IP Library › Granted Patent US 9,422,293

Granted Patent B2

US 9,422,293 · App. 14/157,671 · Granted Aug 23, 2016

Tetrahydro-pyrimidoazepines as modulators of TRPV1

Inventors: Brett D. Allison (Del Mar, CA); Bryan James Branstetter (Carlsbad, CA); J. Guy Breitenbucher (Escondido, CA); Michael D. Hack (San Diego, CA); Natalie A. Hawryluk (San Diego, CA); Alec D. Lebsack (Ladera Ranch, CA); Kelly J. McClure (Ramona, CA); Jeffrey E. Merit (Stanford, CA)

Assignee: Janssen Pharmaceutica NV

C07D487/04

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Quick Facts

Patent No.: US 9,422,293
App. No.: 14/157,671
Granted: Aug 23, 2016
Kind: B2

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Abstract

Certain tetrahydro-pyrimidoazepine compounds are described, which are useful as TRPV1 modulators. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by TRPV1. Thus, the compounds may be administered to treat, e.g., pain, itch, cough, asthma, or inflammatory bowel disease.

Claims (236)

1. A compound of Formula (I):

wherein:

R 1 is NR a R b;

R a and R b taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl or bridged bicyclic heterocycloalkyl group unsubstituted or substituted with one, two, or three moieties independently selected from the group consisting of —C 1-6 alkyl, —C 1-4 alkyl-OH, —C 1-2 alkyl-OC 1-2 alkyl, —OH, —OC 1-4 alkyl, —NR p R q , halo, —CO 2 H, and benzyl substituents;

where R p and R q are each independently —H or —C 1-6 alkyl; or R p and R q taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl;

R 2 is —H or —C 1-6 alkyl;

R 3 is a phenyl group unsubstituted or substituted with one, two, or three R g substituents;

where each R g substituent is —C 1-6 alkyl; —C 1-4 alkyl-OH unsubstituted or substituted with —CF 3 ; saturated monocyclic cycloalkyl; —OH; —OC 1-6 alkyl; phenoxy; —CN; —NO 2 ; —N(R h )R i ; —C 1-4 alkyl-N(R h )R i ; —C(O)N(R h )R i ; —N(R h )C(O)R i ; —N(R h )SO 2 C 1-6 alkyl; —C(O)C 1-6 alkyl; —S(O) 0-2 —C 1-6 alkyl; —SO 2 CF 3 ; —SO 2 N(R h )R i ; —SCF 3 ; halo; —CF 3 ; —OCF 3 ; —CO 2 H; —CO 2 C 1-6 alkyl; —C(R j )(R x )—CN; —C(R j )(R x )—OH; —C(R j )(R x )—CO 2 C 1-6 alkyl; —C(R j )(R x )—CO 2 H; —C(R j )(R x )—C(O)N(R h )R i ;phenyl; or monocyclic heteroaryl;

where R h and R i are each independently —H or —C 1-6 alkyl; or R h and R i (when both are present) taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl group;

R j is independently —H, —C 1-6 alkyl, or —CF 3 ;

R x is —H or —C 1-6 alkyl; or R j and R x taken together with the carbon to which they are attached form a monocyclic cycloalkyl ring;

and

Ar is a pyridyl, group unsubstituted or substituted with one, two, or three R k substituents;

where each R k substituent is independently —C 1-6 alkyl, —C 1-2 alkyl -OH, —OH, —OC 1-6 alkyl, phenoxy, —CN, —NO 2 , —N(R 1 )R m , —C(O)N(R 1 )R m , —N(R 1 )C(O)R m , —N(R 1 )SO 2 C 1-6 alkyl, —N(R 1 ) SO 2 CF 3 , —C(O)C 1-6 alkyl, —S(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , —SO 2 N(R 1 )R m , —SCF 3 , halo, —CF 3 , —OCF 3 , —CO 2 H, or —CO 2 C 1-6 alkyl;

where R 1 and R m are each independently —H, —C 1-6 alkyl, saturated monocyclic cycloalkyl, or —CF 3 ;

or a pharmaceutically acceptable salt of such compound.

2. A compound or pharmaceutically acceptable salt as defined in claim 1 , wherein R a and R b taken together with their nitrogen of attachment form an aziridinyl, pyrrolidinyl, piperidinyl, 2-oxo-piperidin-1-yl, piperazinyl, oxo-piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-1λ 6 -thiomorpholin-4-yl, 1,1-dioxo-λ 6 - [1,2 ]thiazinan-2-yl, azepanyl, 1,4-oxazepanyl, or 7-azabicyclo[2.2.1]hept-7-yl group unsubstituted or substituted with a -C 1-6 alkyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl, fluoro, —OH, or —CO 2 H substituent.

3. A compound, pharmaceutically or pharmaceutically acceptable salt as defined in claim 1 , wherein R 2 is —H.

4. A compound or pharmaceutically acceptable salt as defined in claim 1 , wherein Ar is 2-pyridyl substituted with —CF 3 , —NO 2 , or —N(R 1 )R m .

5. A compound or pharmaceutically acceptable salt as defined in claim 1 , wherein Ar is 2-pyridyl substituted with —CF 3 .

6. A compound selected from the group consisting of:

[2-Isopropyl-7-(3-methyl-quinoxalin-2 -yl)-6,7,8,9-tetrahydro -5H-pyrimido-[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

(4-tert-Butyl-phenyl)-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-yl]-amine;

N 4 -(3-Chloro-4-trifluoromethyl-phenyl)-N 2 ,N 2 -dimethyl-7-(3-trifluoromethyl-pyridin-2-yl) -6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

(4-Bromo-phenyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-yl]-amine;

(4-tert-Butyl-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro -5H-pyrimido[4,5-d]azepin-4-yl]-amine;

N 4 -(4-tert-Butyl-phenyl)-N 2 ,N 2 -dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro -5H-pyrimido[4,5-d]azepine-2,4-diamine;

N 2 ,N 2 -Dimethyl-N 4 -(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;

N 4 -(4-Chloro-phenyl)-N 2 ,N 2 -dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepine-2,4-diamine;

N 4 -(4-Trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepine-2,4-diamine;

[2-Azetidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin -4-yl]-(4-trifluoromethyl-phenyl)-amine;

1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-2-yl]-piperidine-4-carboxylic acid;

1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-2-yl]-piperidin-4-ol;

[2-(4-Isopropyl-piperazin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

4-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-2-yl]-piperazin-2-one;

(R)-1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro -5H-pyrimido[4,5-d]azepin-2-yl]-piperidin-3-ol;

[2-(4-Methyl-piperazin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

(S)-1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro -5H-pyrimido[4,5-d]azepin-2-yl]-piperidin-3-ol;

[2-Piperazin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

[2-Thiomorpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

[2-(4-Benzyl-piperazin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

[2-Pyrrolidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

2-{4-[2-Azetidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol; and

2-{4-[2-Azepan-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol;

and pharmaceutically acceptable salts thereof.

7. A compound selected from the group consisting of:

1-[4-({2-Piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanone;

N-[3-Fluoro-4-(trifluoromethyl)phenyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

N,N-Dimethyl-4-({2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzenesulfonamide;

N-[4-(1,1-Dimethylethyl)-3-nitrophenyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

N-[4-(Methylsulfanyl)phenyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

(2-Fluoro-4-trifluoromethyl-phenyl)-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl) -6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

Methyl 2-methyl-2-[4-({2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoate;

2-[4-({2-Piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propan-2-ol;

1,1,1-Trifluoro-2-[4-({2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propan-2-ol;

2-Methyl-2-[4-({2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoic acid;

4-(1,1-Dimethylethyl)-N1-{2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro -5H-pyrimido[4,5-d]azepin-4-yl}benzene-1,3-diamine;

2-(1,1-Dioxido-1,2-thiazinan-2-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-[3-(Methyloxy)piperidin-1-yl]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-{(2S)-2-[(Methyloxy)methyl]pyrrolidin-1-yl}-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-(4-methylpiperazin-1-yl)-7-[3-(trifluoromethyl)pyridine -2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-Azepan-1-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-Azepan-1-yl-N-[3-chloro-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-Azetidin-1-yl-N-[3-chloro-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-Azetidin-1-yl-N-[(3,4-dichlorophenyl)methyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-(2,6-Dimethylmorpholin-4-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-(1,4-Oxazepan-4-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-(3,3-Difluoropiperidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-(4-Methylpiperidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-(3-Methylpiperidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-(3,3-Difluoroazetidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-(4,4-Difluoropiperidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-(3,3-Difluoropyrrolidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-(2-Methylpyrrolidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-(1,4-oxazepan-4-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-(2-Methylpiperidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-(1,1-Dioxidothiomorpholin-4-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

N-[4-(1,1-Dimethylethyl)phenyl]-2-pyrrolidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-Azetidin-1-yl-N-[4-(1,1-dimethylethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-Piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

N-[4-(1,1-Dimethylethyl)phenyl]-2-(4-methylpiperazin-1-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-Azepan-1-yl-N-[4-(1,1-dimethylethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-pyrrolidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

[1-(4-{[4-(Trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro -5H-pyrimido[4,5-d]azepin-2-yl)piperidin-2-yl]methanol;

[(2S)-1-(4-{[4-(Trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)pyrrolidin-2-yl]methanol;

[(2R)-1-(4-{[4-(Trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)pyrrolidin-2-yl]methanol;

2-(7-Azabicyclo[2.2.1]hept-7-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-[2-(1-Methylethyl)pyrrolidin-1-yl]-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

[4-(4-{[4-(Trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro -5H-pyrimido[4,5-d]azepin-2-yl)morpholin-2-yl]methanol;

[4-(4-{[2-Methyl-4-(trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)morpholin-2-yl]methanol;

2-[(2S or 2R)-2-Methylpiperidin-1-yl]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridine -2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

7-[3-(Ethylsulfonyl)pyridin-2-yl]-2-piperidin-1-yl-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

2-(2-Piperidin-1-yl-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyridine-3-sulfonamide;

N-Cyclopropyl-2-(2-piperidin-1-yl-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H -pyrimido[4,5-d]azepin-7-yl)pyridine-3-sulfonamide;

N-(1-Methylethyl)-2-(2-piperidin-1-yl-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro -7H-pyrimido[4,5-d]azepin-7-yl)pyridine-3-sulfonamide;

2-Methyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propionic acid methyl ester;

2-Piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;

N,N-Dimethyl-4-({2-morpholin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzenesulfonamide;

1-[4-({2-Morpholin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanone;

(3-Chloro-4-trifluoromethyl-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

2-Methyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propionitrile;

2-Methyl-2-{4-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-1-ol;

2-Methyl-2-{4-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propionitrile;

2-Fluoro-4-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-ylamino]-benzoic acid methyl ester;

(6-Methoxy-5-trifluoromethyl-pyridin-2-yl)-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl) -6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoic acid methyl ester;

4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoic acid;

2-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol;

(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl) -6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;

2-{2-Fluoro-4-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol;

2-Methyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propionic acid;

5-Chloro-6-[2-piperidin-1-yl-4-(4-trifluoromethyl-phenylamino)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl]-nicotinic acid methyl ester;

{5-Chloro-6-[2-piperidin-1-yl-4-(4-trifluoromethyl-phenylamino)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl]-pyridin-3-yl}-methanol;

and pharmaceutically acceptable salts thereof.

8. A pharmaceutical composition comprising:

(a) an effective amount of an agent selected from the group consisting of compounds of Formula (I):

wherein:

R 1 is NR a R b

where R p and R q are each independently —H or —C 1-6 alkyl; or R p and R q taken together with their nitrogen of attachment form a saturated monocyclic heterocycloalkyl;

R 2 is —H or —C 1-6 alkyl;

R 3 is a phenyl group unsubstituted or substituted with one, two, or three R g substituents;

where each R g substituent is —C 1-6 alkyl; —Cl 4 alkyl-OH unsubstituted or substituted with —CF 3 ; saturated monocyclic cycloalkyl; —OH; —OC 1-6 alkyl; phenoxy; —CN; —NO 2 ; —N(R h )R i ; —C 1-4 alkyl N(R h )R i ; —C(O)N(R h )R i ; —N(R h )C(O)R i ; —N(R h )SO 2 C 1-6 alkyl; —C(O)C 1-6 alkyl; —S(O) 0-2 —C 1-6 alkyl; —SO 2 CF 3 ; —SO 2 N(R h )R i ; —SCF 3 ; halo; —CF 3 ; —OCF 3 ; —CO 2 H; —CO 2 C 1-6 alkyl; —C(R j )(R x )—CN; —C(R j )(R x )—OH; —C(R j )(R x )—CO 2 C 1-6 alkyl; —C(R j )(R x )—CO 2 H; —C(R j )(R x )—C(O)N(R h )R i ; phenyl; or monocyclic heteroaryl;

R j is independently —H, —C 1-6 alkyl, or —CF 3 ;

R x is —H or —C 1-6 alkyl; or R j and R x taken together with the carbon to which they are attached form a monocyclic cycloalkyl ring;

and

Ar is a pyridyl group unsubstituted or substituted with one, two, or three R k substituents;

where each R k substituent is independently —C 1-6 alkyl, —C 1-2 alkyl-OH, —OH, —OC 1-6 alkyl, phenoxy, —CN, —NO 2 , —N(R 1 )R m , —C(O)N(R 1 )R m , —N(R 1 )C(O)R m , —N(R 1 )SO 2 C 1-6 alkyl, —N(R 1 )SO 2 CF 3 , —C(O)C 1-6 alkyl, —S(O) 0-2 —C 1-6 alkyl, —SO 2 CF 3 , —SO 2 N(R 1 )R m , —SCF 3 , halo, —CF 3 , —OCF 3 , —CO 2 H, or —CO 2 C 1-6 alkyl;

where R 1 and R m are each independently —H, —C 1-6 alkyl, saturated monocyclic cycloalkyl, or —CF 3 ;

and pharmaceutically acceptable salts thereof; and

(b) a pharmaceutically acceptable excipient.

9. A pharmaceutical composition according to claim 8 , wherein said agent is selected from the group consisting of:

[2-Isopropyl-7-(3-methyl-quinoxalin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;

(4-tert-Butyl-phenyl)-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H -pyrimido[4,5-d]azepin-4-yl]-amine;

N 4 -(3-Chloro-4-trifluoromethyl-phenyl)-N 2 ,N 2 -dimethyl-7-(3-trifluoro-methyl-pyridin-2-yl) -6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;