# US 2008/0188452 A1 · Macrocyclic Benzofused Pyrimidine Derivatives

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- Number: US 2008/0188452 A1
- Document ID: US20080188452A1
- Status: Published application
- Kind: A1
- Application number: 11/863,559
- Filed: 2007-09-28
- Published: 2008-08-07
- Earliest claimed: 2006-10-02
- Assignees: AbbVie Inc.
- Inventors: Robert J. Altenbach; Huaqing Liu; Irene Drizin; Marlon D. Cowart; Neil Wishart; David J. Babinski; Robert J. Gregg; Arthur A. Hancock; Kathryn J. Hancock; Timothy A. Esbenshade; Gin C. Hsieh; Jorge D. Brioni; Marie P. Honore; Lawrence A. Black; Chen Zhao; Brian D. Wakefield
- Web page: https://patentgrep.com/patent/US20080188452A1

## CPC

- C07H 17/04: Heterocyclic radicals containing only oxygen as ring hetero atoms
- A61P 11/06: Antiasthmatics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/02: for peripheral neuropathies
- 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 37/00: Drugs for immunological or allergic disorders
- C07D 239/70: condensed with carbocyclic rings or ring systems
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- C07D 453/04: having a quinolyl-4, a substituted quinolyl-4 or a alkylenedioxy-quinolyl-4 radical linked through only one carbon atom, attached in position 2, e.g. quinine
- C07D 471/04: Ortho-condensed systems
- C07D 471/10: Spiro-condensed systems
- C07D 487/04: Ortho-condensed systems
- C07D 487/10: Spiro-condensed systems
- C07D 491/04: Ortho-condensed systems
- C07D 495/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Macrocyclic benzofused pyrimidine compounds, compositions comprising such compounds, methods for making the compounds, and methods of treating and preventing the progression of diseases, conditions and disorders using such compounds and compositions are described herein.

## Claims

### Claim 1

A compound of formula (I):
or a pharmaceutically acceptable, salt, ester, amide, or prodrug thereof, wherein:
G1 is selected from oxygen, sulfur, S(O), S(O)2, NR8 and alkylene;
G2 is selected from oxygen, sulfur, S(O), S(O)2, NR8, and alkylene wherein each carbon of the alkylene and methylene groups of G1 and G2 may be optionally substituted with one or more groups selected from alkyl, fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocycloalkyl, fluorine, acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio, and oxo;
provided that when G1 is oxygen, sulfur, S(O), S(O)2 or NR8, G2 is alkylene;
provided that when G2 is oxygen, sulfur, S(O), S(O)2, or NR8 G1 is alkylene;
R1 is selected from H, NH2, —NH(acyl), —NH(alkyl), —N(alkyl)2, —NH(C═O)aryl, —NH-alkylene(NR8R9), —NH(C═O)-alkylene(NR8R9), —NR8(C═O)NR8R9, —NH—alkylene-heteroaryl, —NHOH, —NHOCH3, —O-alkylene(NR8R9), alkyl, piperazine, fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl, hydroxyalkyl, cyano, alkoxycarbonyl, carboxy, —(C═O)—(NR8R9), —(C═O)—NH-alkylene(NR8R9), and alkoxy;
R2, R3, R4, R5, are each independently selected from hydrogen, alkyl, fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocycloalkyl, aryl, heteroaryl, heterocycle, O-aryl, O-heteroaryl, S-aryl, CONR8R9, NR8COalkyl, NR8(C═O)Oalkyl, acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio, —NR8R9, -carbonyl(NR8R9), —SO2 (NR8R9), and N(R8)SO2(R9);
R3 and R4 taken together with the carbon atoms to which each is attached form a ring, wherein R3 and R4 taken together are —CH2CH2CH2—, —CH2CH2CH2CH2—, or —CH2OCH2—;
R6 is selected from hydrogen, alkyl, fluoroalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, and alkylfluorocycloalkyl;
R7 is selected from fluoroalkyl, hydroxyalkyl, alkoxyalkyl, fluorocycloalkyl, and alkylfluorocycloalkyl;
R8 and R9 each are each independently selected from hydrogen, alkyl, fluoroalkyl, cycloalkyl, cyanoalkyl, fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocycloalkyl, aryl, heteroaryl, heterocycle, acyl, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, amido, formyl, hydroxy, and hydroxyalkyl;
A1 is a group of structure A2 or A3;
wherein A2 is selected from
and A3 is selected from
wherein G3 is O, S, S(O), S(O)2;
n is 1, 2, or 3;
m is 0, 1, or 2;
wherein each carbon atom of groups A1 may be optionally substituted with one or more groups selected from alkyl, fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocycloalkyl, fluorine, acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, alkynyl, amido, carboxy, cyano, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio; provided that when G1 is CH2 and G2 is selected from CH2, CH2CH2, oxygen or sulfur and R1 is selected from NH2, NHalkyl, or alkyl, then A1 is not a group of structure K; and further provided that when G1 is CH2CH2 and G2 is CH2 and R1 is selected from NH2, NHalkyl, or alkyl, then A1 is not a group of structure K.

### Claim 2 (depends on 1)

The compound of claim 1, wherein G1 is oxygen, sulfur, —CH2—, —CH2CH2—, —CH2CH2CH2—, or —CH2CH2CH2CH2—.

### Claim 3 (depends on 1)

The compound of claim 1, wherein G1 is —CH2CH2CH2—, —CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2CH2CH2CH2CH2—, —CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2—, or —CH2CH2CH2CH2CH2CH2CH2CH2CH2CH2—.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R1 is selected from H, NHOH, —NHOCH3, fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl, hydroxyalkyl, cyano, and alkoxy.

### Claim 5 (depends on 1)

The compound of claim 1, wherein A1 is a group selected from A2 or A3 of structure A, B, C, D, E, F, G, H, I, J, L, M, N, O, P, Q, R, S, T, U, V, W, X, Y1, Y2, Y3, Y4, Y5, Y6, Y7, Y8, Y9, Y10, Y11, Y12, Y13, Y14, Y15, 1M, 1N, 1O, 1P, 1Q, 1R, 1S, 1U, 1V, 1W, 1X, 1Y1, 1Y2, 1Y3 or 1Y4.

### Claim 6 (depends on 1)

The compound of claim 1, wherein G2 is oxygen, sulfur, —CH2—, —CH2CH2—, or —CH(CH3)—.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R1 is H, NH2, —NHMe, —NH(C═O)Me, —NH(C═O)phenyl, —NH(C═O)NHMe, —NH(C═O)CH2NH2, —NH(C═O)CH2NHMe, —NH(C═O)CH2NMe2, —NH(C═O)CH2CH2CH2NH2, —NHCH2(pyridin-3-yl), —NHCH2(imidazol-4-yl), —NHCH2CH2NMe2, piperazin-1-yl, —(C═O)OMe, —(C═O)OH.

### Claim 8 (depends on 1)

The compound of claim 1, wherein R2, R3, R4, and R5 each are independently hydrogen, fluorine, chlorine, methyl, methoxy, iodine, pyridin-3-yl, phenyl, —(C═O)OMe, cyano, —NMe(C═O)OMe, —NHMe, or —NH(C═O)Me.

### Claim 9 (depends on 1)

The compound of claim 1, wherein A1 is a group of the formula:

### Claim 10 (depends on 9)

The compound of claim 9, wherein A1 is

### Claim 11 (depends on 1)

The compound of claim 1, wherein the compound is:
6-Methyl-4-[(3R)-3-methylamino-pyrrolidin-1-yl]-5,6-dihydro-benzo[h]quinazolin-2-ylamine;
6-Methyl-4-(3-methylamino-azetidin-1-yl)-5,6-dihydro-benzo[h]quinazolin-2-ylamine;
4-(3-Methylamino-azetidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
6-Methyl-4-piperazin-1-yl-5,6-dihydro-benzo[h]quinazolin-2-ylamine;
4-(3-(R)-Methylamino-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-Piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
1-(3-Methylamino-azetidin-1-yl)-10H-9-oxa-2,4-diaza-phenanthren-3-ylamine;
1-(3-(R)-Methylamino-pyrrolidin-1-yl)-10H-9-oxa-2,4-diaza-phenanthren-3-ylamine;
1-Piperazin-1-yl-10H-9-oxa-2,4-diaza-phenanthren-3-ylamine;
10-Fluoro-4-(3-(R)-methylamino-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
10-Fluoro-4-(3-methylamino-azetidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
10-Fluoro-4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-[(3S)-3-Methylamino-pyrrolidin-1-yl]-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-((3aR,6aR)-1-Methyl-hexahydro-pyrrolo[3,4-b]pyrrol-5-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-((3R)-3-Amino-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-((1S,4S)-2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-(3-Piperidin-1-yl-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-((3aR,6aR)-Hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-Piperazin-1-yl-5,6,7,8-tetrahydro-1,3-diaza-dibenzo[a,c]cycloocten-2-ylamine;
4-Piperazin-1-yl-6,7,8,9-tetrahydro-5H-1,3-diaza-dibenzo[a,c]cyclononen-2-ylamine;
4-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-(3-(R)-Methylamino-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-1,3-diaza-dibenzo[a,c]cyclononen-2-ylamine;
4-((R)-3-Amino-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-1,3-diaza-dibenzo[a,c]cyclononen-2-ylamine;
4-((S)-3-Amino-pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-1,3-diaza-dibenzo[a,c]cyclononen-2-ylamine;
4-(3-Methylamino-azetidin-1-yl)-6,7,8,9-tetrahydro-5H-1,3-diaza-dibenzo[a,c]cyclononen-2-ylamine
4-((3aS,6aS)-Hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-6,7,8,9-tetrahydro-5H-1,3-diaza-dibenzo[a,c]cyclononen-2-ylamine;
4-((1S,4S)-2,5-Diaza-bicyclo[2.2.1]hept-2-yl)-6,7,8,9-tetrahydro-5H-1,3-diaza-dibenzo[a,c]cyclononen-2-ylamine;
4-(4-Methyl-piperazin-1-yl)-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-Piperazin-1-yl-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-((R)-3-Methylamino-pyrrolidin-1-yl)-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-(3-Methylamino-azetidin-1-yl)-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-(3-Methylamino-azetidin-1-yl)-5,6-dihydro-7-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-(3-(R)-Methylamino-pyrrolidin-1-yl)-5,6-dihydro-7-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-(3-(R)-Amino-pyrrolidin-1-yl)-5,6-dihydro-7-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-Piperazin-1-yl-5,6-dihydro-7-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-(3-Methylamino-azetidin-1-yl)-7-oxo-6,7-dihydro-5H-7λ4-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-(3-Methylamino-azetidin-1-yl)-7,7-dioxo-6,7-dihydro-5H-7λ6-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-(3-(R)-Methylamino-pyrrolidin-1-yl)-5,6-dihydro-benzo[h]quinazolin-2-ylamine;
4-(3-Methylamino-azetidin-1-yl)-5,6-dihydro-benzo[h]quinazolin-2-ylamine;
4-Piperazin-1-yl-5,6-dihydro-benzo[h]quinazolin-2-ylamine;
10-chloro-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;
10-methyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;
10-methoxy-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;
9-chloro-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;
9-methyl-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;
9-methoxy-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;
8-chloro-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;
8-Methyl-4-((R)-3-methylamino-pyrrolidin-1-yl)-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
8-methoxy-4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6-dihydro[1]benzoxepino[5,4-d]pyrimidin-2-amine;
4-[(3R)-3-(methylamino)pyrrolidin-1-yl]-5,6,7,8-tetrahydrobenzo[7,8]cycloocta[1,2-d]pyrimidin-2-amine;
4-[(3R)-3-aminopyrrolidin-1-yl]-5,6,7,8-tetrahydrobenzo[7,8]cycloocta[1,2-d]pyrimidin-2-amine;
4-[(3S)-3-aminopyrrolidin-1-yl]-5,6,7,8-tetrahydrobenzo[7,8]cycloocta[1,2-d]pyrimidin-2-amine;
4-(3-aminoazetidin-1-yl)-5,6,7,8-tetrahydrobenzo[7,8]cycloocta[1,2-d]pyrimidin-2-amine;
4-[(3aR,6aR)-hexahydropyrrolo[3,4-b]pyrrol-1(2H)-yl]-5,6,7,8-tetrahydrobenzo[7,8]cycloocta[1,2-d]pyrimidin-2-amine;
4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;
4-(2,8-diazaspiro[4.5]dec-8-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;
4-(1,5-diazocan-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;
4-(4-aminopiperidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;
N4-(2-azetidin-2-ylethyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;
N4-[(2R)-azetidin-2-ylmethyl]-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;
N4-(1-methylpiperidin-4-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;
N4-[(1R,5S)-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;
4-(5-methyl-1,4-diazepan-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;
4-(1-Methyl-piperidin-4-yloxy)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-(1-Methyl-piperidin-3-yloxy)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-((R)-1-Methyl-pyrrolidin-3-yloxy)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-((S)-1-Methyl-pyrrolidin-3-yloxy)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-(Piperidin-4-yloxy)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-((S)-Pyrrolidin-3-yloxy)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-(2-Dimethylamino-ethoxy)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-(1,9-Diaza-spiro[5.5]undec-9-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-((R)-3-Dimethylamino-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-(2,6-Diaza-spiro[3.5]non-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-(2,5-Diaza-spiro[3.5]non-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-(Octahydro-pyrrolo[3,4-c]pyridin-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-(Octahydro-pyrrolo[1,2-a]pyrazin-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-(3,6-Diaza-bicyclo[3.2.1]oct-6-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-(2,6-Diaza-bicyclo[3.2.1]oct-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
N-(4-Piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-acetamide;
N-(4-Piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-benzamide;
4-(5-Methyl-octahydro-pyrrolo[3,4-c]pyridin-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-(3-Methyl-3,6-diaza-bicyclo[3.2.1]oct-6-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
2-Dimethylamino-N-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-acetamide;
2-Methylamino-N-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-acetamide;
2-Amino-N-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-acetamide;
1-Methyl-3-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-urea;
4-Amino-N-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-butyramide;
6-(2-pyridin-3-ylmethylamino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine;
3-Amino-N-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-propionamide;
4-[1,4,7]Triazonan-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
N,N-Dimethyl-N′-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-ethane-1,2-diamine;
4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-5,6-dihydro-7-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-((R)-3-Methylamino-pyrrolidin-1-yl)-6,7,9,10,11,12-hexahydro-5H-1,3-diaza-benzo[3,4]cyclohepta[1,2-b]naphthalen-2-ylamine;
4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6,7,9,10,11,12-hexahydro-5H-1,3-diaza-benzo[3,4]cyclohepta[1,2-b]naphthalen-2-ylamine;
4-Piperazin-1-yl-6,7,9,10,11,12-hexahydro-5H-1,3-diaza-benzo[3,4]cyclohepta[1,2-b]naphthalen-2-ylamine;
9-Iodo-4-((R)-3-methylamino-pyrrolidin-1-yl)-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
9-Iodo-4-piperazin-1-yl-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
9-Iodo-4-octahydro-pyrrolo[3,4-b]pyridin-6-yl-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
2,4-Di-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine
2-Amino-4-octahydro-pyrrolo[3,4-b]pyridin-6-yl-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cycloheptene-9-carbonitrile;
4-Octahydro-pyrrolo[3,4-b]pyridin-6-yl-9-phenyl-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-Octahydro-pyrrolo[3,4-b]pyridin-6-yl-9-pyridin-3-yl-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-((R)-3-Methylamino-pyrrolidin-1-yl)-6,7-dihydro-5-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
2-Amino-4-octahydro-pyrrolo[3,4-b]pyridin-6-yl-5,6-dihydro-7-oxa-1,3-diaza-dibenzo[a,c]cycloheptene-9-carboxylic acid methyl ester;
4-Piperazin-1-yl-6,7-dihydro-5-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6,7-dihydro-5-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-((R)-3-Methylamino-pyrrolidin-1-yl)-5,5-dioxo-6,7-dihydro-5H-5λ6-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
4-((R)-3-Methylamino-pyrrolidin-1-yl)-5-oxo-6,7-dihydro-5-thia-1,3-diaza-dibenzo[a,c]cyclohepten-2-ylamine;
N4-(3-Piperidin-1-yl-propyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;
4-(4-Dimethylamino-piperidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine
10-fluoro-4-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-amine;
4-[1,4]Diazepan-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
(1R,5S)-4-(3,6-Diaza-bicyclo[3.2.0]hept-6-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
4-Piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine;
(3aS,6aS)-4-(Hexahydro-pyrrolo[3,4-b]pyrrol-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
(1S,5S)-4-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
N4-Piperidin-3-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;
N4-(Octahydro-isoindol-4-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;
Methyl-(4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-yl)-amine;
4-(3-(R)-Methylamino-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine;
[1-(6,7-Dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)-azetidin-3-yl]-amine;
8,10-Dimethyl-4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;
6-(2-(1H-imidazol-4-yl)ethylamino-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-4-yl)octahydro-1H-pyrrolo[3,4-b]pyridine;
(2-Amino-4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-10-yl)-methyl-carbamic acid methyl ester;
10-N-Methyl-4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,10-diamine;
(2-Amino-4-octahydro-pyrrolo[3,4-b]pyridin-6-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-10-yl)-methyl-carbamic acid methyl ester;
10-N-methyl-4-[(4aR,7aR)-octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,10-diamine;
N-(2-Amino-4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-11-yl)-acetamide;
4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2-carboxylic acid methyl ester;
4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2-carboxylic acid.

### Claim 12 (depends on 1)

The compound of claim 1, wherein the compound is 4-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine, 4-(3-methylamino-azetidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine, 4-(3-(R)-methylamino-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine, or 4-((3R)-3-amino-pyrrolidin-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim 14 (depends on 1)

A method of treating a mammal having a condition where modulation of histamine H4 receptor activity is of therapeutic benefit, said method comprising administering to a subject having or susceptible to said disorder with a therapeutically effective amount of a compound of the formula (I) of claim 1.

### Claim 15 (depends on 14)

The method of claim 14, wherein the condition or disorder is asthma, allergy, allergic dermatitis, rheumatoid arthritis, inflammation, inflammatory bowel disease, colitis, ulcerative colitis, Crohn's disease, psoriasis, psoriatic arthritis, osteoarthritis, eczema, hives, multiple sclerosis, auto-immune encephalomyelitis, auto-immune disease, scleroderma, lupus, dermatitis, atopic dermatitis, rhinitis, allergic rhinitis, chronic obstructive pulmonary disease, septic shock, acute respiratory distress syndrome, cancer, pruritis, itching, pain, inflammatory pain, hyperalgesia, inflammatory hyperalgesia, migraine, cancer pain, osteoarthritic pain, post-surgical pain, non-inflammatory pain, neuropathic pain, sub-categories of neuropathic pain including peripheral neuropathic pain syndromes, chemotherapy-induced neuropathy, complex regional pain syndrome, HIV sensory neuropathy, neuropathy secondary to tumor infiltration, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia, postmastectomy pain, trigeminal neuralgia, central neuropathic pain syndromes, central poststroke pain, multiple sclerosis pain, Parkinson disease pain, or spinal cord injury pain, or a combination thereof.

### Claim 16 (depends on 14)

The method of claim 14, wherein the condition or disorder is asthma.

### Claim 17 (depends on 14)

The method of claim 14, wherein the condition or disorder is inflammation, inflammatory pain, or inflammatory hyperalgesia, or a combination thereof.

### Claim 18 (depends on 14)

The method of claim 14, wherein the condition or disorder is neuropathic pain.

### Claim 19 (depends on 14)

The method of claim 14, wherein the condition or disorder is hyperalgesia, migraine, cancer pain, visceral pain, osteoarthritis pain, or post-surgical pain, or a combination thereof.

### Claim 20 (depends on 1)

A method of treating pain comprising administering a histamine H4 receptor ligand of formula (I) according to claim 1, or a salt, ester, amide, or prodrug thereof, in combination with a histamine H1 antagonist; a histamine H2 antagonist, histamine H3 antagonist; a modulator of TNF-α, an anti-inflammatory corticocosteroids; a 5-lipoxygenase inhibitor; a leukotriene antagonist; a LTB4 antagonist; a non-steroidal anti-inflammatory drug; a COX-2 inhibitor; a β-adrenergic receptor agonist; an anti-nociceptive opiate agonist, an anti-nociceptive alpha adrenergic agonist, a TRPV1 antagonist, a nicotinic acetylcholine receptor agonist, a CB-1 agonist; a CB-2 agonist; a P2X7 antagonist; a metabotropic glutamate receptor antagonist; or an adrenergic agonist, or a combination thereof.