituted with one or more substituents —RX3;
each -LZ- is saturated aliphatic C1-4alkylene;
—R11B is —CRJ1RJ2—C(═O)—NRJ3RJ4;
—RJ1 is independently —H or saturated aliphatic C1-4alkyl;
—RJ2 is independently —H or saturated aliphatic C1-4alkyl;
—RJ3 is independently —H, saturated aliphatic C1-4alkyl, phenyl, or benzyl;
—RJ4 is independently —H, saturated aliphatic C1-4alkyl, phenyl, or benzyl;
or —NRJ3RJ4 is a C3-10heterocyclyl group, and is optionally substituted with one or more substituents —RX2;
—R12 is independently —H or —R12A;
—R12A is saturated aliphatic C1-4alkyl;
wherein each —RX1 is independently selected from:
—F, —Cl, —Br, —I, phenyl, —CF3, —OH, —ORS, —OCF3, —NH2, —NHRS, —NRS2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RS, —NRSC(═O)RS, —C(═O)RS, —C(═O)OH, —C(═O)ORS, —C(═O)NH2, —C(═O)NHRS, —C(═O)NRS2, —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, —C(═O)—{N—(C1-4alkyl)-piperizino}-, —SRS, —S(═O)RS, and —S(═O)2RS;
wherein each —RS is independently saturated aliphatic C1-6alkyl, phenyl, or —CH2-phenyl;
wherein each phenyl is optionally substituted with one or more groups selected from: —F, —Cl, —Br, —I, —RSS, —CF3, —OH, —ORSS, or —OCF3, wherein each —RSS is saturated aliphatic C1-4alkyl;
and wherein each —RX2 is independently selected from:
—F, —Cl, —Br, —I, —RT, phenyl, —OH, —ORT, —C(═O)RT, —NH2, —NHRT, —NRT2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RT, and —NRTC(═O)RT;
wherein each —RT is independently saturated aliphatic C1-6alkyl, phenyl, or —CH2-phenyl;
wherein each phenyl is optionally substituted with one or more groups selected from: —F, —Cl, —Br, —I, —RTT, —CF3, —OH, —ORTT, or —OCF3, wherein each —RTT is saturated aliphatic C1-4alkyl,
and wherein each —RX3 is independently selected from:
—F, —Cl, —Br, —I,
—RV,
—CH═CH2, —C≡CH, cyclopropyl,
—CF3, —CHF2, —OCF3, —OCHF2,
—CN,
—NO2,
—OH, —ORV,
-LV-OH, -LV-ORV,
—O-LV-OH, —O-LV-ORV,
—NH2, —NHRV, —NRV2,
pyrrolidino, piperidino, morpholino,
piperizino, N—(C1-4alkyl)-piperizino,
-LV-NH2, -LV-NHRV, -LV-NRV2,
-LV-pyrrolidino, -LV-piperidino, -LV-morpholino,
-LV-piperizino, -LV-{N—(C1-4alkyl)-piperizino},
-LV-imidazol-2-yl, -LV-{N—(C1-4alkyl)-imidazol-2-yl},
—O-LV-NH2, —O-LV-NHRV, —O-LV-NRV2,
—O-LV-pyrrolidino, —O-LV-piperidino, —O-LV-morpholino,
—O-LV-piperizino, —O-LV-{N—(C1-4alkyl)-piperizino},
—O-LV-imidazol-2-yl, —O-LV-{N—(C1-4alkyl)-imidazol-2-yl},
—NHC(═O)RV, —NRVC(═O)RV,
—C(═O)RV,
—C(═O)OH, —C(═O)ORV,
—C(═O)NH2, —C(═O)NHRV, —C(═O)NRV2,
—C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino,
—C(═O)-piperizino, —C(═O)—{N—(C1-4alkyl)-piperizino}-,
—NHC(═O)NH2, —NHC(═O)NHRV, —NHC(═O)NRV2,
—NHC(═O)-pyrrolidino, —NHC(═O)-piperidino, —NHC(═O)-morpholino,
—NHC(═O)-piperizino, —NHC(═O)—{N—(C1-4alkyl)-piperizino}-,
—S(═O)2RV,
—S(═O)2NH2, —S(═O)2NHRV, —S(═O)2NRV2, and
═O;
wherein each -LV- is saturated aliphatic C1-4alkylene;
wherein each —RV is independently saturated aliphatic C1-6alkyl, phenyl, —CH2-phenyl, C5-6heteroaryl, or —CH2—C5-6heteroaryl;
wherein each phenyl is optionally substituted with one or more groups selected from: —F, —Cl, —Br, —I, —RVV, —CF3, —OH, —ORVV, or —OCF3;
wherein each C5-6heteroaryl is optionally substituted with one or more groups selected from: —F, —Cl, —Br, —I, —RVV, —CF3, —OH, —ORVV, or —OCF3;
wherein each —RVV is saturated aliphatic C1-4alkyl;
and additionally, two adjacent groups —RX3 may together form —OCH2O—, —OCH2CH2O—, —CH2OCH2— or —OCH2CH2—;
and additionally, two adjacent groups —RX3 may, together with the ring atoms to which they are attached, form a C5-7carbocyclic ring or a C5-7heterocyclic ring.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein —R1 is —R1A, and —R1A is -iPr.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein —R3 is —H and —R6 is —H.

### Claim 4 (depends on 2)

The compound according to claim 2, wherein —R3 is —H and —R6 is —H.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein —R7 is independently —R7A or —R7B; —R7A is -tBu; —R7B is -L7B1-R7BB; -L7B1- is —CH2—; —R7BB is —R7BB1; and —R7BB1 is phenyl.

### Claim 6 (depends on 4)

The compound according to claim 4, wherein —R7 is independently —R7A or —R7B; —R7A is -tBu; —R7B is -L7B1-R7BB; -L7B1- is —CH2—; —R7BB is —R7BB1; and —R7BB1 is phenyl.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein —R9 is —H; —R10 is —R10A; and —R10A is phenyl, and is optionally substituted with one or more substituents —RX3.

### Claim 8 (depends on 6)

The compound according to claim 6, wherein —R9 is —H; —R10 is —R10A; and —R10A is phenyl, and is optionally substituted with one or more substituents —RX3.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein —R9 is —H; —R10 is —R10B; and —R10B is pyridyl, and is optionally substituted with one or more substituents —RX3.

### Claim 10 (depends on 6)

The compound according to claim 6, wherein —R9 is —H; —R10 is —R10B; and —R10B is pyridyl, and is optionally substituted with one or more substituents —RX3.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein —R9 is —H; —R10 is —R10B; and —R10B is independently indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, or isoquinolinyl, and is optionally substituted with one or more substituents —RX3.

### Claim 12 (depends on 6)

The compound according to claim 6, wherein —R9 is —H; —R10 is —R10B; and —R10B is independently indazolyl, benzimidazolyl, benzothiazolyl, quinolinyl, or isoquinolinyl, and is optionally substituted with one or more substituents —RX3.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein —R9 is —H; —R10 is —R10D; and —R10D is independently:

### Claim 14 (depends on 6)

The compound according to claim 6, wherein —R9 is —H; —R10 is —R10D; and —R10D is independently:

### Claim 15 (depends on 1)

The compound according to claim 1, wherein the group —N(R9)—C(═O)—R10 is the following group:

### Claim 16 (depends on 6)

The compound according to claim 6, wherein the group —N(R9)—C(═O)—R10 is the following group:

### Claim 17 (depends on 1)

The compound according to claim 1, wherein:
—R11 is —R11A;
—R11A is -LZ-RZ4;
-LZ- is —CH2— or —CH(Me)-; and
—RZ4 is independently selected from:
and
—R12 is —H.

### Claim 18 (depends on 8)

The compound according to claim 8, wherein:
R11 is —R11A;
—R11A is -LZ-RZ4;
-LZ- is —CH2— or —CH(Me)-; and
—RZ4 is independently selected from:
and
—R12 is —H.

### Claim 19 (depends on 10)

The compound according to claim 10, wherein:
R11 is —R11A;
—R11A is -LZ-RZ4;
-LZ- is —CH2— or —CH(Me)-; and
—RZ4 is independently selected from:
and
—R12 is —H.

### Claim 20 (depends on 12)

The compound according to claim 12, wherein:
—R11 is —R11A;
—R11A is -LZ-RZ4;
-LZ- is —CH2— or —CH(Me)-; and
—RZ4 is independently selected from:
and
—R12 is —H.

### Claim 21 (depends on 14)

The compound according to claim 14, wherein:
—R11 is —R11A;
—R11A is -LZ-RZ4;
-LZ- is —CH2— or —CH(Me)-; and
—RZ4 is independently selected from:
and
—R12 is —H.

### Claim 22 (depends on 16)

The compound according to claim 16, wherein:
—R11 is —R11A;
—R11A is -LZ-RZ4;
-LZ- is —CH2— or —CH(Me)-; and
—RZ4 is independently selected from:
and
—R12 is —H.

### Claim 23 (depends on 1)

The compound according to claim 1, wherein:
—R11 is —R11B;
—RJ1 is independently —H, -Me, -Et, -nPr, or -iPr;
—RJ2 is —H;
—NRJ3RJ4 is independently selected from:
1,2,3,4-tetrahydro-isoquinolin-2-yl, and
2,3-dihydro-1H-indol-1-yl; and
—R12 is —H.

### Claim 24 (depends on 8)

The compound according to claim 8, wherein:
—R11 is —R11B;
—RJ1 is independently —H, -Me, -Et, -nPr, or -iPr;
—RJ2 is —H;
—NRJ3RJ4 is independently selected from:
1,2,3,4-tetrahydro-isoquinolin-2-yl, and
2,3-dihydro-1H-indol-1-yl; and
—RJ2 is —H.

### Claim 25 (depends on 10)

The compound according to claim 10, wherein:
—R11 is —R11B;
—RJ1 is independently —H, -Me, -Et, -nPr, or -iPr;
—RJ2 is —H;
—NRJ3RJ4 is independently selected from:
1,2,3,4-tetrahydro-isoquinolin-2-yl, and
2,3-dihydro-1H-indol-1-yl; and
—R12 is —H.

### Claim 26 (depends on 12)

The compound according to claim 12, wherein:
—R11 is —R11B;
—RJ1 is independently —H, -Me, -Et, -nPr, or -iPr;
—RJ2 is —H;
—NRJ3RJ4 is independently selected from:
1,2,3,4-tetrahydro-isoquinolin-2-yl, and
2,3-dihydro-1H-indol-1-yl; and
—R12 is —H.

### Claim 27 (depends on 14)

The compound according to claim 14, wherein:
—R11 is —R11B;
—RJ1 is independently —H, -Me, -Et, -nPr, or -iPr;
—RJ2 is —H;
—NRJ3RJ4 is independently selected from:
1,2,3,4-tetrahydro-isoquinolin-2-yl, and
2,3-dihydro-1H-indol-1-yl; and
—R12 is —H.

### Claim 28 (depends on 16)

A compound according to claim 16, wherein:
—R11 is —R11B;
—RJ1 is independently —H, -Me, -Et, -nPr, or -iPr;
—RJ2 is —H;
—NRJ3RJ4 is independently selected from:
1,2,3,4-tetrahydro-isoquinolin-2-yl, and
2,3-dihydro-1H-indol-1-yl; and
—R12 is —H.

### Claim 29 (depends on 1)

The compound according to claim 1, wherein
each —RX1, if present, is independently selected from: —F, —Cl, —Br, —I, —OH, —ORS, —NH2, —NHRS, —NRS2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RS, —NRSC(═O)RS, —C(═O)NH2, —C(═O)NHRS, —C(═O)NRS2, —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, and —C(═O)—{N—(C1-4alkyl)-piperizino}-;
each —RX2, if present, is independently selected from: —RT, —OH, —ORT, —C(═O)RT, —NH2, —NHRT, —NRT2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RT, and —NRTC(═O)RT; and
each —RX3, if present, is independently selected from: —F, —Cl, —Br, —I, —RV, —CN, —OH, —ORV, —NH2, —NHRV, —NRV2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, -LV-NH2, -LV-NHRV, -LV-NRV2, -LV-pyrrolidino, -LV-piperidino, -LV-morpholino, -LV-piperizino, -LV-{N—(C1-4alkyl)-piperizino}, —C(═O)OH, —C(═O)ORV, —C(═O)NH2, —C(═O)NHRV, —C(═O)NRV2, —NHC(═O)NH2, —S(═O)2NH2, —S(═O)2NHRV, —S(═O)2NRV2, and ═O.

### Claim 30 (depends on 18)

The compound according to claim 18, wherein
each —RX1, if present, is independently selected from: —F, —Cl, —Br, —I, —OH, —ORS, —NH2, —NHRS, —NRS2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RS, —NRSC(═O)RS, —C(═O)NH2, —C(═O)NHRS, —C(═O)NRS2, —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, and —C(═O)—{N—(C1-4alkyl)-piperizino}-;
each —RX2, if present, is independently selected from: —RT, —OH, —ORT, —C(═O)RT, —NH2, —NHRT, —NRT2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RT, and —NRTC(═O)RT; and
each —RX3, if present, is independently selected from: —F, —Cl, —Br, —I, —RV, —CN, —OH, —ORV, —NH2, —NHRV, —NRV2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, -LV-NH2, -LV-NHRV, -LV-NRV2, -LV-pyrrolidino, -LV-piperidino, -LV-morpholino, -LV-piperizino, -LV-{N—(C1-4alkyl)-piperizino}, —C(═O)OH, —C(═O)ORV, —C(═O)NH2, —C(═O)NHRV, —C(═O)NRV2, —NHC(═O)NH2, —S(═O)2NH2, —S(═O)2NHRV, —S(═O)2NRV2, and ═O.

### Claim 31 (depends on 19)

The compound according to claim 19, wherein
each —RX1, if present, is independently selected from: —F, —Cl, —Br, —I, —OH, —ORS, —NH2, —NHRS, —NRS2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RS, —NRSC(═O)RS, —C(═O)NH2, —C(═O)NHRS, —C(═O)NRS2, —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, and —C(═O)—{N—(C1-4alkyl)-piperizino}-;
each —RX2, if present, is independently selected from: —RT, —OH, —ORT, —C(═O)RT, —NH2, —NHRT, —NRT2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RT, and —NRTC(═O)RT; and
each —RX3, if present, is independently selected from: —F, —Cl, —Br, —I, —RV, —CN, —OH, —ORV, —NH2, —NHRV, —NRV2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, -LV-NH2, -LV-NHRV, -LV-NRV2, -LV-pyrrolidino, -LV-piperidino, -LV-morpholino, -LV-piperizino, -LV-{N—(C1-4alkyl)-piperizino}, —C(═O)OH, —C(═O)ORV, —C(═O)NH2, —C(═O)NHRV, —C(═O)NRV2, —NHC(═O)NH2, —S(═O)2NH2, —S(═O)2NHRV, —S(═O)2NRV2, and ═O.

### Claim 32 (depends on 20)

The compound according to claim 20, wherein
each —RX1, if present, is independently selected from: —F, —Cl, —Br, —I, —OH, —ORS, —NH2, —NHRS, —NRS2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RS, —NRSC(═O)RS, —C(═O)NH2, —C(═O)NHRS, —C(═O)NRS2, —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, and —C(═O)—{N—(C1-4alkyl)-piperizino}-;
each —RX2, if present, is independently selected from: —RT, —OH, —ORT, —C(═O)RT, —NH2, —NHRT, —NRT2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RT, and —NRTC(═O)RT; and
each —RX3, if present, is independently selected from: —F, —Cl, —Br, —I, —RV, —CN, —OH, —ORV, —NH2, —NHRV, —NRV2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, -LV-NH2, -LV-NHRV, -LV-NRV2, -LV-pyrrolidino, -LV-piperidino, -LV-morpholino, -LV-piperizino, -LV-{N—(C1-4alkyl)-piperizino}, —C(═O)OH, —C(═O)ORV, —C(═O)NH2, —C(═O)NHRV, —C(═O)NRV2, —NHC(═O)NH2, —S(═O)2NH2, —S(═O)2NHRV, —S(═O)2NRV2, and ═O.

### Claim 33 (depends on 21)

The compound according to claim 21, wherein
each —RX1, if present, is independently selected from: —F, —Cl, —Br, —I, —OH, —ORS, —NH2, —NHRS, —NRS2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RS, —NRSC(═O)RS, —C(═O)NH2, —C(═O)NHRS, —C(═O)NRS2, —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, and —C(═O)—{N—(C1-4alkyl)-piperizino}-;
each —RX2, if present, is independently selected from: —RT, —OH, —ORT, —C(═O)RT, —NH2, —NHRT, —NRT2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RT, and —NRTC(═O)RT; and
each —RX3, if present, is independently selected from: —F, —Cl, —Br, —I, —RV, —CN, —OH, —ORV, —NH2, —NHRV, —NRV2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, -LV-NH2, -LV-NHRV, -LV-NRV2, -LV-pyrrolidino, -LV-piperidino, -LV-morpholino, -LV-piperizino, -LV-{N—(C1-4alkyl)-piperizino}, —C(═O)OH, —C(═O)ORV, —C(═O)NH2, —C(═O)NHRV, —C(═O)NRV2, —NHC(═O)NH2, —S(═O)2NH2, —S(═O)2NHRV, —S(═O)2NRV2, and ═O.

### Claim 34 (depends on 22)

The compound according to claim 22, wherein
each —RX1, if present, is independently selected from: —F, —Cl, —Br, —I, —OH, —ORS, —NH2, —NHRS, —NRS2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RS, —NRSC(═O)RS, —C(═O)NH2, —C(═O)NHRS, —C(═O)NRS2, —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, and —C(═O)—{N—(C1-4alkyl)-piperizino}-;
each —RX2, if present, is independently selected from: —RT, —OH, —ORT, —C(═O)RT, —NH2, —NHRT, —NRT2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RT, and —NRTC(═O)RT; and
each —RX3, if present, is independently selected from: —F, —Cl, —Br, —I, —RV, —CN, —OH, —ORV, —NH2, —NHRV, —NRV2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, -LV-NH2, -LV-NHRV, -LV-NRV2, -LV-pyrrolidino, -LV-piperidino, -LV-morpholino, -LV-piperizino, -LV-{N—(C1-4alkyl)-piperizino}, —C(═O)OH, —C(═O)ORV, —C(═O)NH2, —C(═O)NHRV, —C(═O)NRV2, —NHC(═O)NH2, —S(═O)2NH2, —S(═O)2NHRV, —S(═O)2NRV2, and ═O.

### Claim 35 (depends on 24)

The compound according to claim 24, wherein
each —RX1, if present, is independently selected from: —F, —Cl, —Br, —I, —OH, —ORS, —NH2, —NHRS, —NRS2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RS, —NRSC(═O)RS, —C(═O)NH2, —C(═O)NHRS, —C(═O)NRS2, —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, and —C(═O)—{N—(C1-4alkyl)-piperizino}-;
each —RX2, if present, is independently selected from: —RT, —OH, —ORT, —C(═O)RT, —NH2, —NHRT, —NRT2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RT, and —NRTC(═O)RT; and
each —RX3, if present, is independently selected from: —F, —Cl, —Br, —I, —RV, —CN, —OH, —ORV, —NH2, —NHRV, —NRV2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, -LV-NH2, -LV-NHRV, -LV-NRV2, -LV-pyrrolidino, -LV-piperidino, -LV-morpholino, -LV-piperizino, -LV-{N—(C1-4alkyl)-piperizino}, —C(═O)OH, —C(═O)ORV, —C(═O)NH2, —C(═O)NHRV, —C(═O)NRV2, —NHC(═O)NH2, —S(═O)2NH2, —S(═O)2NHRV, —S(═O)2NRV2, and ═O.

### Claim 36 (depends on 25)

The compound according to claim 25, wherein
each —RX1, if present, is independently selected from: —F, —Cl, —Br, —I, —OH, —ORS, —NH2, —NHRS, —NRS2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RS, —NRSC(═O)RS, —C(═O)NH2, —C(═O)NHRS, —C(═O)NRS2, —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, and —C(═O)—{N—(C1-4alkyl)-piperizino}-;
each —RX2, if present, is independently selected from: —RT, —OH, —ORT, —C(═O)RT, —NH2, —NHRT, —NRT2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RT, and —NRTC(═O)RT; and
each —RX3, if present, is independently selected from: —F, —Cl, —Br, —I, —RV, —CN, —OH, —ORV, —NH2, —NHRV, —NRV2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, -LV-NH2, -LV-NHRV, -LV-NRV2, -LV-pyrrolidino, -LV-piperidino, -LV-morpholino, -LV-piperizino, -LV-{N—(C1-4alkyl)-piperizino}, —C(═O)OH, —C(═O)ORV, —C(═O)NH2, —C(═O)NHRV, —C(═O)NRV2, —NHC(═O)NH2, —S(═O)2NH2, —S(═O)2NHRV, —S(═O)2NRV2, and ═O.

### Claim 37 (depends on 26)

The compound according to claim 26, wherein
each —RX1, if present, is independently selected from: —F, —Cl, —Br, —I, —OH, —ORS, —NH2, —NHRS, —NRS2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RS, —NRSC(═O)RS, —C(═O)NH2, —C(═O)NHRS, —C(═O)NRS2, —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, and —C(═O)—{N—(C1-4alkyl)-piperizino}-;
each —RX2, if present, is independently selected from: —RT, —OH, —ORT, —C(═O)RT, —NH2, —NHRT, —NRT2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RT, and —NRTC(═O)RT; and
each —RX3, if present, is independently selected from: —F, —Cl, —Br, —I, —RV, —CN, —OH, —ORV, —NH2, —NHRV, —NRV2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, -LV-NH2, -LV-NHRV, -LV-NRV2, -LV-pyrrolidino, -LV-piperidino, -LV-morpholino, -LV-piperizino, -LV-{N—(C1-4alkyl)-piperizino}, —C(═O)OH, —C(═O)ORV, —C(═O)NH2, —C(═O)NHRV, —C(═O)NRV2, —NHC(═O)NH2, —S(═O)2NH2, —S(═O)2NHRV, —S(═O)2NRV2, and ═O.

### Claim 38 (depends on 27)

The compound according to claim 27, wherein
each —RX1, if present, is independently selected from: —F, —Cl, —Br, —I, —OH, —ORS, —NH2, —NHRS, —NRS2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RS, —NRSC(═O)RS, —C(═O)NH2, —C(═O)NHRS, —C(═O)NRS2, —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, and —C(═O)—{N—(C1-4alkyl)-piperizino}-;
each —RX2, if present, is independently selected from: —RT, —OH, —ORT, —C(═O)RT, —NH2, —NHRT, —NRT2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RT, and —NRTC(═O)RT; and
each —RX3, if present, is independently selected from: —F, —Cl, —Br, —I, —RV, —CN, —OH, —ORV, —NH2, —NHRV, —NRV2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, -LV-NH2, -LV-NHRV, -LV-NRV2, -LV-pyrrolidino, -LV-piperidino, -LV-morpholino, -LV-piperizino, -LV-{N—(C1-4alkyl)-piperizino}, —C(═O)OH, —C(═O)ORV, —C(═O)NH2, —C(═O)NHRV, —C(═O)NRV2, —NHC(═O)NH2, —S(═O)2NH2, —S(═O)2NHRV, —S(═O)2NRV2, and ═O.

### Claim 39 (depends on 28)

The compound according to claim 28, wherein
each —RX1, if present, is independently selected from: —F, —Cl, —Br, —I, —OH, —ORS, —NH2, —NHRS, —NRS2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RS, —NRSC(═O)RS, —C(═O)NH2, —C(═O)NHRS, —C(═O)NRS2, —C(═O)-pyrrolidino, —C(═O)-piperidino, —C(═O)-morpholino, —C(═O)-piperizino, and —C(═O)—{N—(C1-4alkyl)-piperizino}-;
each —RX2, if present, is independently selected from: —RT, —OH, —ORT, —C(═O)RT, —NH2, —NHRT, —NRT2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, —NHC(═O)RT, and —NRTC(═O)RT; and
each —RX3, if present, is independently selected from: —F, —Cl, —Br, —I, —RV, —CN, —OH, —ORV, —NH2, —NHRV, —NRV2, pyrrolidino, piperidino, morpholino, piperizino, N—(C1-4alkyl)-piperizino, -LV-NH2, -LV-NHRV, -LV-NRV2, -LV-pyrrolidino, -LV-piperidino, -LV-morpholino, -LV-piperizino, -LV-{N—(C1-4alkyl)-piperizino}, —C(═O)OH, —C(═O)ORV, —C(═O)NH2, —C(═O)NHRV, —C(═O)NRV2, —NHC(═O)NH2, —S(═O)2NH2, —S(═O)2NHRV, —S(═O)2NRV2, and ═O.

### Claim 40

A compound selected from the following compounds and pharmaceutically acceptable salts thereof:

### Claim 41 (depends on 1)

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

### Claim 42 (depends on 1)

A method of preparing a composition comprising admixing the compound according to claim 1 and a pharmaceutically acceptable carrier, diluent, or excipient.

### Claim 43 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
asthma;
bronchial hyperreactivity associated with asthma; or bronchial hyperresponsiveness associated with asthma;
airway remodelling associated with an allergic lung disease;
asthma co-presented with a chronic obstructive lung disease;
rhinitis;
allergic conjunctivitis;
atopic dermatitis;
an allergic condition which is triggered by dust mites;
an allergic condition which is triggered by dust mite Group 1 peptidase allergen; or
canine atopy.

### Claim 44 (depends on 43)

The method according to claim 43, wherein the treatment further comprises treatment with one or more additional therapeutic agents selected from agents used, or likely to be used, in the treatment of a respiratory disease.

### Claim 45 (depends on 1)

A method of inhibiting a dust mite Group 1 peptidase allergen, in vitro or in vivo, comprising contacting said dust mite Group 1 peptidase allergen with an effective amount of the compound according to claim 1.

### Claim 46 (depends on 1)

A method of inhibiting a dust mite Group 1 peptidase allergen in a cell, in vitro or in vivo, comprising contacting the cell with an effective amount of the compound according to claim 1.

### Claim 47 (depends on 1)

An acaricide composition comprising the compound according to claim 1.

### Claim 48 (depends on 1)

A method of killing mites, comprising exposing said mites to an effective amount of the compound according to claim 1.

### Claim 49 (depends on 1)

A method of controlling a mite population comprising exposing mites to an effective amount of the compound according to claim 1.

### Claim 50 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
asthma.

### Claim 51 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
atopic asthma; allergic asthma; atopic bronchial IgE-mediated asthma; bronchial asthma; extrinsic asthma; allergen-induced asthma; or allergic asthma exacerbated by respiratory virus infection.

### Claim 52 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
infective asthma.

### Claim 53 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
infective asthma caused by bacterial infection; infective asthma caused by fungal infection; infective asthma caused by protozoal infection; or infective asthma caused by viral infection.

### Claim 54 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
bronchial hyperreactivity associated with asthma; or bronchial hyperresponsiveness associated with asthma.

### Claim 55 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
airway remodelling associated with an allergic lung disease.

### Claim 56 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
airway remodelling associated with asthma.

### Claim 57 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
asthma co-presented with a chronic obstructive lung disease.

### Claim 58 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
asthma co-presented with emphysema; or asthma co-presented with chronic bronchitis.

### Claim 59 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
rhinitis.

### Claim 60 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
allergic rhinitis; perennial rhinitis; persistent rhinitis; or IgE-mediated rhinitis.

### Claim 61 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
allergic conjunctivitis.

### Claim 62 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
IgE-mediated conjunctivitis.

### Claim 63 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
atopic dermatitis.

### Claim 64 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
an allergic condition which is triggered by dust mites.

### Claim 65 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
an allergic condition which is triggered by dust mite Group 1 peptidase allergen.

### Claim 66 (depends on 1)

A method of treatment, comprising administering to a subject in need of treatment a therapeutically-effective amount of the compound according to claim 1, wherein the treatment is treatment of:
canine atopy.