Macrocyclic benzofused pyrimidine derivatives

1. A compound of formula (I):

or a pharmaceutically acceptable, salt, ester, or amide thereof, wherein:

G 1 and G 2 make —CH 2 CH 2 CH 2 —, wherein each carbon of —CH 2 CH 2 CH 2 — may be optionally substituted with one or more groups selected from the group consisting of 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;

R 1 is selected from the group consisting of NH 2 , —NH(acyl), —NH(alkyl), —N(alkyl) 2 , —NH(C═O)aryl, —NH(C═O)CH 3 , —NH-alkylene(NR 8 R 9 ), —NH(C═O)-alkylene(NR 8 R 9 ), —NR 8 (C═O)NR 8 R 9 , —NH-alkylene-heteroaryl, —NHOH, —NHOCH 3 , —O-alkylene(NR 8 R 9 ), piperazine, fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl, hydroxyalkyl, cyano, alkoxycarbonyl, carboxy, —(C═O)—(NR 8 R 9 ), —(C═O)—NH-alkylene(NR 8 R 9 ), and alkoxy;

R 2 , R 3 , R 4 , and R 5 are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocycloalkyl, aryl, heteroaryl, heterocycle, O-aryl, O-heteroaryl, S-aryl, —CONR 8 R 9 , —NR 8 COalkyl, —NR 8 (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, —NR 8 R 9 , -carbonyl(NR 8 R 9 ), —SO 2 (NR 8 R 9 ), and —N(R 8 )SO 2 (R 9 );

R 6 is selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, and alkylfluorocycloalkyl;

R 7 is selected from the group consisting of fluoroalkyl, hydroxyalkyl, alkoxyalkyl, fluorocycloalkyl, and alkylfluorocycloalkyl;

R 8 and R 9 each are each independently selected from the group consisting of hydrogen, alkyl, fluoroalkyl, cycloalkyl, cyanoalkyl, fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocycloalkyl, aryl, heteroaryl, heterocycle, acyl, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, amido, formyl, hydroxy, and hydroxyalkyl;

A 1 is a group of structure A 2 selected from the group consisting of:

n is 1, 2, or 3;

m is 0, 1, or 2;

wherein each carbon atom of groups A 1 may be optionally substituted with one or more groups selected from the group consisting of 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, and alkylthio;

provided that when R 1 is NH 2 , NHalkyl, or alkyl, then A 1 is not a group of structure K.

2. The compound of claim 1 , wherein R 1 is selected from the group consisting of —NHOH, —NHOCH 3 , fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl, hydroxyalkyl, cyano, and alkoxy.

3. The compound of claim 1 , wherein A 1 is a group selected from A 2 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, or Y15.

4. The compound of claim 1 , wherein R 1 is NH 2 , —NHCH 3 , —NH(C═O)CH 3 , —NH(C═O)phenyl, —NH(C═O)NHCH 3 , —NH(C═O)CH 2 NH 2 , —NH(C═O)CH 2 NHCH 3 , —NH(C═O)CH 2 N(CH 3 ) 2 , —NH(C═O)CH 2 CH 2 CH 2 NH 2 , —NHCH 2 (pyridin-3-yl), —NHCH 2 (imidazol-4-yl), —NHCH 2 CH 2 N(CH 3 ) 2 , piperazin-1-yl, —(C═O)OCH 3 , or —(C═O)OH.

5. The compound of claim 1 , wherein R 2 , R 3 , R 4 , and R 5 each are independently hydrogen, fluorine, chlorine, methyl, methoxy, iodine, pyridin-3-yl, phenyl, —(C═O)OCH 3 , cyano, —NCH 3 (C═O)OCH 3 , —NHCH 3 , or —NH(C═O)CH 3 .

6. The compound of claim 1 , wherein A 1 is a group of the formula:

7. The compound of claim 6 , wherein A 1 is

8. The compound of claim 1 , wherein the compound is:

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;

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;

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-(Hexahydro-pyrrolo[3,4-c]pyrrol-2-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine;

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;

N 4 -(2-azetidin-2-ylethyl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;

N 4 -[(2R)-azetidin-2-ylmethyl]-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;

N 4 -(1-methylpiperidin-4-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;

N 4 -[(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-(1,9-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;

2,4-Di-piperazin-1-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine;

N 4 -(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;

(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;

N 4 -Piperidin-3-yl-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;

N 4 -(Octahydro-isoindol-4-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2,4-diamine;

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-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;

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; or

4-(Octahydro-pyrrolo[3,4-b]pyridin-6-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-d]pyrimidine-2-carboxylic acid.

9. The compound of claim 1 , wherein the compound is

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.

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

11. A method of treating pain in a mammal, said method comprising administering to a subject having or susceptible to said pain with a therapeutically effective amount of a compound of claim 1 .

12. The method of claim 11 , wherein the pain is inflammatory pain, cancer pain, osteoarthritic pain, post-surgical pain, non-inflammatory pain, neuropathic pain, 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, spinal cord injury pain, or a combination thereof.

13. The method of claim 11 , wherein the pain is neuropathic pain.

14. The method of claim 11 , wherein the pain is cancer pain, visceral pain, osteoarthritis pain, or post-surgical pain, or a combination thereof.

15. A method of treating pain comprising administering a compound of claim 1 , or a salt, ester, or amide thereof, in combination with a histamine H, antagonist; a histamine H 2 antagonist, a histamine H 3 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.