11 863 925 method for pain treatment

8/2/2019 11 863 925 Method for Pain Treatment

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1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1us 20080194538Al(19) United States(12) Patent Application PublicationCowart et al. (10) Pub. No.: US 2008/0194538 Al(43) Pub. Date: Aug. 14,2008(54) METHOD FOR PAIN TREATMENT 11/863,925(76) Inventors: Marlon D. Cowart, Round Lake

Beach, IL (US); Robert J.Altenbach, Chicago, IL (US);Huaqing Liu, Buffalo Grove, IL(US); Irene Drlzln, Wadsworth, IL(US); Neil Wishart, Jefferson, MA(US); David J. Babinski, Dallas,TX (US); Robert J. Gregg,Libertyville, IL (US); Arthur A.Hancock, Libertyville, IL (US);Timothy A. Esbenshade,Schaumburg, IL (US); Gin C.Hsieh, Long Grove, IL (US); JorgeD. Brlonl, Vernon Hills, IL (US);Marie P. Honore, Evanston, IL(US); Lawrence A. Black,Libertyville, IL (US); Chen Zhao,Libertyville, IL (US); Brian D.Wakefield, Evanston, IL (US);Kathryn J. Hancock, legalrepresentative, Libertyville, IL (US)

Correspondence Address:PAUL D. YASGERABBOTT LABORATORIES100 ABBOTT PARK ROAD, DEPT. 377/AP6AABBOTT PARK, IL 60064-6008 (US)

(21) Appl. No.:(22) Filed: Sep.28,2007

Related U.S. Application Data(60) Provisional applicat ion No. 60/848,954, fi led on Oct.

2,2006.

Publication Classification(51) Int. Cl.

A61K 311397A61K 311506A61P 25100A61P 25102A61P 19102

(2006.01)(2006.01)(2006.01)(2006.01)(2006.01)

(52) U.S. Cl. 514/210.21; 514/252.14; 514/267

(57) ABSTRACT

This invention discloses a method of treating pain by admin-istering histamine H4 receptor ligands and composit ionscomprising the same.


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US 2008/0194538 Al

METHOD FOR PAIN TREATMENT

[0001] This application claims priority to provisional appli-cation Ser. No. 60/848,954 filed on Oct. 2, 2006.

BACKGROUND OF THE INVENTION[0002] 1. Technical Field of the Invention[0003] This invention relates to a method for pain treat-ment. The method more particularly relates to administeringhistamine H4 receptor ligands or compositions comprisingthe same for treating various forms of pain as furtherdescribed herein.[0004] 2. Description of Related Technology[0005] Pain of various types and manifestations affects vir-tually all humans and animals. In the clinic, pain is the one ofthe most serious significant medical issues in health care, andaffects the widest group of patients. A substantial number ofmedical disorders and condit ions produce pain as part of thedisorder or condition. The condition of pain can refer tovarious forms of pain, for example, inflammatory pain, postsurgical pain, and neuropathic pain, among others.[0006] Some methods for treating pain are currentlyknown. Such methods typically involve the administration ofa pharmaceutical agent that works through specific biologicalmechanisms to treat different pain states. However, signifi-cant drawbacks for available analgesic and antinociceptiveagents exist. For example, selective and non-selectivecyclooxygenase inhibitors have been associated with cardio-vascular risks, gastric lesions, and bleeding side effects.Opioids have been associated with addiction, abuse liability,respiratory depression, and constipation. Moreover, evengiven such drawbacks, many current agents are only able toprovide a partial or measured degree of rel ief against someforms of pain.[0007] In particular, patients suffering from neuropathicpain are not well treated by any of the currently availabledrugs or by agents. Neuropathic pain can develop in responseto previous injury or ongoing tissue injury, nerve injury, ordiabetes. It is distinct from other types of pain (e.g. inflam-matory pain) in that it persists long after signs of the originalinjury or damage have disappeared. Neuropathic pain also isassociated with allodynia, hyperalgesia, or causalgia (Dwor-kin Clinical Journal of Pain (2002) vol. 18(6) pp. 343-9).Allodynia is the perception of pain following a stimulus thatwould not normally be painful. Hyperalgesia is an enhancedresponse to a mildly noxious stimulus. Causalgia is describedas a chronic burning pain that shows persistence in theabsence of obvious noxious stimuli.[0008] In addition to neuropathic pain, there are other typesof pain that are not inflammatory or not due to ongoinginflammation, including osteoarthritis pain, cancer pain, vis-ceral pain.[0009] Neuropathic pain is particularly difficult to treat andis not well treated with current therapies. The topic of neuro-pathic pain has been reviewed in the scientific literature, forexample, Smith, et al. Drug Development Research (2001)vol. 54(3), pp. 140-153; Collins andChessell Expert Opinionon Emerging Drugs (2005) vol. 10(1), pp. 95-108; Vinik andMehrabyan Medical Clinics of North America (2004), vol.88(4), pp. 947-999; Dray, Urban, and Dickenson Trends inPharmacological Sciences (1994) vol. 15(6) pp. 190-7;Dworkin Clinical Journal of Pain (2002) vol. 18(6) pp. 343-9.As such, it would be part icularly beneficial to identify new

Aug. 14 , 20081

methods for treating pain and, more particularly, neuropathicpain. Itwould be part icularly beneficial if such methods arebased on previously unexplored mechanisms for pain treat-ment that may offer improved pain relief or are less associatedwith side effects.[0010] Histamine is understood to modulate a number ofphysiological activities, acting through specific histaminereceptors (reviewed in Parsons and Ganellin, British Journalof Pharmacology (2006) 147, SI27-S135; Igaz and Hegyesi,in Histamine: Biology and Medical Aspects (2004), 89-96;Editor(s): A. Falus; Pub. S. Karger A G, Basel). Four hista-mine receptors have been identified to date as playing distinctphysiological roles. These are the histamine HI receptor, thehistamine H2 receptor, the histamine H3 receptor, and thehistamine H4 receptor. The histamine H4receptor is the mostrecently identified histamine receptor and has been charac-terized as a distinct histamine receptor; itis found in a numberof mammalian tissues and has been found to modulate anumber of physiological processes, including immunologicalfunction.[0011] The histamine H4 receptor (also alternately knownherein as the H4 receptor) is a member of the 7 -transmem-brane G-protein coupled receptor (GPCR) family, and islocated on the cell surface membrane, where it binds to theendogenous molecule histamine, and transduces signals thatmodulate specific cellular activities. General aspects of thehistamine H4 receptor, its pharmacology, and known ligandsof the H4 receptor have been reviewed in de Esch, et al.(Trends in Pharmacological Science (2005), v. 26, pp. 462-469). The human histamine H4receptor is distinct from otherhuman histamine receptors, has low protein sequence homol-ogy with other human histamine receptors: 23% primaryamino acid sequence identity with the histamine HI receptor,22% primary amino acid sequence identity with the histamineH2 receptor, and 31% primary amino acid sequence identitywith the histamine H3receptor. The H4receptor was reportedby Nakamura, et al. (Biochemical and Biophysical ResearchCommunications (2000), v. 279, pp. 615-620), and was sub-sequently cloned by numerous research groups (e.g. Naka-mura, ibid.; Coge, et al., Biochemical and BiophysicalResearch Communications (2001) v. 284, pp. 301-309; Liu,et al . Molecular Pharmacology (2001) v. 59, pp. 420-426;Morse, et al. Journal of Pharmacology and ExperimentalTherapeutics (2001), v. 296, pp. 1058-1066; Nguyen, et al.Molecular Pharmacology (2001), v. 59, pp. 427-433; Zhu, etal. Molecular Pharmacology, (2001), v. 59, pp. 434-441). Foran overview of the early efforts on cloning and characteriza-t ion of histamine H4 receptors see Hough, Molecular Phar-macology, (2001), v. 59, pp. 415-419.[0012] A search for H4 receptor cDNA by RTPCR (reversetranscriptase polymerase chain reaction) of cellular and tissuemRNA located H4 cDNA in various cells and tissues (Naka-mura, ibid.). This has been confirmed in addit ional studieslocating H4 cDNA in cells such as leukocytes, eosinophils,mast cells, dendritic cells, and basophils, (Nakamura, ibid.;de Esch, ibid.; Ling, et al . British Journal of Pharmacology(2004) 142, 161-171). Furthermore, H4 cDNAhas beeniden-t ified in several tissues, prominently bone marrow, spleen,lymph nodes, but also in heart, kidney, liver, lung, pancreas,skeletal muscle, leukocyte, prostate, small intestine, testis,and also in different brain regions ((Nakamura, ibid; de Esch,ibid; Coge, ibid).[0013] Study of histamine H4 ligands in animal diseasemodels, as well as in in vitro and ex vivo studies, have dem-


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onstrated that the histamine H4 receptor plays an importantrole in various physiological and pathophysiological pro-cesses. For example, in experiments with histamine H4 defi-cient (knock out) animals and cells and tissues from suchhistamine H4deficient animals, the histamine H4receptor hasbeen demonstrated to play an important role in various physi-ological and pathophysiological processes. However, studyof diseases and disorders where histamine H4 receptors havebeen found to play an important role predominantly havebeen related to, for example, asthma, allergy, rheumatoidarthritis, and inflammation.

SUMMARY OF THE INVENTION[0014] The invention provides a method of pain treatmentcomprising administering a histamine H4 receptor ligand, asalt, ester, or amide thereof, or a composition comprising suchligand, salt, ester, or amide. The histamine H4 receptorligands modulate or regulate the activity of histamine H4receptors. The ligands can demonstrate antagonist, inverseagonist, or partial agonist activity.[0015] Antagonists are ligands that block receptor activa-tion by an agonist . In the case of the histamine H4 receptor, ahistamine H4receptor antagonist blocks activation of the his-tamine H4receptor by a histamine H4 receptor agonist such asthe endogenous agonist ligand histamine. Inverse agonists areligands that block receptor activation. More generally, theyblock intrinsic activation of a receptor that occurs in theabsence of an activation by an agonist, and also block receptoractivation by an agonist. Partial agonists are ligands that bindto receptors but only partially activate the receptor; in sodoing, partial agonists compete with full agonists and blockfull activation of the receptor. In the case of the histamine H4receptor, the endogenous agonist histamine is a full agonist.[0016] Preferably the ligands are histamine H4 receptorantagonists. More preferably the ligands are histamine H4receptor inverse agonists.[0017] Histamine H4receptor ligands of various structuralclasses have been identified and some are reviewed inSchwartz, Expert Opinion in Therapeutic Patents (2003) vol.13, pp. 851-865. Addit ional histamine H4 receptor l igandsalso are provided, and are considered within the scope of theinvention.[0018] The various forms of pain that can be treated caninclude all types of pain. Examples of pain for which themethod can be carried out include, but are not limited to, forexample, inflammatory pain, chemically induced pain, painresulting from surgery, pain resulting from burns, pain result-ing from osteoarthritis, non-inflammatory pain, post surgicalpain, and neuropathic pain.[0019] This invention discloses the novel method of treat-ing pain (including diverse types of pain, including inflam-matory pain, post surgical pain, and neuropathic pain) byadministration of histamine H4receptor ligands. The utility ofhistamine H4 receptor ligands to treat neuropathic pain isnovel. This invention discloses the novel utility of histamineH4receptor ligands to treat pain, including distinctly differenttypes of pain, including inflammatory pain, chemicallyinduced pain, pain resulting from surgery, pain resulting fromburns, pain resulting from osteoarthritis, non-inflammatorypain, and to treat neuropathic pain. The method of the inven-tion can demonstrate particular benefit in its effectiveness intreating osteoarthritis pain, post-surgical pain, and neuro-pathic pain.

Aug. 14 , 20082

[0020] These methods and further methods contemplatedas part of the invention are further described herein.

DETAILED DESCRIPTION OF THE INVENTIONHistamine H4Receptor Ligands and Compositions Thereof[0021] A number of histamine H4 receptor ligands areknown. Such compounds have been demonstrated to modu-late or regulate the activity of histamine H4 receptors. Theligands can demonstrate antagonist, inverse agonist, or partialagonist activity. Antagonists are ligands that block receptoractivation by an agonist. In the case of the histamine H4receptor, a histamine H4receptor antagonist blocks activationof the histamine H4receptor by a histamine H4 receptor ago-nist such as the endogenous agonist ligand histamine. Inverseagonists are ligands that block receptor activation. More gen-erally, they block intrinsic receptor activation that occurs inthe absence of an activation by an agonist, and they also act asantagonists, blocking receptor activation by an agonist. Par-t ial agonists are ligands that bind to receptors but only par-tially activate the receptor; in so doing, partial agonists com-pete with full agonists and block full activation of thereceptor. In the case of the histamine H4receptor, the endog-enous agonist histamine is a full agonist. Preferably theligands are histamine H4 receptor antagonists. More prefer-ably the ligands are histamine H4 receptor inverse agonists.Administering histamine H4receptor ligands, or a salt, ester,or amide thereof, in accordance with the invention are usefulfor treating pain, and particularly inflammatory pain, osteoar-thritis pain, post surgical pain, and neuropathic pain.[0022] Histamine H4receptor ligands of various structuralclasses have been identified and some are reviewed inSchwartz, Expert Opinion in Therapeutic Patents (2003) vol.13, pp. 851-865. To date, examples of histamine H4 receptorligands generally have a formula (I)-(XI).[0023] For example, some histamine H4receptor ligands offormula (I):

(I)

its tautomeric or stereoisomeric form, or a salt thereof:whereinR1represents


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whereinn represents an integer of I, 2 or 3;P represents an integer of 0 or I;R4 represents hydrogen orC

I_6alkyl optionally substituted by

halogen, cyano, hydroxy, carboxy, amino, N-(CI_6alkyl)amino, N,N-di(CI_6alkyl)amino, CI_6alkylthio, CI_6alkoxy,or C3_8cyc!oalkyl;R, and R6 independently represent hydrogen or CI_6alkyloptionally substituted by halogen, cyano, hydroxy, carboxy,amino, N-(CI_6alkyl)amino, N,N-di-(CI_6alkyl)amino,CI_6alkylthio, CI_6alkoxy, or C3_8cyc!oalkyl;R2 represents hydrogen, halogen or CI_6alkyl; andR3 represents aryl or heteroaryl,whereinsaid aryl and heteroaryl are optionally having one or moresubstituents selected from the group consisting of halogen,carboxy, hydroxy, cyano, nitro, C3_8CYc!0 alkyl, phenyl,CI_6alkanoyl, amino, N-(CI_6alkyl)amino, N-(CI_6al-kanoyljamino, N (CI_6alkylsulfonyl)amino, N-(phenylsulfo-nyljamino, N-(CI_6alkoxycarbonyl)amino, N-(aryl)amino,N-(aryl CI_6alkyl)amino, N,N-di(CI_6alkyl)amino,CI_6alkoxy-carbonyl, CI_6alkylthio, aminocarbonyl,N-(CI_6alkyl)aminocarbonyl, N,N-di-(CI_6alkyl)aminocar-bonyl, CI_6alkylsulfonyl, sulfamoyl, aryICI_6alkoxycarbo-nyl, CI_6alkyl optionally substituted by cyano, hydroxy, car-boxy, amino, N-(CI_6alkyl)-amino, N,N-di(CI_6alkyl)amino, CI_6alkylthio, CI_6alkoxy, or mono-, di-, or tri-halogen, and CI_6alkoxy optionally substituted byC3_8cyc!oalkyl, or mono-, di-, or tri-halogen have beendescribed in W02005/054239AI, filed Nov. 24, 2004, andW02005/014556AI, fi led Jul. 23, 2004, to Sato, et al ., eachof which is herein incorporated by reference, as is the genusof histamine H4 receptor antagonists described. Such com-pounds may be prepared by the following general syntheticmethods:

3Aug. 14 , 2008

(1)

[0024] Compounds offormula (6), wherein RI, R2 and R3are defined in formula (1), can be made as described inScheme I. A keto-ester of formula (I) can be reacted withguanidine (2) or a salt of guanidine (2) in a solvent such asethanol using a base such as sodium ethoxide to providecompounds offormula (3). Compounds offormula (3) can bereacted with a reagent such as POCI3, POBr3, or triflic anhy-dride to provide compounds of formula (4) wherein X. is aleaving group such as Cl, Br, or triflate. An intermediate offormula (4) can be reacted with a an amine of formula (5)wherein H is a proton on a nitrogen atom of the amine, toprovide compounds offormula (6).

&herne_2RN : ) : ~

H2NAN XR3-LIR-H

~X Y R(8)N : ) : R ' N : ) : R '

H2NAN X X R-H H2NAN R3(7) R3-LI Y (6)~ N : ) : R '

H2NAN R3(4)


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[0025] Compounds offormula (6), wherein RI, R2 and R3are defined in formula (1), can also be made as described inScheme 2. A pyrimidine of formula (7), wherein X. is aleaving group such as chlorine or bromine, can be reactedwith an amine of formula (5), wherein H is a hydrogenattached to a nitrogen atom of the amine, to provide com-pounds of formula (8). Compounds of formula (7), forexample 2-amino-4,6-dichloropyrimidine (CAS # 56-05-3),can be obtained from commercial sources or prepared by oneskilled in the art. Alternatively, a compound of formula (8)can be reacted with an organometallic reagent offormula (9),wherein LI represents a metal such as tin, zinc, or boron.R3-LI reagents include reagents such as a boronic acids offormula R3B(OH)2 or pinacolboranyl-Rj, and an organostan-nanes such as (R3)SnBu3. The organometall ic reagent (9) isreacted with a compound of formula (8) in the presence of apalladium catalyst such as Pd(Ph3P)4 and a base, such asNa2C03, for example under the conditions such as used forthe Suzuki reaction, the Stille reaction or the Negishi reaction,to provide compounds of formula (6). Alternatively, a com-pound of formula (7) can be reacted with a compound offormula (9), in a mauner as described for the conversion ofcompounds of formula (8) to compounds of formula (6), toprovide a compound of formula (4). Compound of formula(4) can be reacted with a compound (5), in a mauner asdescribed for the conversion of compounds of formula (7) tocompounds offormula (8), to provide a compound of formula(6).[0026] Examples of compounds offormula (1 ) include, butare not limited to, 5-((4aR,7aR)-tetrahydro-lH-pyrrolo[3,4-b]pyridin-6(2H, 7H, 7aH)-yl)biphenyl-3-amine; 3-(naphtha-len-l-yl)-5-(( 4aR,7aR)-tetrahydro-lH-pyrrolo[3,4-b ]pyri-din-6(2H, 7H, 7aH)-yl)aniline; 5-((4aR, 7aR)-tetrahydro-l H-pyrrolo[3,4-b ]pyridin-6(2H, 7H,7aH)-yl)-3'-(trifluoromethyl)biphenyl-3-amine; 3',4'-dichloro-5-(( 4aR,7aR)-tetrahydro-l H-pyrrolo[3,4-b ]pyridin-6(2H, 7H, 7aH)-yl)biphenyl-3-amine; 6-f1uoro-5-((4aR,7aR)-tetrahydro-lH-pyrrolo[3,4-b]pyridin-6(2H,7H,7aH)-yl)biphenyl-3-amine;5-(I-methylhexahydropyrrolo[3,4-b ]pyrrol-5(1 H)-yl)biphe-nyl-3-amine; 1-(5-amino-3'-chlorobiphenyl-3-yl)-N-methy-lazetidin-3-amine; 1-(5-amino-3'-f1uorobiphenyl-3-yl)-N-methylazetidin-3-amine; 1-(5-amino-2-f1uorobiphenyl-3-yl)-N-methylazetidin-3-amine; and 1-(5-aminobiphenyl-3-yl)-N-ethylazetidin-3-amine.[0027] Other compounds that have been characterized ashistamine H4 receptor ligands are compounds of structure(lIa) and (lIb):

Aug. 14 , 20084

-continued(lIb)

(lIa)

wherein[0028] Z is oxygen or sulfur;[0029] R7 is hydrogen or chosen from alkyl or cycloalkyl;[0030] the piperidine moiety is optionally substituted fromone or more groups selected from alkyl, cycloalkyl, CF3, orCH20H;[0031] A3 is a heterocyclic group selected from indol-2-yl,benzoimidazol-2-yl, benzofuran-2-yl, benzothiophen-2-yl,4H-thieno[3,2-b ]pyrrole-5-yl, 4H-furo[3,2-b ]pyrrole-5-yl,6H-thieno[2,3-b ]pyrrole-5-yl, 6H-furo[2,3-b ]pyrrole-5-yl,benzol d]oxazol-2-yl, or benzol d]thiazol-2-yl;[0032] A4 is a heterocyclic group selected from 3-oxo-3,4-dihydroquinoxalin-2-yl, and 3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-2-yl, 3-thioxo-3,4-dihydroquinoxalin-2-yl,3-thioxo- 3,4-dihydropyrido [3,2-b]pyrazin -2-yI, 3-imino- 3,4-dihydroquinoxalin-2-yl, or 3-imino-3,4-dihydropyrido[3,2-b ]pyrazin-2-yl;[0033] wherein the carbon atoms of A3 and A4 are option-ally substituted with one or more groups selected from alkyl,fluoroalkyl, cyanoalkyl, cycloalkyl , fluorocycloalkyl,cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocycloalkyl,aryl, heteroaryl, heterocycle, O-aryl, O-heteroaryl, S-aryl,CONR8R9, NR8COalkyl, acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,alkoxysulfonyl, alkylcarbonyl, alkyl sulfonyl , alkynyl,amido, carboxy, cyano, fluoroalkoxy, formyl, haloalkoxy,haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro,alkylthio, -NR8R9' -carbonyl(NR8R9)' -S02 (NR8R9),and N(R8)S02(R9);[0034] wherein R8 and R9are each independently selectedfrom hydrogen, alkyl, fluoroalkyl, cycloalkyl, cyanoalkyl,fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, alky-Ifluorocycloalkyl, aryl, heteroaryl, heterocycle, acyl, alkoxy-alkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, amido,formyl, hydroxy, and hydroxyalkyl;[0035] The following references describe histamine H4receptor ligands that are a subset offormula (Ila), and providegeneral synthetic methods, as well as specific examples ofhistamine H4 receptor ligands in the following U.S. or Inter-national Patent Publications: US2004/0048878Al, filed Sep.5,2003, to Cai, et a!.; U.S. Pat. No. 6,803,362B2, filed Mar. 8,2002, to Carruthers, et a!. ;US2003/0207893Al, filed Mar. 8,2002, to Carruthers et a!.; W02004/022061Al, fi led Sep. 5,2003, to Dunford eta!. ; and W02002/072548A2, filed Mar. 8,2002 to Carruthers, et al., each of which is herein incorpo-rated by reference.[0036] The following reference describes histamine H4receptor ligands that are a subset of formula (Ilb), and providegeneral synthetic methods, as well as specific examples ofhistamine H4 receptor ligands in the following U.S. or Inter-national Patent Publications: US2005/0070527 AI, filed Sep.29,2004, to Edwards and Venable; each publication of whichis herein incorporated by reference.


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[0037] Compounds offonnula (lIa) and (lIb) may be pre-pared by the following general synthetic methods:

oA~OH

(10)

(11)

Lawesson'sreagent

(12) (13)

[0038] Compounds of formula (12) and (13), wherein R7and A, are defined in formula (Ila), can be made as describedin Scheme 3. An acid offonnula (10) can be coupled with apiperazine of structure (II) using conventional methods ofamide bond formation. For example, the carboxyl group ofcompound (10) may be activated as an active ester, acidchloride, anhydride, mixed anhydride, carbonic mixed anhy-dride or the like and treated with an amine offonnula (II) toprovide compounds of formula (12). For example, the com-pound offonnula (10) may be converted to the correspondingactive ester upon treatment with l-hydroxybenzotraizole inthe presence of a carbodiimide for example dicyclohexylcar-bodiimide, optionally inthe presence ofa base such as triethylamine. Acids of formula (10) can be obtained from commer-cial sources or prepared by one skilled in the art. Compoundsoffonnula (12) can be treated with Lawesson's reagent in asolvent such as THF to provide compounds offonnula (13).[0039] Compounds of formula (lIb) can be generated byreaction of 2,3-dihalo substituted pyrido[3,2-b ]pyrazines or2,3-dihalo substi tuted quinoxalines with a suitably substi-tuted piperazine, followed by treatment with ammonia,hydrogen sulfide or water to provide compounds of formulalIb. 2,3-Dihalo substituted pyrido[3,2-b ]pyrazines and 2,3-dihalo substituted quinoxalines can be generated by the halo-genation of pyrido[3,2-b ]pyrazine-2,3(IH,4H)-diones andquinoxaline-2,3(IH,4H)-diones, respectively, using reagentssuch as thionyl chloride, thionyl bromide or phosphohorusoxychloride. Pyrido[3,2-b ]pyrazine-2,3(1 H,4H)-diones andquinoxaline-2,3(IH,4H)-diones can be generated by the reac-tion of pyridine-2,3-diamines and benzene-I,2-diamines,respectively, with oxylate derivatives such as dimethyl oxy-late, diethyl oxylate or oxalyl chloride.[0040] Examples of compounds of formula (lIa) include,but are not limited to, (5-chloro-IH-indol-2-yl)(3,4-dimeth-ylpiperazin-I-yl)methanone; (5-bromobenzofuran-2-yl)( 4-methylpiperazin-I-yl)methanone; (IH-indol-2-yl)( 4-meth-ylpiperazin-I-yl)methanethione; (7-methyl-IH-indol-2-yl)(4-methylpiperazin-I-yl)methanone; (2,3-dimethyl-4H-thieno[3,2-b ]pyrrol-5-yl)( 4-methylpiperazin-I-yl)

Aug. 14, 20085

methanone; (2-chloro-3-methyl-4H -thieno[3,2-b ]pyrrol-5-yl)(4-methylpiperazin-I-yl)methanone; and (2,3-dichloro-4H -thieno[3,2-b ]pyrrol-5-yl)( 4-methylpiperazin-I-yl)methanone.[0041] Examples of compounds of formula (lIb) include,but are not limited to, 8-methyl-3-(4-methylpiperazin-I-yl)quinoxalin-2(IH)-one; 8-methyl-3-(piperazin-I-yl)quinoxa-lin-2(1 H)-one; 3-(4-methylpiperazin-I-yl)-6-(trifluorom-ethyl)quinoxalin-2(IH)-one; 7 -chloro-6- f1uoro-3-(4 -methylpiperazin-I-yl)quinoxalin-2(IH)-one; and 6-chloro-7-f1uoro-3-( 4-methylpiperazin-I-yl)quinoxalin-2(IH)-one.[0042] Compounds offormula (III) are histamine H4recep-tor l igands and are described in US2006/0111416AI, fi ledNov. 21, 2005, to Lane and Price, the publication which isherein incorporated by reference. Compounds of formula(III):

(III)

whereinRll is H or (Cl-C4) alkyl optionally substituted with ahydroxy;X is N or C-R19 wherein R19 is H or methyl;Yis OorNH;[0043] R16 i s H or methyl; andRw R13, R14 and R15 are each independently selected fromH, halo, cyano, (C. -C4) alkyl, (Cl-C4)alkoxy, trifluorom-ethyl, trifluoromethoxy, hydroxy, (CH2)r---C(O)O-R17'(CH,)r-O-(CH2)p-RlS and (CH2)r-RlS' wherein p andrare both independently 0 or I, R17 is H or (C. -C4)alkyl andRI8is phenyl.[0044] Compounds of formula (III) may be prepared by thefollowing general synthetic methods:

(20)


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-continued

Lawesson'sreagentTHF

(22)

(23)

(24)

[0045] Compounds offormula (22) and (24), wherein Rll,R12, R13, R14, R15, R16and X are defined in formula (III) canbe made as described in Scheme 4. Acids of formula (20) canbe coupled with amines of formula (21) using conventionalmethods of amide bond formation. For example, the carboxylgroup of compound (20) may be activated as an active ester,acid chloride, anhydride, mixed anhydride, carbonic mixedanhydride or the like and treated with an amine of formula(21) to provide compounds offormula (22). For example, thecompound of formula (20) may be converted to the corre-sponding active ester upon treatment with l-hydroxyben-zotraizole in the presence of a carbodiimide for exampledicyclohexylcarbodiimide in the presence of a base such astriethyl amine. Acids of formula (20) can be obtained fromcommercial sources or prepared by one skilled in the art.Compounds of formula (22) can be treated with Lawesson'sreagent in a solvent such as THF to provide compounds offormula (23). Compounds offormula (23) can be treated withan excess of ammonia or an ammonium equivalent in thepresence of an activating reagent such as methyl iodide ormercuric acetate in a suitable solvent such as THF to providecompounds offormula (24).

Aug. 14, 20086

(25)

(21)

(27)

(28)

[0046] Compounds offormula (28), wherein Rw R12, R13,R14, R15 and R16 and Yare defined in formula (III) can bemade as described in Scheme S.A diamine of structure (2S)can be condensed with acetimidate (26) in a solvent such asacetic acid to provide benzimidazoles of formula (27). Ben-zimidazoles of formula (27) can be treated with amines offormula (21) and a source of ammonia to provide compoundsofformula (28).[0047] Examples of compounds of formula (III) include,but are not limited to, (S-f1uoro-IH-benzo[d]imidazol-2-yl)(S-methylhexahydropyrrolo[3,4-c]pyrrol-2(IH)-yl)metha-nimine; (S,6-difluoro-IH-benzo[d]imidazol-2-yl)(S-methyl-hexahydropyrrolo [3,4-c]pyrrol- 2(1H)-y l)methanimine;(6-f1uoro-7-methyl-I H-benzo] d]imidazol-2-yl)( S-methyl-hexahydropyrrolo [3,4-c]pyrrol- 2(1H)-y l)methanimine;(7-methyl-I H-benzo] d]imidazol-2-yl)( S-methylhexahydro-pyrrolo[3,4-c]pyrrol-2(IH)-yl)methanimine; (7-f1uoro-IH-indol-2-yl)(S-methylhexahydropyrrolo[3,4-c]pyrrol-2(IH)-yl)methanone; and (S-chloro-IH-indol-2-yl)(S-methylhexahydropyrrolo [3,4-c ]pyrrol- 2(1H)- Y l)methanone.[0048] Compounds of structure (IV) are histamine H4receptor ligands and are described in W02006/0S096SAI,filed Nov. II, 200S, to Harris, et al., which publication isherein incorporated by reference.


8/49

US 2008/0194538 Al

whereinA' represents a fully saturated or partially unsaturated ring of5 to 7 atoms, at least one of which is a nitrogen atom;B' represents aryl or heteroaryl ring of 5 to 6 atoms, whereinB' is optionally substituted with one up to three groups offormula R25, where R25 represents independently: H, F,o,Br, I, Cl_4alkyl, C3_6-cyc!oalkyl, heterocycloalkyl, Cl_4-alkoxy, C3_6cyc!oalkoxy, OH, OCF3, CF3, cyano, orNR26R27; R26 and R27being independently H or Cl_4-alkyl;X' represents 0, NH, S, or CH2;R21represents H, or Cl_4-alkyl;R22represents H, optionally substituted Cl_4alkyl, optionallysubstituted C3_6-cyc!oalkyl, or optionally substituted aryl orheteroaryl;R23 and R24 represent independently H, or Cl_2-alkyl; or R23and R24taken together may represent a Cl_4-alkylene group;and corresponding N-oxides, pharmaceutically acceptablesalts, solvates, metabolites and prodrugs of such compounds.[0049] Compounds offormula (IV) can be prepared by thefollowing synthetic methods:

(30)

or

(31)

(IV)

Aug. 14 , 20087

-continued

(35)

(34)

(36)

(37)

[0050] Compounds offormula (34), (36) and (37), whereinR21, R22, R23, R24,A ', B' and X' are defined in formula (IV)can be made as described in Scheme 6. Compounds of for-


9/49

US 2008/0194538 Al

mula (31) can be prepared from compounds offormula (30),wherein R28=C(=O)NH2, CN or C( O)Oalkyl, by reac-tion with a suitable condensing agent. Wherein R22=H, suit-able condensing agents include formic acid, formamide andtrialkyl orthoformates. Wherein R22=alkyl or cycloalkyl,suitable condensing agents include symmetrical alkyl anhy-drides, alkyl amides, alkyl esters and alkyl nitriles. WhereinR22=aryl or heteroaryl, suitable condensing agents includearyl acid chlorides, heteroaryl acid chlorides, aryl aldehydesand heteroaryl aryl aldehydes. An additional reagent such asHCl gas or POCl3 may be required in the conversion of com-pounds of formula (30) to compounds of (31). Compounds offormula (30) can be obtained from commercial sources orprepared by one skilled in the art. Compounds of formula(32), wherein R29=Cl or Br, can be prepared by the reaction ofcompounds of formula (31) with a suitable halogenatingreagent, such as POCl3 or POBry Compounds of formula(34) can be prepared by the reaction of cyclic diamines offormula (33) with compounds of formula (32) in an inertsolvent, usually with heating, optionally in the presence of abase such as triethyl amine, and optionally using a palladiumcatalyst such as a mixture of palladium bis(trifluoroacetate)and tri(tert-butyl)phosphine. Compounds offormula (36) canbe prepared by the reaction of compounds of formula (32)with a substituted alkene of formula (35), wherein R30 is asuitable metal-containing group such as a boronate ester or atrialkyl or a triarylstannane, in the presence of a suitablepalladium catalyst such as tris( dibenzylideneacetone )dipal-ladium. Compounds of formula (37) can be prepared byreduction of compounds of formula (36) using condit ionssuch as catalytic hydrogenation.[0051] Examples of compounds of formula (IV) include,but are not limited to, 8-chloro-2-methyl-4-( 4-methylpiper-azin-I-yl)benzofuro[3,2-d]pyrimidine; 8-chloro-4-(8-me-thy 1 -3,8-diazabicyclo[3.2 .I]octan -3-Y l)benzofuro [3,2-d]py-rimidine; 8-chloro-4-( 1-methylpyrrolidin -3-yl)benzofuro [3,2-d]pyrimidine; 8-chloro-4-(I-methylpiperidin-4-yl)benzofuro[3 ,2-d]pyrimidine. Other structural classes ofcompounds with reported histamine H4receptor activity canbe found among non-imidazole compounds (see Arienti, et a!.(US2005/0070550AI); Buzard, et a!. (W020051092066A2)), and among imidazole-containing compoundsfound in Anthes, et a!. W02004/066960AI; and Burns, et a!.(W02005/014579AI). Such publications related to non-imi-dazole and imidazole-containing compounds are hereinincorporated by reference.[0052] Also suitable for the invention are compounds offormula (V):

wherein:[0053] R3I is selected from H, -NH(alkyl), -NHOH,-NHOCH3, alkyl, f luoroalkyl, cyanoalkyl, cycloalkyl, f luo-rocycloalkyl, hydroxyalkyl, cyano, and alkoxy;

Aug. 14, 20088

[0054] R32, R33, R34, R35, R36, R40 are each independentlyselected from the group consisting of hydrogen, alkyl, fluo-roalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl,cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocycloalkyl,aryl, heteroaryl, heterocycle, O-aryl, O-heteroaryl, S-aryl,CONR38R39, NR38COalkyl, acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,alkoxysulfonyl, alkylcarbonyl, alkyl sulfonyl , alkynyl,amido, carboxy, cyano, fluoroalkoxy, formyl, haloalkoxy,haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro,alkylthio, -NR38R39' -carbonyl(NR38R39), -S02(NR38R39), and N(R38)S02(R39);[0055] R37 is selected from the group consist ing of hydro-gen, alkyl, f luoroalkyl, cyanoalkyl, hydroxyalkyl, alkoxy-alkyl, cycloalkyl, fluorocycloalkyl, cycloalkoxyalkyl, alkyl-cycloalkyl, and alkylfluorocycloalkyl;[0056] R38, and R39 are each independently selected fromhydrogen, alkyl, fluoroalkyl, cycloalkyl, cyanoalkyl, fluoro-cycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocy-cloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hetero-cycle, acyl, alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl,alkylsulfonyl, amido, formyl, hydroxy, and hydroxyalkyl;[0057] Al is a group of structure

(V)

nis 1,2, or3;m is 0, I, or 2;wherein each carbon atom of groups A, may be optionallysubstituted with one or more groups selected from alkyl,fluoroalkyl, cyanoalkyl, cycloalkyl , fluorocycloalkyl,cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocycloalkyl,fluorine, acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy,alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkyl sulfonyl ,alkynyl, amido , carboxy, cyano, fluoroalkoxy, formyl,haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mer-capto, nitro, and alkylthio;


10/49

US 2008/0194538 Al

[0058] A2 is a phenyl ring of structure

or a hydrogen, iodine, heteraromatic group, heterocycle,-NR38R39' alkyl group, a group of structure Aj, an aromaticring, a naphthyl ene,wherein the carbon atoms of the group A2 may be optionallysubstituted with one or more groups selected from alkyl,fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl,cycloalkoxyalky I, alkylcycloalky I, alkylfluorocycloalky I,aryl, heteroaryl, heterocycle, O-aryl, O-heteroaryl, S-aryl,CONR38R39, NR38COalkyl, acyl, acyloxy, alkenyl, alkoxy,alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxyimino,alkoxysulfonyl, alkylcarbonyl, alkyl sulfonyl , alkynyl,amido, carboxy, cyano, fluoroalkoxy, formyl, haloalkoxy,haloalkyl, halogen, hydroxy, hydroxyalkyl, mercapto, nitro,alkylthio, -NR38R39' -carbonyl(NR38R39), -S02(NR38R39), and N(R38)S02(R39);or a pharmaceutically acceptable, sal t, ester, amide, or pro-drug thereof.[0059] Compounds offormula (V) can be prepared by thefollowing synthetic methods:

o 0A2AAo/R

(42)

base~o-(LG)JA ' \ R

46)R3J

o 0 H N A N H 2J L J L R (47)Ai I' .....--~--~

~o(44)

R3JN A NA , A f O H~o(48)

R3JN A NA,~rC"

~o(49)

H-AJ(50)

Aug. 14, 20089

-continuedR3J

N A NA , Y A .~o(41)

[0060] Compounds of formula (41), wherein R31' R40' Aland A2 have been defined in formula (V) can be prepared asdescribed in Scheme 7. Alternatively, keto-esters of formula(42) can be reacted with a compoundofformula (45), wherein(LG)I is a leaving group such fluorine, chlorine, bromine,iodine, mesylate or triflate, to provide compounds of formula(44). Alternatively, ketones of formula (46) can be reactedwith a carbonate such as dimethyl carbonate, or a chlorofor-mate such as ethyl chloroformate, in the presence of a basesuch as sodium hydride to provide keto-esters of formula(44), wherein R=Iower alkyl. Keto-esters offormula (44) canbe treated with an ami date or guanidate of formula (47), suchas guanidine nitrate, in the presence of a base such as potas-sium carbonate and heated in a solvent such as DMF toprovide 4-hydroxy-pyrimidines offormula (48). 4-Hydroxy-pyrimidines of formula (48) can exist as shown in the struc-ture in Scheme 7 or in a tautomeric form. Pyrimidines offormula (48) can be treated with a chlorinating reagent suchas POCI3, usually with heating, to provide pyrimidines offormula (49) wherein (LG)2=CI. A base such as Et3N orN,N-dimethylaniline in a solvent such as toluene, dioxane orchloroform may be required. Pyrimidines of formula (49) canalso be treated with a sulfonating reagent such as para-tolu-ensulfonyl chloride in the presence of a base such as triethy-lamine and a solvent such as pyridine or chloroform to pro-vide 2-amino-pyrimidines of formula (49) wherein (LG)2=O-S02-R', wherein R' is lower alkyl, lower f1uoroalkylor aryl. Pyrimidines of formula (49), wherein (LG)2=CI orO-S02-R', can be treated with amines of formula (50),wherein H is a hydrogen on a nitrogen atom, and heated,optionally in the presence of a base such as triethylamine ordiisopropyethylamine, and optionally in the presence of asolvent such as ethanol, 2-methoxyethanol, toluene or aceto-nitrile, to provide compounds of formula (41). Compounds offormula (41) may contain a protecting group such as Boc thatcan be removed to provide compounds of formula (41).[0061] Diamines of formula (50) may contain up to twodifferent N-H groups. Diamines offormula (50) that containtwo different N-H groups may selectively react with com-pounds offormula (49) to provide one isomer offormula (41),wherein only one of the two different N-H groups partici-pated in the reaction. Alternatively, diamines offormula (50)that contain two different N-H groups may non-selectivelyreact with compounds offormula (49) to provide two isomersof formula (41), wherein either of the two N-H groupsparticipated in the reaction, Mixtures of isomers of com-pounds of formula (41) can be separated by methods knownto those skil led in the art, such as chromatography and crys-tallization.[0062] Compounds offormula (41) may contain anN-R37group on the cyclic amine of formula A, as defined in formula(V). Compounds offormula (41), wherein one or more of the


11/49

US 2008/0194538 Al

R3 7 groups of A, is hydrogen, can be reacted with an appro-priate reagent such as R37 -(LG)3' wherein (LG)3 is a leavinggroup such as chlorine, bromine, iodine, mesylate, tosylate ortriflate, to provide compounds of formula (1 ) wherein R37 isnot hydrogen.

NaHcs;-MelTHF

(46)

R3JN A NA'~'/

~o(53)

H-AJ(50)

o 0R Jl Jl /R0 I'....

(LG)4(57)

~H(63)

o 0R Jl Jl /R

0/ I' "0~o(56)

Aug. 14, 200810

-continued

R3JN A NA'~A'

~o(41)

[0063] Compounds of formula (41), wherein R 3U R 40' Aland A2 have been defined in formula (V) can be prepared asdescribed in Scheme 8. Ketones of formula (46) can bereacted with carbon disulfide and iodomethane in the pres-ence of abase such as NaH in a solvent such as THF toprovidecompounds offormula (S2). Compounds offormula (S2) canbe treated with an amidate or guanidate of formula (47) toprovide sulfides offormula (S3) . Sulfides offormula (S3) canbe treated with an oxidizing agent such as MCPBA orOxone to provide sulfones of formula (S4) . Sulfones offormula (S4) can be treated with amines offormula ( SO ) andheated, optionally in the presence of a base such as triethylamine or diisopropyethylamine, and optionally in the pres-ence of a solvent such as ethanol, 2-methoxyethanol, aceto-nitrile or toluene, to provide compounds of formula (41).

R3JN A NH O O H~o(58)

R3JN A NJ L _ A(LG){- T


12/49

US 2008/0194538 Al

R31N A N"C)'~"G"

~o(59)

-continuedR31

N A NJLA(LG){' T ~1

~o(60)

A~(62)

R31N A NJLAAi T


13/49

US 2008/0194538 Al

rimidine-2,4-diamine; 4-tert-Butyl-6-( 4-methyl-piperidin-l-yI)-pyrimidin- 2-ylamine; 4-tert -Buty 1-6-(4-ethy 1-piperazin-l-yl)-pyrimidin-2-ylamine; 4-Methyl-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-Methoxy-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 6-(4-Methyl-piperazin-l-yl)-pyrimidine-2,4-diamine; 4,6-Bis-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-tert-Butyl-6-(2-dimethy lamino-ethoxy)- pyrimidin -2-ylamine;4-Adamantan-l-yl-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-(4-Methyl-piperazin-l-yl)-6-phenyl-pyrimi-din-2-ylamine; 4-( 4-Methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-(4-Methyl-piperazin-l-yl)-6-p-tolyl-pyrimidin-2-ylamine; 4-(4-Methyl-piperazin-l-yl)-6-m-tolyl-pyrimidin-2-ylamine; 4-(4-Methyl-piperazin-l-yl)-6-o-tolyl-pyrimidin-2-ylamine; 4-(4-Methoxy-phenyl)-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-(3-Methoxy -pheny 1)-6-(4-methy 1-piperazin -1-yl)-pyrimidin -2-ylamine; 4-(2- Methoxy-phenyl)-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-( 4-Chloro-phenyl)-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-(3-Chloro-phenyl)-6-(4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine;4-Biphenyl-4-yl-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-(4- Methyl-piperazin-l-yl)-6-naphthalen-2-yl-pyrimidin-2-ylamine; 4-(4-Methyl-piperazin-l-yl)-6-naph-thalen-l-yl-pyrimidin-2-ylamine; 4-( 4-Methyl-piperazin-l-yl)-6-pyridin-4-yl-pyrimidin-2-ylamine; 4-Biphenyl-3-yl-6-(4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine;4-Biphenyl-2-yl-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-tert-Butyl-6-(I-methyl-l,2,3,6-tetrahydro-pyri-din -4-yl)- pyrimidin -2-ylamine; 4-tert -Buty 1-6-(1-methy I-pi-peridin-4-yl)-pyrimidin-2-ylamine; 4-tert-Butyl-6-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrimidin-2-ylamine; 2'-Methoxy-6-(4-methyl-piperazin-l-yl)-[ 4,5']bipyrimidinyl-2-ylamine;5-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-I-methyl-1H-pyridin-2-one; 4-(6-Methoxy-pyridin-3-yl)-6-(4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 6-(4-Me-thyl-piperazin-l-yl)-[ 4,5']bipyrimidinyl-2-ylamine; 4-(6-Fluoro-pyridin-3-yl)-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-(4-Methyl-piperazin-l-yl)-6-(I-methyl-l H-pyrazol-4-yl)-pyrimidin-2-ylamine; 4-(2,6-Difluoro-pyridin-3-yl)-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 5-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-nicotinonitrile; 4-(2,6-Dimethoxy-phenyl)-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine;4-(4- Methoxy-pyridin-3-yl)-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-(4- Methyl-piperazin-l-yl)-6-pyrro-lidin-l-yl-pyrimidin-2-ylamine; 4-Iodo-6-( 4-methyl-piper-azin-l-yl)-pyrimidin-2-ylamine; 4-( 4-Methyl-piperazin-l-yl)-6-( 4-phenyl-imidazol-l-yl)-pyrimidin-2-ylamine; 1-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-imidazolidin-2-one; 4-(1- Methyl-l ,2,3,6-tetrahydro-pyridin-4-yl)-6-pyrrolidin-l-yl-pyrimidin-2-ylamine; 4-(1-Methy I-piperidin -4-y 1)-6-pyrrolidin -1-y 1-pyrimidin -2-ylamine; 4-(2,7 -Diaza-spiro[3.5]non-7 -yl)-pyrimidin-2-ylamine; 5-Methyl-4-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-[2-Amino-5-methyl-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-benzonitrile; 5-Methoxy-4-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-( 4-Methyl-piperazin-l-yl)-5-phenyl-pyrimidin-2-ylamine; 4-[2-Amino-5-methoxy-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-benzonitrile; 4-[2-Amino-6-( 4-methyl-piperazin-l-yl)-5-phenyl-pyrimidin-4-yl]-benzonitrile; 4-(4-Methyl-piperazin-l- y1)-6-(2-methy Isulfany 1-pheny 1)-pyrimidin -2-ylamine; 4-(4- Methyl-piperazin-l-yl)-6-( 4-methylsulfanyl-

Aug. 14, 200812

phenyl)-pyrimidin-2-ylamine; 3-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-1,5,5-trimethyl-imidazolidine-2,4-dione; 1-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-3-methyl-imidazolid in-2-one; 1-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-3-methyl-l,3-dihydro-benzoimidazol-2-one; 1-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-1 ,3-dihydro-benzoimidazol-2-one; 6-(4-Methyl-piperazin-l-yl)-N4-phenyl-pyrimidine-2,4-diamine; N4-Methyl-6-( 4-methyl-piperazin-l-yl)-N4-phenyl-pyrimidine-2,4-diamine;4-( 4-Methyl-piperazin-l-yl)-6-morpholin-4-yl-pyrimidin-2-ylamine; 4-(4-Methyl-piperazin-l-yl)-6-piperidin-l-yl-pyri-midin-2-ylamine; 4-(3- Dimethylamino-pyrrolidin-l-yl)-6-(4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-(4-Methyl-piperazin-l-yl)-6-piperazin-l-yl-pyrimidin-2-ylamine; {(S)-I-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-pyrrolidin-2-yl }-methanol; 1-[2-Amino-6-(4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-pyrrolidin-3-ol;4-( 4-Methyl-piperazin-l-yl)-6-(2-methyl-pyrrolidin-l-yl)-pyrimidin-2-ylamine; N4-Methyl-6-( 4-methyl-piperazin-l-yl)-pyrimidine-2,4-diamine; N4,N4- Diethyl-6-( 4-methyl-piperazin-l-yl)-pyrimidine-2,4-diamine; N4, N4-Dimethyl-6-(4-methyl-piperazin-l-yl)-pyrimidine-2,4-diamine;N4-Benzyl- N4-methyl-6-( 4-methyl-piperazin-l-yl)-pyrimi-dine-2,4-diamine; 4-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-imidazole-l-sulfonic acid dimethylamide;3-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-benzonitrile; 2-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyri-midin-4-yl]-benzonitrile; 4-(4-Methyl-piperazin-l-yl)-6-(1H-pyrazol-4-y I)-pyrimidin- 2-y lamine; 4-(1H -Imidazol-4-yl)-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-(1-Methyl-l H-imidazol-4-yl)-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-[2-Amino-6-((3aR,6aS)-5-methyl-hexahydro- pyrrolo[3 ,4-c ]pyrrol- 2-y1)-pyrimidin -4-yl]-benzonitrile; 4-piperazin-l-yl-6-pyridin-3-yl-pyrimidin-2-ylamine; 4-(2-Amino-6-piperazin-l-yl-pyrimidin-4-yl)-benzonitrile; 2-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-phenol; 4-[2-Amino-6-( 4-cyclopropylmethyl-piperazin-l-yl)-pyrimidin-4-yl]-benzonitrile; [(S)-I-(2-Amino-6-piperazin-l-yl-pyrimidin-4-yl)-pyrrolidin-2-yl]-methanol; 4-(6-Methoxy-pyridin-3-yl)-6-piperazin-l-yl-pyrimidin-2-ylamine; 4-(3- Iodo-phenyl)-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine;4-(4- Iodo- pheny 1)-6-(4-methy I-piperazin-l- y1)-pyrimidin-2-ylamine; 4-tert-Butyl-2-methoxy-6-(4-methyl-piperazin-l-y I)-pyrimidine; 4-tert -Buty 1-6-piperidin-4- yI-pyrimidin -2-ylamine; 4-(2,6-Dimethyl-pyridin-3-yl)-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-(3,5-Dimethyl-1H-pyrazol-4-yl)-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-(4-Methyl-piperazin-l-yl)-6-(1,3,5-trimethyl-IH-pyrazol-4-yl)-pyrimidin-2-ylamine; 4-(2-Methoxy-pyridin-3-yl)-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-Imidazol-l-yl-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; N4-Azetidin-3-yl-pyrimidine-2,4-diamine; 1-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-IH-pyridin-2-one; 4-(4-Chloro-imidazol-l-yl)-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; {1-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-1 H-imidazol-4-yl }-methanol; 4-Chloro-6-( 4-methyl-piperazin-l-yl)-pyrimidine-2,5-diamine; 4-Chloro-5-methyl-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine; 4-(4-Methyl-piperazin-l-yl)-pyrimidine-2,5-diamine; 4-Benzoimidazol-l-yl-6-( 4-methyl-piperazin-l-yl)-pyrimidin-2-ylamine;2-[2-Amino-6-( 4-methyl-piperazin-l-yl)-pyrimidin-4-yl]-


14/49

US 2008/0194538 Al

2H-pyridazin-3-one; N4-Benzyl-6-( 4-methyl-piperazin-l-yl)-pyrimidine-2,4-diamine; and 4-piperazin-l-yl-pyrimi-din-2-ylamine.[0068] Compounds offormula (VI) are histamine H4recep-tor ligands. Compounds offormula (VI)

" ' 5

~5

or a pharmaceutically acceptable, sal t, ester, amide, or pro-drug thereof, wherein:[0069] G1 is selected from oxygen, sulfur, S(O), S(O)2'NR48 and alkylene;[0070] G2 is selected from oxygen, sulfur, S(O), S(O)2'NR48, and alkylene wherein each carbon of the alkylene andmethylene groups ofG 1and G2may be optionally substitutedwith one or more groups selected from alkyl, fluoroalkyl,cyanoalky I, cycloalky I, fluorocycloalky I, cycloalkoxyalky I,alkylcycloalkyl, alkylfluorocycloalkyl, f luorine, acyl, acy-loxy, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycar-bonyl, alkylcarbonyl, alkyl sulfonyl, alkynyl, amido, carboxy,cyano, fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen,hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio, and oxo;[0071] provided that when G1 is oxygen, sulfur, S(O),S(O), or NR48, G2 is alkylene;[0072] provided that when G2 is oxygen, sulfur, S(O), S(O)2' or NR48, G1 is alkylene;[0073] Rl is selected from H, NH2, -NH(acyl), -NH(alkyl), -N(alkyl)2' -NH(C=O)aryl, -NH-alkylene(NR48R49), -NH(C=O)-alkylene(NR48R49), -NR48(C=O)NR48R49, -NH-alkylene-heteroaryl, -NHOH,-NHOCH3, -O-alkylene(NR48R49), alkyl, piperazine,fluoroalkyl, cyanoalkyl, cycloalkyl, fluorocycloalkyl,hydroxyalkyl, cyano, alkoxycarbonyl, carboxy, -(C=O)-(NR48R49), -(C=O)-NH-alkylene(NR48R49), andalkoxy;[0074] R42, R43, R44, R4S' are each independently selectedfrom hydrogen, alkyl, f luoroalkyl, cyanoalkyl, cycloalkyl,fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, alky-Ifluorocycloalkyl , aryl , heteroaryl , heterocycle, O-aryl ,O-heteroaryl, S-aryl , CONR48R49, NR48COalkyl, NR48(C=O)Oalkyl, acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy,alkoxyalkyl, alkoxycarbonyl, alkoxyimino, alkoxysulfonyl,alkylcarbonyl, alkyl sulfonyl, alkynyl, amido, carboxy, cyano,fluoroalkoxy, formyl, haloalkoxy, haloalkyl, halogen,hydroxy, hydroxyalkyl, mercapto, nitro, alkylthio,-NR48R49, -carbonyl(NR48R49), -S02 (NR48R49), andN(R48)S02(R49);[0075] R43and R44taken together with the carbon atoms towhich each is attached form a ring, wherein R43and R44takentogether are ---CH2CH2CH2-, ---CH2CH2CH2CH2-, or-CH20CH2-;

Aug. 14 , 200813

(VI)

[0076] R46 is selected from hydrogen, alkyl, f luoroalkyl,cyanoalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, fluorocy-cloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, and alkylfluoro-cycloalkyl;[0077] R47 is selected from fluoroalkyl , hydroxyalkyl,alkoxyalkyl, fluorocycloalkyl, and alkylfluorocycloalkyl;[0078] R48 and R49 each are each independently selectedfrom hydrogen, alkyl, fluoroalkyl, cycloalkyl, cyanoalkyl,fluorocycloalkyl, cycloalkoxyalkyl, alkylcycloalkyl, alky-Ifluorocycloalkyl, aryl, heteroaryl, heterocycle, acyl, alkoxy-alkyl, alkoxycarbonyl, alkylcarbonyl, alkylsulfonyl, amido,formyl, hydroxy, and hydroxyalkyl;[0079] As is a group of structure A7 or A8;wherein A, is selected from

A

B

c

D

E

F

G


15/49

US 2008/0194538 Al

-continued

N__/ ~6,

~6

Aug. 14, 200814

-continuedH Q

R

s

K

TL

u

M

v

N

wo

p x


16/49

US 2008/0194538 Al

-continued

" . - 8I~8

("\\".~,N' ~~I~8

Yl

Y2

Y3

Y4

Y5

Y6

Y7

Y8

Y9

Aug. 14, 200815

-continuedYI0( - N X N - ~ 6 ' YllY12

Y13

Y14

Y15

andAs is selected from

1M

IN


17/49

US 2008/0194538 Al

-continued

e_G~ 3 e n )n

nN__

/ ~6,~6

Aug. 14, 200816

-continued10 lW

IP IX

lQ lY l

lY 2

lR

lY 3

IS or

lY 4

1U wherein G3 is 0, S, S(O), S(0)2;nis 1,2, or3;[0080] m is 0,1, or 2;wherein each carbon atom of groups As may be optionallysubstituted with one or more groups selected from alkyl,f1uoroalkyl, cyanoalkyl, cycloalkyl , f1uorocycloalkyl ,cycloalkoxyalkyl, alkylcycloalkyl, alkylfluorocycloalkyl,fluorine, acyl, acyloxy, alkenyl, alkoxy, alkoxyalkoxy,alkoxyalkyl, alkoxycarbonyl, alkylcarbonyl, alkyl sulfonyl,alkynyl, amido, carboxy, cyano, f1uoroalkoxy, formyl,haloalkoxy, haloalkyl, halogen, hydroxy, hydroxyalkyl, mer-capto, nitro, alkylthio; provided that when G1 is CH2 and G2is selected from CH2, CH2CH2, oxygen or sulfur and R, isselected from NH2, NHalkyl, or alkyl, then As is not a groupof structure K; and further provided that when G 1 is CH2CH2and G2is CH2 and R, is selected from NH2, NHalkyl, or alkyl,then As is not a group of structure K.

IV


18/49

US 2008/0194538 Al

[0081] Compounds offonnula (VI) can be prepared by thefollowing synthetic methods:

(LG)5

~5(75)

[0082] Compounds offormula (77), wherein R4U R42, R43,R44, R4S'As, G1 and G2 are defined in formula (VI) may beprepared as outl ined in Scheme 10. Ketones offonnula (71),which are obtained either from commercial sources or syn-thesized through the methods outlined herein, when treatedwith sodium hydride, followed by treatment with either acarbonate such as dimethyl carbonate, or a chloroformatesuch as ethyl chloroformate, will provide keto-ester contain-ing compounds of formula (72), wherein R=lower alkyl.Compounds offonnula (72) when treated with a compoundof formula (73), such as guanidine nitrate , in the presence ofa base such as potassium carbonate under heated conditionsin a solvent such as DMF will provide compounds offonnula(74). Compounds offonnula (74) can exist as shown in thestructure in Scheme 10 or in a tautomeric form. Compoundsofformula (74) when treated with a chlorinating reagent suchas, but not limited to, POCI3, with or without heating as

Aug. 14 , 200817

needed, wil l provide compounds of formula (75), wherein(LG)s=CI. Alternatively, compounds of formula (74) mayalso be treated with reagents such as para-toluensulfonylchloride, methylsulfonyl chloride or trifluoromethanesulfo-nyl chloride in the presence of a base such as triethylamine ina solvent such as pyridine or chloroform to provide com-pounds of formula (75) wherein (LG)S=0-S02-R',wherein R' is lower alkyl, lower fluoroalkyl or aryl. Com-pounds offormula (75), wherein (LG)s=Cl or -0-S02-R', when treated with compounds of formula (76), wherein(76) contains a primary or secondary nitrogen atom and Hisa hydrogen atom on said nitrogen atom, under heated condi-tions in the presence or absence of a base such as triethy-lamine or diisopropyethylamine, in a solvent such as ethanol,2-methoxyethanol, toluene or acetonitrile, will provide com-pounds of formula (77).[0083] Compounds of formula (77) wherein R41=H andR42, R43,R44, R4S' G1 and G, are defined in formula (VI) maybe prepared by treating a compound of formula (72) withthiourea with heating inthe presence ofa base such as sodiummethoxide in a solvent such as methanol, followed by reduc-tion of the resulting product using a reagent such as Raneynickel to provide compounds of formula (74) wherein R41=H.Compounds offonnula (74) wherein R41=H can be treatedaccording to the method above to provide compounds offormula (77) wherein R41=H.[0084] Compounds of formula (77), may be further treatedaccording to conditions known to one skilled in the art to alterfunctional groups contained with in the compound, forexample, the removal of a protecting group such as Boc orhydrolysis of an ester group that will generate compounds ofthe present invention or used within the scope of otherschemes described herein.[0085] Compounds offormula (76) that contain two differ-ent nitrogen atoms may selectively react with compounds offormula (75) to provide one isomer of formula (77). Suchselectivity may be the result of substitution or protectinggroups attached to one of the nitrogen atoms. Alternatively,compounds offonnula (76) that contain two different N-Hgroups may react with compounds offonnula (75) in a non-selective manner wherein a mixture of two different com-pounds of formula (77) are obtained from the reaction. Mix-tures of compounds of formula (77) are generally separatedby methods known to one skilled in the art, such as silicabased colunm chromatography and/or selective recrystalliza-tion.[0086] Compounds of formula (77) generated through themethods outlined in Scheme 10, may contain a Br, I or-0-Tffunctional group in one of the posit ions represented by R42,R43,R44o r R4S' These functional groups may be uti lized as asite for introducing a carbon or nitrogen atom containingsubstituent at that position. Such reactions are known to oneskil led in the art. For example, compounds of formula (77),containing a Br, I or 0- Tf functional group in one of theposit ions represented by R42, R43, R44 or R4S when treatedwith an aryl or heteroaryl boronic acids or boronic estersaccording to the conditions known to one skil led in the art asthe Suzuki reaction will provide compounds wherein the Br,I or 0- Tf has been replaced by an aryl or heteroaryl group.Alternatively, using the Stille coupling reaction, compoundsofformula (77) wherein one ofR42, R43,R44or R4Sis Br, I or0- Tf when treated with a vinyl, aryl or heteroaryl stannaneswill provide compounds wherein the Br, I or O-Tfhas beenreplaced by the vinyl, aryl or heteroaryl group. Alternatively,


19/49

US 2008/0194538 Al

compounds of formula (77) wherein one ofR42, R43, R44 orR45isBr, I or 0- Tf when treated with amines, heterocycles orheteroaryls containing an NH group will provide compoundsof wherein the Br, I or 0- Tfhas been replaced by the amine,heterocycle or heteroaryl group. Procedures and conditiondescribing these transformations may be found in the follow-ing references: J. Hartwig et al., Angew. Chern. Int. Ed.37:2046-2067 (1998); J. P. Wolfe et al., Ace. Chern. Res.,13:805-818 (1998); M. Sugahara et al., Chern. Pharm. Bull.,45:719-721 (1997); J. P.Wolfe et al., J. Org. Chem., 65:1158-1174, (2000); F. Y. Kwong et al., Org. Lett., 4:581-584,(2002); A. Klapars et al., J. Amer. Chern. Soc., 123:7727-7729 (2001); B. H. Yang et al., J. Organomet. Chem., 576:125-146 (1999); A. Kiyomori et al., Tet. Lett. , 40:2657 -2640(1999); and Hartwig, J. Org. Chem., 64(15):5575-5580(1999). Alternatively, compounds of formula (77) whereinone ofR42, R43,R44o r R4Sis Br, I or 0- Tf, may be subjectedto conditions commonly known as the Heck and Sonogashirareaction, to introduce an alkene or alkyne group at the site ofthe Br, I or 0- Tfmoiety.

Scheme 11~ 3 * : 0# /GI~/R~4 G2 0

~5

NaOR-eOR(85)

~2

(86)~5(71)

(87)

Aug. 14 , 200818

[0087] Compounds offormula (77), which are representa-tive of compounds of general formula (VI) wherein R41, R42,R43, R44, R4S'As, G1 and G2 are as defined in formula (VI),may be prepared as outlined in Scheme 11. Compounds offormula (85), wherein R is lower alkyl or benzyl as obtainedfrom commercial sources of prepared by one skilled inthe art,when treated with either sodium, lithium or potassiumhydroxide in a mixture of aqueous alcohol such as aqueousmethanol or ethanol will provide compounds of formula (86).Compounds of formula (86) when heated in the presence ofan acid such as polyphosphoric acid orheated in the presenceofP20s (phosphorus pentoxide), will provide compounds offormula (71). Alternatively, compounds offormula (86) whentreated with thionyl chloride under heated conditions willprovide compounds of formula (87). Compounds of formula(87) when heated in the presence of a Lewis acid such asaluminum trichloride in a solvent such as toluene or carbondisulfide will provide compounds offormula (71). The com-pounds offormula (71) can be treated according to the meth-ods outlined in Scheme 10 to provide compounds of formula(77).

oScheme 10

~5(77)


20/49

US 2008/0194538 Al

Scheme 12: ~ C ( H~5(89)~ 3 * : 0 , , "= , "# /GI~/R

~ G2 0

~5

oScheme 10

~5(71)

~5(77)

[0088] Compounds offonnula (77), which are representa-tive of compounds of general formula (VI) wherein R41, R42,R43, R44, R4S and As are defined in formula (VI), G1is alky-lene, and G2=0, S, NR48 or NR a, Ra is hydrogen, alkyl or anitrogen protecting group such as Boc, alkyIsulfony I,aryIsul-fonyl or phosphate, may be prepared as outlined in Scheme12. Compounds offormula (89), wherein G2=0, S, NR48 orNRa, wherein R, is hydrogen, alkyl or a nitrogen protectinggroup such as Boc, alkylsulfonyl, arylsulfonyl or phosphate,when treated with an ester of formula (90) wherein R is loweralkyl, G1 is alkyl ene, and wherein (LG)6 is chloro, bromo,iodo or methanesulfonyl, in the presence of a base such asK2C03, Et3N or sodium hydride, in a solvent such as acetone,CH2CI2 or THF, will provide compounds of formula (85).Compounds of formula (85) when heated in the presence ofan acid such as polyphosphoric acid or heated in the presenceof P20S' or subjected to conditions such as described inScheme 11can be cyclized to provide compounds of formula(71). Compounds offormula (71) when processed as outlinedin Scheme 10 will provide compounds offormula (57), whichare representative of compounds of general formula (VI).

Aug. 14, 200819

Scheme 13

: : ~ : / R~5

(91)

~ ;~ :~ /R N .H~4~G~ 0

~5(92)o o

Scheme 10

~5(72)

" ' 5

~5(77)

[0089] Compounds offonnula (77), which are representa-tive of compounds of the present invention wherein R41, R42,R43, R44, R4S and As have been defined in formula (VI),wherein G1 is alkylene, and wherein G2=0, S, NR48 or NRa,wherein R, is hydrogen, alkyl or a nitrogen protecting groupsuch as Boc, alkyl sulfonyl , aryl sulfonyl or phosphate, may beprepared as outl ined in Scheme 13. Compounds of formula(91), wherein R is lower alkyl, G2=0, S, NR48 or NRa,wherein R, is hydrogen, alkyl or a nitrogen protecting groupsuch as Boc, alkyl sulfonyl, arylsulfonyl or phosphate, whentreated with a compound of formula (90) wherein G1 is C1_Salkylene, R is lower alkyl, and wherein (LG)6 is a leavinggroup such as chIoro, bromo, iodo or methane sulfonyl, in thepresence of a base such asK2C03, Et3N or sodium hydride, ina solvent such as acetone, CH2CI2, DMF or THF, will providecompounds of formula (92). Compounds of formula (92)when treated with a base such as sodium hydride in a solventsuch as THF will provide compounds offonnula (72). Com-pounds of formula (72) when treated as outlined in Scheme 10will provide compounds offonnula (77), which are represen-tative of compounds offonnula (VI) wherein G1is alkyleneand G2 is 0, S, NR48 or NRa.


21/49

US 2008/0194538 Al

[0090] Preferred examples of compounds of formula (VI)include, but are not limited to 6-methyl-4-[(3R)-3-methy-lamino-pyrrolidin -1-y 1]-5,6-dihydro-benzo [h]quinazolin- 2-ylamine; 6-methyl-4-(3-methylamino-azetidin-l-yl)-5,6-di-hydro-benzo[h]quinazolin-2-ylamine; 4-(3-methylamino-azetidin-l-yl)-6,7 -dihydro-5H -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; 6-methyl-4-piperazin-l-yl-5,6-dihydro-benzo[h]quinazolin-2-ylamine; 4-(3-(R)-methylamino-pyrrolidin-l-yl)-6,7 -dihydro-5H -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; 4-piperazin-l-yl-6,7-dihydro-5H -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; 1-(3-methylamino-azetidin-l-yl)-1 OH-9-oxa-2,4-diaza -phenanthren- 3-ylamine; 1-(3- (R)-methy lamino-pyrrolidin-l-yl)-1 OH-9-oxa-2,4-diaza-phenanthren-3-ylamine; I-piperazin-l-yl-l0H-9-oxa-2,4-diaza-phenanthren-3-ylamine; 10-f1uoro-4-(3-(R)-methylamino-pyrrolidin-l-yl)-6,7 -dihydro-5H -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; 10-f1uoro-4-(3-methylamino-azetidin-l-yl)-6,7 -dihydro-5H -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; 10-f1uoro-4-piperazin-l-yl-6, 7-dihydro-5H -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; 4-[(3S)-3-methylamino-pyrrolidin-l-yl]-6,7-dihydro-5H -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; 4-((3aR,6aR)-I-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-l-yl)-6,7-dihydro-5H -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; 4-((1 S,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-l-yl-pyrrolidin-l-yl)-6, 7-dihydro-5H-benzo[6,7]cyclohepta[I,2-d]pyrimidin-2-ylamine;4-( (3aR,6aR)-hexahydro-pyrrolo[3,4-b ]pyrrol-l-yl)-6, 7-di-hydro- 5H-benzo [6,7]cyclohepta[ 1,2-d]pyrimidin -2-ylamine; 4-piperazin-l-yl-5,6,7 ,8-tetrahydro-l ,3-diaza-dibenzo[a,c]cycloocten-2-ylamine; 4-piperazin-l-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-l-yl)-6,7 ,8,9-tetrahydro-5H -1,3-diaza-dibenzo[ a.c]cyclononen-2-ylamine; 4-( (R)-3-amino-pyrrolidin-l-yl)-6, 7 ,8,9-tetrahydro-5H -1,3-diaza-dibenzo[ a.c]cyclononen-2-ylamine; 4-( (S)-3-amino-pyrrolidin-l-yl)-6, 7 ,8,9-tetrahydro-5H -1,3-diaza-dibenzo[ a.c]cyclononen-2-ylamine; 4-(3-methylamino-azetidin-l-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-l-yl)-6,7 ,8,9-tetrahydro-5H -1,3-diaza-dibenzo[ a,c]cyclononen-2-ylamine; 4-((1 S,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-l-yl)-5,6-dihydro-7 -oxa-l ,3-diaza-dibenzo[ a.c]cyclohepten-2-ylamine; 4-piperazin-l-yl-5,6-dihydro-7 -oxa-l ,3-diaza-dibenzo [a.c]cyclohepten- 2-ylamine; 4-((R)-3-methy lamino-pyrrolidin-l-yl)-5,6-dihydro-7 -oxa-l ,3-diaza-dibenzo[ a,c]cyclohepten-2-ylamine; 4-(3-methylamino-azetidin-l-yl)-5,6-dihydro-7 -oxa-l ,3-diaza-dibenzo[ a.c]cyclohepten-2-ylamine; 4-(3-methylamino-azetidin-l-yl)-5,6-dihydro-7-thia-l ,3-diaza-dibenzo[ a.c]cyclohepten-2-ylamine; 4-(3-(R)-methylamino-pyrrolidin-l-yl)-5,6-dihydro-7 -thia-l ,3-diaza-dibenzo[ a.c ]cyclohepten-2-ylamine; 4-(3-(R)-amino-pyrrolidin-l-yl)-5,6-dihydro-7 -thia-l ,3-diaza-dibenzo[ a,c]cyclohepten-2-ylamine; 4-piperazin-l-yl-5,6-dihydro-7-thia-l ,3-diaza-dibenzo[ a.c]cyclohepten-2-ylamine; 4-(3-

Aug. 14, 200820

methylamino-azetidin-l-yl)-7 -oxo-6, 7-dihydro-5H-7M-thia-l ,3-diaza-dibenzo[ a.c]cyclohepten-2-ylamine; 4-(3-methylamino-azetidin -1-y1)-7,7-dioxo-6, 7-dihydro- 5H-7A6-thia-l ,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-l-yl)-5,6-dihydro-benzo[h]quinazolin-2-ylamine; 4-piperazin-l-y1-5,6-dihydro-benzo [h]quinazolin- 2-ylamine; 10-chloro-4-[(3R)-3-(methylamino )pyrrolidin-l-yl]-5,6-dihydro[ 1]benzoxepino[5,4-d]pyrimidin-2-amine; 10-methyl-4-[(3R)-3-(methylamino )pyrrolidin-l-yl]-5,6-dihydro[l]benzoxepino[5,4-d]pyrimidin-2-amine; 10-methoxy-4-[(3R)-3-(methylamino )pyrrolidin-l-yl]-5,6-dihydro[ 1]benzoxepino[5,4-d]pyrimidin-2-amine; 9-chloro-4-[(3R)-3-(methylamino )pyrrolidin-l-yl]-5,6-dihydro[l]benzoxepino[5,4-d]pyrimidin-2-amine; 9-methyl-4-[(3R)-3-(methylamino )pyrrolidin-l-yl]-5,6-dihydro[l]benzoxepino[5,4-d]pyrimidin-2-amine; 9-methoxy-4-[(3R)-3-(methylamino )pyrrolidin-l-yl]-5,6-dihydro[l]benzoxepino[5,4-d]pyrimidin-2-amine; 8-chloro-4-[(3R)-3-(methylamino )pyrrolidin-l-yl]-5,6-dihydro[l]benzoxepino[5,4-d]pyrimidin-2-amine; 8-methyl-4-((R)-3-methylamino-pyrrolidin-l-yl)-5,6-dihydro-7 -oxa-l ,3-diaza-dibenzo[ a,c]cyclohepten-2-ylamine; 8-methoxy-4-[(3R)-3-(methylamino )pyrrolidin-l-yl]-5,6-dihydro[l]benzoxepino[5,4-d]pyrimidin-2-amine; 4-[(3R)-3-(methylamino)pyrrolidin-l-yl]-5,6,7 ,8-tetrahydrobenzo[7,8]cycloocta[1 ,2-d]pyrimidin-2-amine; 4-[(3R)-3-aminopyrrolidin-l-yl]-5,6,7,8-tetrahydro benzo [7,8] cycloocta[ 1,2-d]pyrimidin -2-amine; 4-[(3S)-3-aminopyrrolidin-l-yl]-5,6,7,8-tetrahydrobenzo[7,8]cycloocta[I,2-d]pyrimidin-2-amine;4-(3-aminoazetidin-l-yl)-5,6, 7,8-tetrahydrobenzo [7,8]cy-cloocta[ 1,2-d]pyrimidin -2-amine; 4-[(3aR,6aR)- hexahydro-pyrrolo[3,4-b ]pyrrol-l (2H)-yl]-5,6, 7,8-tetrahydrobenzo[7,8]cycloocta[I ,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-l-yl)-6, 7-dihydro-5H-benzol 6,7]cyclohepta[1 ,2-d]pyrimidin-2-amine; 4-(4-aminopiperidin-l-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-benzol 6,7]cyclohepta[1 ,2-d]pyrimidine-2,4-diamine; N4 -(1-methylpiperidin-4-yl)-6, 7-dihydro-5H -benzo] 6,7]cyclohepta[I,2-d]pyrimidine-2,4-diamine; N4-[(IR,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-l ,4-diazepan-l-yl)-6, 7-dihydro-5H -benzo] 6,7]cyclohepta[ 1,2-d]pyrimidin-2-amine; 4-(I-methyl-piperidin-4-yloxy )-6, 7-dihydro-5H -benzo] 6,7]cyclohepta[l,2-d]pyrimidin -2-ylamine; 4-( l-methyl-piperidin- 3-yloxy)-6,7-dihydro-5H -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; 4-((R)-I-methyl-pyrrolidin-3-yloxy)-6,7-dihydro-5H-benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine;4-( (S)-I-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]pyrimi-din-2-ylamine; 4-( (S)-pyrrolidin-3-yloxy)-6, 7-dihydro-5H-benzol 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; 4-(2-dimethylamino-ethoxy )-6,7 -dihydro-5H -benzo] 6,7]cyclohepta[I,2-d]pyrimidin-2-ylamine; 4-(1,9-diaza-spiro[5.5]undec-9-yl)-6, 7-dihydro-5H -benzo] 6,7]cyclohepta[ 1,


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2-d]pyrimidin-2-ylamine; 4-((R)-3-dimethylamino-pyrroli-din-I-yl)-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[ I ,2-d]pyri-midin-2-ylamine; 4-(2,6diaza-spiro[3 .S]non-2-yl)-6, 7-dihy-dro-SH-benzo[6,7]cyclohepta[I,2-d]pyrimidin-2-ylamine;4-(2,S-diaza-spiro[3.S]non-2-yl)-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[I,2-d]pyrimidin-2-ylamine; 4-(octahydro-pyr-rolo[3,4-c ]pyridin-2-yl)-6, 7-dihydro-SH -benzo] 6,7]cyclo-hepta[ I,2-d]pyrimidin-2-ylamine; 4-(octahydro-pyrroloj l ,2-a]pyrazin-2-yl)-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[l,2-d]pyrimidin -2-ylamine; 4-(3 ,6-diaza- bicyclo[3.2 .I]oct -6-yl)-6,7 -dihydro-SH -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; 4-(2,6-diaza-bicyclo[3 .2.I]oct-2-yl)-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; N-( 4-piperazin-I-yl-6,7 -dihydro-SH-benzo[6,7]cyclohepta[I,2-d]pyrimidin-2-yl)-acetamide; N -( 4-piperazin-I-yl-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[ I,2-d]pyrimidin-2-yl)-benzamide; 4-(S-methyl-octahydro-pyrrolo[3,4-c ]pyridin-2-yl)-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[1,2-d]pyrimidin-2-ylamine; 4-(3-methyl-3,6-diaza-bicyclo[3.2.I]oct-6-yl)-6,7 -dihydro-SH -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; 2-Dimethylamino-N-( 4-piperazin-l-yl-6,7 -dihydro-SH -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-yl)-acetamide; 2-methylamino- N-(4-piperazin-l-yl-6,7 -dihydro-SH -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-yl)-acetamide; 2-Amino- N -(4-piperazin-I-yl-6,7-dihydro-SH -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-yl)-acetamide; l-methyl-3-( 4-piperazin-I-yl-6,7 -dihydro-SH-benzol 6,7]cyclohepta[1 ,2-d]pyrimidin-2-yl)-urea;4-Amino- N-(4-piperazin-I-yl-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[ I ,2-d]pyrimidin -2-yl)-butyramide; 6-(2-pyridin-3-ylmethylamino-6,7 -dihydro-SH -benzo] 6,7]cyclohepta[l,2-d]pyrimidin -4-y l)octahydro-lH -pyrrolo [3,4-b]pyridine;3-amino-N -(4-piperazin-I-yl-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[I,2-d]pyrimidin-2-yl)-propionamide; 4-[1,4,7]triazonan-I-yl-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[ I,2-d]pyrimidin-2-ylamine; N,N-dimethyl-N'-( 4-piperazin-I-yl-6,7-dihydro-SH -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-yl)-ethane-I,2-diamine; 4-(octahydro-pyrrolo[3,4-b ]pyridin-6-yl)-S,6-dihydro-7 -thia-I ,3-diaza-dibenzo[ a.c]cyclohepten-2-ylamine; 4-((R)-3-methylamino-pyrrolidin-I-yl)-6, 7,9, 10,II, 12-hexahydro-SH -I ,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,II, 12-hexahydro-SH -I ,3-diaza-benzo[3,4]cyclohepta[1 ,2-b]naphthalen-2-ylamine;4-piperazin-I-yl-6, 7,9,10, II ,12-hexahydro-SH-I ,3-diaza-benzo[3,4]cyclohepta[1 ,2-b]naphthalen-2-ylamine; 9-iodo-4-( (R)-3-methylamino-pyrrolidin-I-yl)-S,6-dihydro-7 -oxa-I,3-diaza-dibenzo[ a,c]cyclohepten-2-ylamine; 9-iodo-4-piperazin-I-yl-S,6-dihydro-7 -oxa-I ,3-diaza-dibenzo[ a,c]cyclohepten-2-ylamine; 9-iodo-4-octahydro-pyrrolo[3,4-b]pyridin-6-yl-S,6-dihydro-7 -oxa-I ,3-diaza-dibenzo[ a,c]cyclohepten-2-ylamine; 2,4-d]-piperazin-I-yl-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidine; 2-amino-4-octahydro-pyrrolo[3,4-b ]pyridin-6-yl-S,6-dihydro-7-oxa-l,3-diaza-dibenzo[ a, c ]cycloheptene-9-carbonitrile;4-octahydro-pyrrolo [3,4-b]pyridin -6-y 1-9-pheny 1-S , 6-dihy-dro-7 -oxa -1,3 -diaza-dibenzo [a,c] cyclohepten -2-ylamine;4-octahydro-pyrrolo [3,4-b]pyridin -6-y 1-9-pyridin -3-y1-S , 6-dihydro-7 -oxa-I ,3-diaza-dibenzo[ a.c]cyclohepten-2-ylamine; 4-((R)-3-methylamino-pyrrolidin-I-yl)-6,7 -dihy-dro-S-thia-I ,3-diaza-dibenzo[ a,c]cyclohepten-2-ylamine;2-amino-4-octahydro-pyrrolo[3,4-b ]pyridin-6-yl-S,6-dihy-dro-7 -oxa-I ,3-diaza-dibenzo[ a,c]cycloheptene-9-carboxylicacid methyl ester; 4-piperazin-I-yl-6, 7-dihydro-S-thia-1 ,3-

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diaza-dibenzo[ a.c]cyclohepten-2-ylamine; 4-(octahydro-pyrrolo[3,4-b ]pyridin-6-yl)-6, 7-dihydro-S-thia-I ,3-diaza-dibenzo[ a,c]cyclohepten-2-ylamine; 4-((R)-3-methylamino-pyrrolidin-I-yl)-S,S-dioxo-6,7 -dihydro-SH -SA6-thia-1 ,3-diaza-dibenzo[ a.c ] cyclohepten-2-ylamine; 4-( (R)-3-methylamino-pyrrolidin-I-yl)-S-oxo-6,7 -dihydro-S-thia-I,3-diaza-dibenzo[ a.c ]cyclohepten-2-ylamine; N4-(3-piperidin-I-yl-propyl)-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[ I ,2-d]pyrimidine-2,4-diamine; 4-(4-dimethyl aminopiperidin -1-yl)-6, 7-dihydro- SH -benzo [6,7]cyclohepta[ I , 2-d]pyrimidin-2-ylamine; 10-fJuoro-4-octahydro-6H -pyrrolo[3,4-b ]pyridin-6-yl-6, 7-dihydro-SH-benzol 6,7]cyclohepta[1 ,2-d]pyrimidin-2-amine; 4-[1,4]diazepan-I-yl-6,7 -dihydro-SH -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; (IR,SS)-4-(3,6-Diaza-bicyclo[3.2.0]hept-6-yl)-6,7 -dihydro-SH -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; 4-piperazin-I-yl-6,7-dihydro-SH-benzol 6,7]cyclohepta[1 ,2-d]pyrimidine; (3aS,6aS)-4-(Hexahydro-pyrrolo[3,4-b ]pyrrol-I-yl)-6, 7-dihydro-SH-benzol 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; (I S,SS)-4-(3,6-Diaza-bicyclo[3.2.0]hept-3-yl)-6,7-dihydro-SH-benzol 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine;N4-piperidin-3-yl-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[l,2-d]pyrimidine-2,4-diamine; N4-(octahydro-isoindol-4-yl)-6,7-dihydro-SH -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidine-2,4-diamine; methyl-( 4-piperazin-I-yl-6, 7-dihydro-SH -benzo[6,7]cyclohepta[I,2-d]pyrimidin-2-yl)-amine; 4-(3-(R)-methyl amino- pyrrolidin -1-yl)-6, 7-dihydro- SH -benzo [6,7]cyclohepta[ I ,2-d]pyrimidine; [1-(6,7 -dihydro-SH -benzo] 6,7]cyclohepta[ I ,2-d]pyrimidin -4-y l)-azetidin -3-yl]-amine;8,I 0-dimethyl-4-piperazin-I-yl-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[ I ,2-d]pyrimidin-2-ylamine; 6-(2-(lH -imidazol-4-yl)ethylamino-6,7 -dihydro-SH -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-4-yl)octahydro-1 H-pyrrolo[3,4-b ]pyridine;(2-amino-4-piperazin-I-yl-6,7 -dihydro-SH -benzo] 6,7]cy-clohepta] l ,2-d]pyrimidin-1 O-yl)-methyl-carbamic acidmethyl ester; 10-N-methy 1-4-piperazin -1-yl-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidine-2, IO-diamine;(2-amino-4-octahydro-pyrrolo[3,4-b ]pyridin-6-yl-6, 7-dihy-dro-SH -benzo] 6,7]cyclohepta[ I ,2-d]pyrimidin-1 O-yl)-me-thyl-carbamic acid methyl ester; 10-N-methyl-4-[(4aR,7aR)-octahydro-6H -pyrrolo[3,4-b ]pyridin-6-yl]-6, 7-dihydro-SH-benzol 6,7]cyclohepta[1 ,2-d]pyrimidine-2, 10-diamine;N-(2-amino-4-piperazin-I-yl-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[I,2-d]pyrimidin-ll-yl)-acetamide; 4-(octahy-dro-pyrrolo[3,4-b ]pyridin-6-yl)-6, 7-dihydro-SH -benzo] 6,7]cyclohepta[ I ,2-d]pyrimidine-2-carboxylic acid methyl ester;4-(octahydro-pyrrolo[3,4-b ]pyridin-6-yl)-6, 7-dihydro-SH-benzol 6,7]cyclohepta[1 ,2-d]pyrimidine-2-carboxylic acid.[0091] Particularly preferred examples of compounds offormula (VI) include, but are not limited to 4-((R)-3-amino-pyrrolidin-I-yl)-6,7 -dihydro-SH -benzo] 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; 4-piperazin-I-yl-6,7 -dihydro-SH-benzol 6,7]cyclohepta[1 ,2-d]pyrimidin-2-ylamine; and 4-(3-methylamino-azetidin-I-yl)-6,7 -dihydro-SH -benzo] 6,7]cyclohepta[ I ,2-d]pyrimidin -2-ylamine.[0092] Compounds of formula (VII) are histamine H4receptor ligands and are described in EPI7 67S37AI, fi ledSep. 21, 200S, to Dyke, et al., and in W0200710908S2, fi ledFeb. 7, 2007, to Reid, et al., and in W02007/0908S3, filedAug. 16,2007, to Reid, et al., and in W02007/0908S4, filedAug. 16,2007, to Reid, et al ., which publicat ions are hereinincorporated by reference.


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US 2008/0194538 Al

[0093] Compounds offormula:

or a pharmaceutically acceptable salt, ester, prodrug, ormetabolite thereof, wherein:A6 represents heterocyclyl, preferably azetidinyl orpyrrolidi-nyl, having at least one nitrogen ring atom, which nitrogen isattached to the pyrimidine ring in formula (VII) and whereinA6 is substituted with -NRsl RS2' Rss and is optionally sub-stituted with one or more other substituents independentlyselected from the group consisting of CI_4 alkyl; F, Cl, Br,C36 cycloalkyl, OH, and OCI_4 alkyl, wherein each CI_4alkyl,C3_6 cycloalkyl is optionally substi tuted with one or morehalogen; Rso represents H, CI_4 alkyl, C3_6 cycloalkyl,wherein each CI_4alkyl, C3_6cycloalkyl, is optionally substi-tuted with one or more halogen or Rso represents -NRs6RS7wherein RS6 and RS7 are independently H, ---C(0)CH3'-S02CH3' CI-4 alkyl, C3_6cycloalkyl, wherein each CI_4alkyl, C3_6cycloalkyl is optionally substituted with one ormore halogen;RSI and RS2 are independently H, CI_4 alkyl or C3_6cycloalkyl; wherein each CI-4 alkyl is optionally substitutedwith one or more substituents selected from the group con-sisting of halogen and C3_6cycloalkyl and wherein each C3_6cycloalkyl is optionally substituted with one ormore halogen;Optionally RSl' RS2jointly form together with the nitrogen towhich they are attached to a heterocyclyl ring;RS3and RS4 are independently H, F, Cl, Br, CN, CI-4 alkyl,OH, OCI_4 alkyl, ceO)OH, ceO)OCI_4 alkyl, ceO)NH2, ceO)NHCI_4 alkyl, ceO)N(CI_4 alkyl), wherein each CI_4 alkyl isoptionally substituted with one or more halogen. Rss isselected from the group consisting ofH, CI-4 alkyl; F,Cl, Br,C3_6 cycloalkyl, OH, and OCI_4 alkyl, wherein each CI_4alkyl, C3_6cycloalkyl is optionally substituted with one ormore halogen; or optionally Rss form together with Rj, (-Rss-RS2-)a ---C1_4 alkyl-group.[0094] Examples of compounds of formula (VII) include,but are not limited to N-[(R,S)-1-(8-chloro-2-methylbenzo[4,5] furo [3,2-d]-pyrimidin -4-y l)-pyrrolidin -3-yI]N -methy-1amine; N-[ (R,S)-1-(8-chlorobenzo[ 4,5]furo[3,2-d]-pyri-midin-4-yl)-pyrrolidin-3-yl]N -methylamine; [(R,S)-1-(8-chloro-2-methylbenzo[ 4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]-dimethylamine; N-[(R)-1-(8-chlorobenzo[4,5] furo [3,2-d]pyrimidin-4- yl)pyrrolidin -3-yI]N-methylamine; N-[(S)-1-(8-chlorobenzo[ 4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl)N-methylamine; N-[1-(8-chlorobenzo[ 4,5]furo[3,2-d]pyrimidin-4-yl)azetidin-3-yl]amine; N -[1-(8-chlorobenzo[ 4,5]furo[3,2-d]pyrimidin-4-yl)azetidin-3-yl]N-methylamine; N-[1-(8-chlorobenzo[4,5]furo[3,2-d]pyrimidin-4-yl)azetidin-3-yl]N,N-

Aug. 14, 200822

(VII)

dimethyl amine; [(R)-1-(2-amino-8-chlorobenzo[ 4,5]furo[3,2-d]-pyrimidin-4-yl)pyrrolidin-3-yl]N-methylamine; [(S)-l-(2-amino-8-chlorobenzo [4,5]furo [3,2-d]-pyrimidin-4- y1)pyrrolidin-3-yl]N -methylamine; [1-(2-ethylamino-8-chiorobenzo [4,5] furo [3,2-d]-pyrimidin-4-y l)azetidin -3-yl]N-ethylamine; 4-((R)-3-methylamino-pyrrolidin-l-yl)-benzol 4,5]furo[3,2-d]pyrimidin-2-ylamine; 8-methyl-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 8-f1uoro-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine;8-bromo-4-( (R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin- 2-y lamine; 7-chloro-4-( (R)-3-methy-lamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; N-[1-(2-amino-8-chlorobenzo[ 4,5]furo[3,2-d]pyrimidin-4-yl)azetidin-3-yl]N-methylamine; 4-(3-methylamino-azetidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin -2-Ylamine; 8-bromo-4-(3 -methy lamino-azetidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 8-methyl-4-(3-methylamino-azetidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin -2-Ylamine; 8-f1uoro-4-(3 -methy lamino-azetidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine;8-methoxy -4-((R)- 3-methy lamino-pyrrolidin -l-y l)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine; 4-((R)-3-methy-lamino-pyrrolidin-l-yl)-8-trifluoromethoxy-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 9-f1uoro-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 9-methyl-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine;9-methoxy -4-((R)- 3-methy lamino-pyrrolidin -l-y l)-benzo[4,5]furo[3,2-d]pyrimidin-2-ylamine; 7-methyl-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimi-din-2-ylamine; 7-methoxy-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine;4-((R)-3-methylamino-pyrrolidin-l-yl)-7 -trifluoromethyl-benzol 4,5]furo[3,2-d]pyrimidin-2-ylamine; 7-methoxy-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 6-chloro-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine;6-methyl-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 6-methoxy-4-((R)-3-me-thylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 8-methoxy-4-(3-methylamino-azetidin-l-yl)-benzol 4,5]furo[3,2-d]pyrimidin-2-ylamine; 4-(3-methylamino-azetidin-l-yl)-8-trifluoromethoxy-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 9-f1uoro-4-(3-methylamino-azetidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 9-methyl-4-(3-methylamino-azetidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine;9-methoxy-4-(3-methylamino-azetidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin- 2-ylamine; 7-methy 1-4-(3-methy-lamino-azetidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 7-methoxy-4-(3-methylamino-azetidin-l-yl)-benzol 4,5]furo[3,2-d]pyrimidin-2-ylamine; 4-(3-methylamino-azetidin -1-y1)-7-trifluoromethy 1-benzol 4,5]furo[3,2-d]pyrimidin-2-ylamine; 6-chloro-4-(3-methylamino-azetidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 6-methyl-4-(3-methylamino-azetidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine;6-methoxy-4-(3-methylamino-azetidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin- 2-ylamine; 8-chloro-4- [3-(cyclopro


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US 2008/0194538 Al

pylmethyl-amino )-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 8-chloro-4-((R)-3-dimethylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine;4-((R)-3-amino-pyrrolidin-l-yl)-8-chloro-benzo[ 4,5]furo[3,2-d]pyrimidin -2-ylamine; 8-chloro-4-( 4-methy lamino-pip-eridin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine;4-(4-amino-piperidin-l-yl)-8-chloro-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 4-(3-amino-azetidin-l-yl)-8-chloro-benzol 4,5]furo[3,2-d]pyrimidin-2-ylamine; [8-chloro-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-yl]-methyl-amine; [8-chloro-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-yl]-dimethyl-amine; N-[8-chloro-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-yl]-acetamide; N-[8-chloro-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-yl]-methanesulfonamide; [8-chloro-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-yl]-cyclopropyl-amine; [8-chloro-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-yl]-methyl-amine; [8-chloro-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-yl]-dimethyl-amine; N-[8-chloro-4-(3-methylamino-azetidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-yl]-acetamide; N-[8-chloro-4-(3-methylamino-azetidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-yl]-methanesulfonamide; [8-chloro-4-(3-methylamino-azetidin-l-y l)-benzo [4,5]furo [3,2-d]pyrimidin -2-yl]-cyclopropy 1-amine; [(R)-I-(2-amino-8-chlorobenzo[ 4,5]furo[3,2-d]pyrimidin-4-yl)pyrrolidin-3-yl]N-methylamine; 4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 8-methyl-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine;8-f1uoro-4-( (R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 8-bromo-4-((R)-3-methy-lamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 7-chloro-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzol 4,5]furo[3,2-d]pyrimidin-2-ylamine; 8-methoxy-4-((R)-3-methylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin- 2-ylamine; 8-chloro-4-[3-( cyclopropy lmethy 1-amino )-pyrrolidin-l-yl]-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; 8-chloro-4-((R)-3-dimethylamino-pyrrolidin-l-yl)-benzo[ 4,5]furo[3,2-d pyrimidin-2-ylamine; 4-((R)-3-amino-pyrrolidin-l-yl)-8-chloro-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; N-[I-(2-ethylamino-8-chlorobenzo[ 4,5]furo[3,2-d]-pyrimidin-4-yl)azetidin-3-yl]N-methylamine;4-(3-methylamino-azetidin-l-yl)-8-chloro-benzo[ 4,5]furo[3,2-d]pyrimidin-2-ylamine; [8-chloro-4-(3-methylamino-azetidin-l-yl)-benzo[ 4,5]furo[3,2-d]pyrimidin-2-yl]methy-lamine; and [8-chloro-4-(3-methylamino-azetidin-l-yl)-benzol 4,5]furo[3,2-d]pyrimidin-2-yl]dimethylamine.[0095] Compounds of formulae (VIII) and (IX) are hista-mine H4 receptor ligands and are described in US200510070550Al, filed Sep. 29, 2004, to Arienti, et al., whichpublication is herein incorporated by reference.

Aug. 14, 200823

[0096] Compounds of formulae

(VIII)

(IX)

wherein:W is N or CR62;X" is NorCH;Y' is 0, NR67, or CR67R68;Z' is N or CR69;[0097] nil is 0, 1, or 2;each of R69 is, independently from other substituent assign-ments, H, Cl_4alkyl, C2_salkenyl, C2_salkynyl, C3_6cy-cloalkyl, ---Cl_4alkoxy, -Cl_4alkylamino, ---Cl_4alkylthio,---Cl_4alkylsulfonyl, -OC3_6cycloalkyl, -OCH2Ph, cyano,---CF3, F, Cl, Br, I, nitro, -OCF3, SCF3, -ORc, -SRc,S(O)RC, -S02Rc, -C(O)RC, phenyl, benzyl, phenethyl,C(O)NRaRb, ---C(O)ORC, _NRaRb, ---CH2NRaRb or---CH20Rc; wherein each of'R", Rb and RCis, independentlyfrom other substituent assignments, selected from H,Cl_4alkyl, C3_6cycloalkyl, phenyl, (C3_6cycloalkyl)C1_zalkyl-, benzyl and phenethyl , or R" and Rb taken togetherwith the nitrogen to which they are attached, form a 4-7membered heterocyclic ring HetCycl, wherein said ring Het-Cycl has 0 or 1 additional heteroatoms selected from 0, S,>NH and >NCl_6alkyl, and wherein any phenyl, phenethyl,benzyl, alkyl or cycloalkyl moiety in any of said R69, R", Rb ,RC, and said ring HetCycl is optionally, and independentlyfrom other substituent assignments, substituted with 1, 2 or 3substituents selected from Cl_3alkyl, halo, hydroxy, amino,and Cl_3alkoxy;each of R60_62 is, independently from other substituentassignments, H, Cl_4alkyl, F, Cl, Br, I, CF3, -OCF3, -ORc,SRc, S(O)RC, -S02Rc, Cl_4alkoxy, cyano, nitro, ---C(O)NRaRb, ---C(O)phenyl, ---C(0)Cl_6alkyl, S(0)Cl_4alkyl, orS02Cl_4alkyl; or, R60 and R61 for a compound of formula(VIII) taken together with the carbon atoms to which they areattached form a cyclic structure Cycl selected from aryl,heteroaryl, 5- or 6-membered carbocycle, and 5- or 6-mem-bered heterocycle with 1 or 2 heteroatoms, wherein saidcyclic structure Cyc 1is, independently from other substituentassignments, substituted with 0, 1, or 2 substituents selectedfrom Cl_3alkyl, halo, hydroxy, amino, and Cl_3alkoxy; or, R61


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US 2008/0194538 Al

and R62 for a compound of formula (IX) taken together withthe carbon atoms to which they are attached form a cyclicstructure Cyc2 selected from aryl, heteroaryl, 5- or 6-mem-bered carbocycle, and 5-or 6-memberedheterocycle with lor2 heteroatoms. wherein said cyclic structure Cyc2 is, inde-pendently from other substituent assignments, substitutedwith 0, 1, or 2 substituents selected from Cl_3alkyl, halo,hydroxy, am

11 863 925 method for pain treatment

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