JP2008531690A5

JP2008531690A5 -

Info

Publication number: JP2008531690A5
Application number: JP2007558085A
Authority: JP
Filing date: 2006-02-24
Publication date: 2009-04-16

Claims

Compounds of formula (I), or pharmaceutically acceptable salts, solvates or prodrugs thereof, and stereoisomers and tautomers thereof:

Wherein W, Z and X are each CR ⁴ and Y is CR ^{4 "} ;
L is-(CR ⁵ = CR ⁶ )-or-(C≡C)-;
R ¹ is hydrogen, C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkoxy, amino C ₁ -C ₆ alkoxy, substituted amino C ₁ -C ₆ alkoxy, di C ₁ -C ₆ alkylamino C ₁ -C ₆ alkoxy, cycloalkyl C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylarylamino, aryl C ₁ -C ₆ alkyloxy, amino, aryl, aryl C ₁ -C ₆ alkyl, substituted sulfonyl, sulfanyl, aminosulfonyl, arylsulfonyl, azido, carboxy, carbamoyl, cyano, cycloheteroalkyl, di C ₁ -C ₆ alkylamino, halo, heteroaryl Bicycloaryl or bicycloheteroaryl substituted by aryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro, thio or oxo;
R ³ is CR ^{6 ′} R ⁷ R ⁸ ;
Each R ⁴ is independently hydrogen, C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkoxy, amino C ₁ -C ₆ alkoxy, substituted amino C ₁ -C ₆ alkoxy, di C ₁ -C ₆ alkylamino C ₁ -C ₆ alkoxy, cycloalkyl C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkylarylamino, aryl C ₁ -C ₆ alkyloxy, amino, aryl, aryl C ₁ -C ₆ alkyl, substituted sulfonyl, sulfanyl, aminosulfonyl, arylsulfonyl, azido, carboxy, carbamoyl, cyano, cycloheteroalkyl, di C ₁ -C ₆ alkylamino , Halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thio;
R ^{4 "} is substituted alkyl, methyl, halo, substituted sulfonyl, alkoxy, or amino;
Each of R ⁵ and R ⁶ is independently H, halo, or C ₁ -C ₆ alkyl; and
R ^{6 ′} is hydrogen, halo or C ₁ -C ₆ alkyl; each of R ⁷ and R ⁸ is independently halo or C ₁ -C ₆ alkyl; or R ⁷ and R ⁸ are together To form a C ₃ -C ₈ cycloalkyl ring. ).

The compound of claim 1, wherein each of R ⁵ and R ⁶ is independently H, halo, or C ₁ -C ₆ alkyl.

The compound of claim 1, wherein R ¹ is:

Wherein each of A ¹ , A ² , A ³ , A ⁴ , B ¹ and B ² is independently CR ^{4 ′} or N; and each R ^{4 ′} is independently H, C ₁ -C ₆ alkyl, halo, or hydroxy C ₁ -C ₆ alkyl).

The compound of claim 1, wherein R ¹ is:

Wherein each of A ⁵ and A ⁸ is independently CR ^{4 ′} R ^{4 ′} , NR ^{4 ′} , O, S, SO or SO ₂ ; each of A ⁶ and A ⁷ is independently CR ^{4 ′} , N, NR ^{4 ′} , CR ^{4 ′} R ^{4 ′} or CO; each of B ³ and B ⁴ is independently CR ^{4 ′} or N; when R ^{4 ′} is bound to C When R ^{4 ′} is H, C ₁ -C ₆ alkyl, halo, or hydroxy C ₁ -C ₆ alkyl, and R ^{4 ′} is attached to N, then R ^{4 ′} is H or C ₁ -C ₆ alkyl; and the dotted bond represents one single bond or one double bond).

The compound of claim 1, wherein R ¹ is:

Wherein each of A ⁹ , A ¹⁰ and A ¹¹ is independently CR ^{4 ′} , CR ^{4 ′} R ^{4 ′} , CO, CS, N, NR ^{4 ′} , 0, S, SO or SO ₂ Each of B ⁵ and B ⁶ is independently CR ^{4 ′} or N;
When R ^{4 ′} is bonded to C, R ^{4 ′} is H, C ₁ -C ₆ alkyl, halo, or hydroxy C ₁ -C ₆ alkyl, and when R ^{4 ′} is bonded to N, R ^{4 ′} is H or C ₁ -C ₆ alkyl;
Each dotted bond independently represents one single bond or one double bond. ).

The compound of claim 1, wherein R ¹ is:

Wherein each ring is optionally substituted with one or more R ^{4 ′} , where when the ring carbon atom is substituted with R ^{4 ′} , the R ^{4 ′} is C ₁ -C ₆ alkyl, halo, Or hydroxy C ₁ -C ₆ alkyl, and when the ring —NH— group N is substituted with R ^{4 ′} , then R ^{4 ′} is C ₁ -C ₆ alkyl).

The compound of claim 1, wherein R ¹ is:

The compound of claim 1, wherein R ¹ is:

Wherein each of A ¹ , A ² , A ³ , A ⁴ , B ¹ and B ² is independently CH or N; and R ^{4 ′} is C ₁ -C ₆ alkyl or hydroxy C ₁ -C ₆ alkyl).

The compound of claim 1, wherein R ¹ is:

Wherein each of A ⁵ and A ⁸ is independently CH ₂ , CHMe, NH, NMe, O, S, SO or SO ₂ ;
Each of B ³ and B ⁴ is independently CR ^{4 ′} or N;
R ^{4 ′} is C ₁ -C ₆ alkyl or hydroxy C ₁ -C ₆ alkyl. ).

The compound of claim 1, wherein R ¹ is:

Wherein each of A ⁹ , A ¹⁰ and A ¹¹ is independently CH, CH ₂ , N, NH, 0 or S; each of B ⁵ and B ⁶ is independently CH or N Yes; R ^{4 ′} is H, C ₁ -C ₆ alkyl or hydroxy C ₁ -C ₆ alkyl; each dotted bond independently represents one single bond or one double bond. .

The compound of claim 1, wherein R ¹ is:

(Wherein R ^{4 ′} is H, C ₁ -C ₆ alkyl, halo or hydroxy C ₁ -C ₆ alkyl).

R ^{4 'is} a hydroxy C ₁ -C ₆ alkyl, any one compound according to claim 9-11.

R ^{4 'is,} - (CH ₂₎ be _n -OH; and, n is selected from 1-3, wherein compound of claim 12.

R ^{4 'is} a CH ₂ OH, 13. A compound according.

The compound of claim 1, wherein R ¹ is:

(Wherein the N of the -NH- group each ring optionally ^'substituted with, where R ^4' R ⁴ is C ₁ -C ₆ alkyl.).

The compound of claim 1, wherein R ^{4 "} is methyl, chloro, trifluoromethyl, fluoro or SO ₂ Me.

The compound of claim 1, wherein each R ⁴ is H.

The compound of claim 1, wherein L is-(CR ⁵ = CR ⁶ )-; and wherein each of R ⁵ and R ⁶ is independently H, halo or C ₁ -C ₆ alkyl. .

2. The compound of claim 1, wherein L is —CH═CH—.

2. The compound according to claim 1, wherein L is —C≡C—.

R ³ is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, compound of claim 1.

R ³ is CF _3, A compound according to claim 1 wherein.

The compound according to claim 1, wherein R ³ is t-Bu.

Wherein each of W, Z and X is CR ⁴ and Y is CR ^{4 "} ;
L is-(CR ⁵ = CR ⁶ )-or-(C≡C)-;
R ¹ is a substituted or unsubstituted formula:

Wherein each of B ³ and B ⁴ is independently CR ^{4 ′} or N; each of A ⁵ and A ⁸ is independently CR ^{4 ′} R ^{4 ′} , NR ^{4 ′} , 0, S , be a SO or SO _2; R ^{4 'is} C ₁ -C ₆ alkyl or a hydroxyl C ₁ -C ₆ alkyl).;
R ³ is CR ^{6 ′} R ⁷ R ⁸ ;
R ⁴ is independently hydrogen, C ₁ -C ₆ alkyl, hydroxyl C ₁ -C ₆ alkyl, C ₂ -C ₆ acyl, C ₂ -C ₆ acylamino, C ₁ -C ₆ alkylamino, C _1- C ₆ alkylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkyl arylamino, aryl C ₁ -C ₆ alkyloxy, amino, aryl, aryl C ₁ -C ₆ alkyl, substituted sulfonyl, sulfanyl, aminosulfonyl, arylsulfonyl, azido, carboxy, carbamoyl, cyano, cycloheteroalkyl, di C ₁ -C ₆ alkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, a nitro or thio ;
R ^{4 "} is substituted alkyl, methyl, halo, substituted sulfonyl, alkoxy or amino;
Each of R ⁵ and R ⁶ is independently H, halo, C ₁ -C ₆ alkyl, or hydroxyl C ₁ -C ₆ alkyl;
R ^{6 ′} is hydrogen, halo, C ₁ -C ₆ alkyl or hydroxyl C ₁ -C ₆ alkyl; each of R ⁷ and R ⁸ is independently halo, C ₁ -C ₆ alkyl or hydroxyl C ₁ be -C ₆ alkyl; or, R ⁷ and R ⁸ together form a C ₃ -C ₈ cycloalkyl ring substituted or unsubstituted. ).

R ^{4 'is} a hydroxyl C ₁ -C ₆ alkyl, claim 24 A compound according.

R ^{4 'is} - (CH ₂₎ be _n -OH; and wherein n is selected from 1-6, 24. A compound according.

R ^{4 'is} a CH ₂ OH, claim 24 A compound according.

R ^{4 "is} methyl, chloro, trifluoromethyl, fluoro or SO ₂ Me, claim 24 A compound according.

Each R ⁴ is H, claim 24 A compound according.

R ¹ is the following formula, according to claim 24, wherein the compound:

(Wherein the N of each ring —NH— group is optionally substituted with R ^{4 ′} , where R ^{4 ′} is C ₁ -C ₆ alkyl).

R ¹ is the following formula, according to claim 24, wherein the compound:

.

25. The compound of claim 24, which is of formula (IV) or (V):

.

Wherein each of W, Z and X is CR ⁴ and Y is CR ^{4 "} ;
L is substituted or unsubstituted — (CR ⁵ ═CR ⁶ ) — or — (C≡C) —;
R ¹ is substituted or unsubstituted:

And
Wherein each of A ⁹ , A ¹⁰ and A ¹¹ is independently CR ^{4 ′} , CR ^{4 ′} R ^{4 ′} , CO, CS, N, NR ^{4 ′} , O, S, SO or SO ₂ ; Each of B ⁵ and B ⁶ is independently CR ^{4 ′} or N;
Each R ^{4 ′} is independently H, substituted or unsubstituted C ₁ -C ₆ alkyl or aryl;
Each dotted bond represents one single bond or one double bond;
R ³ is CR ^{6 ′} R ⁷ R ⁸ ;
Each of R ⁴ is independently hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, acyl, acylamino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkyl aryl amino, aryl C ₁ -C ₆ alkyloxy, amino, aryl, aryl C ₁ -C ₆ alkyl, substituted sulfonyl, sulfanyl, aminosulfonyl, arylsulfonyl, azido, Is carboxy, carbamoyl, cyano, cycloheteroalkyl, diC ₁ -C ₆ alkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thio;
R ^{4 "} is substituted alkyl, methyl, halo, substituted sulfonyl, alkoxy, or amino;
Each of R ⁵ and R ⁶ is independently H, halo, or substituted or unsubstituted C ₁ -C ₆ alkyl; and
R ^{6 ′} is hydrogen, halo, or substituted or unsubstituted C ₁ -C ₆ alkyl;
Each of R ⁷ and R ⁸ is independently halo, or substituted or unsubstituted C ₁ -C ₆ alkyl; or
R ⁷ and R ⁸ together form a substituted or unsubstituted C ₃ -C ₈ cycloalkyl ring. ).

R ^{4 "is} methyl, chloro, trifluoromethyl, fluoro or SO ₂ Me, claim 33 A compound according.

Each R ⁴ is H, claim 33 A compound according.

34. The compound of claim 33, wherein R ¹ is a substituted or unsubstituted formula:

Compounds of formula (VI), or pharmaceutically acceptable salts, solvates or prodrugs thereof, and stereoisomers and tautomers thereof:

Wherein each of W, Z and X is CR ⁴ and Y is CR ^{4 "} ;
Each of B ⁷ , B ⁸ and B ⁹ is independently N or CR ⁴ ;
L is substituted or unsubstituted — (CR ⁵ ═CR ⁶ ) — or — (C≡C) —;
R ³ is CR ^{6 ′} R ⁷ R ⁸ ;
Each of R ⁴ is independently hydrogen, substituted or unsubstituted C ₁ -C ₆ alkyl, acyl, acylamino, C ₁ -C ₆ alkylamino, C ₁ -C ₆ alkylthio, C ₁ -C ₆ alkoxy, C ₁ -C ₆ alkoxycarbonyl, C ₁ -C ₆ alkyl aryl amino, aryl C ₁ -C ₆ alkyloxy, amino, aryl, aryl C ₁ -C ₆ alkyl, substituted sulfonyl, sulfanyl, aminosulfonyl, arylsulfonyl, azido, Is carboxy, carbamoyl, cyano, cycloheteroalkyl, diC ₁ -C ₆ alkylamino, halo, heteroaryloxy, heteroaryl, heteroalkyl, hydroxyl, nitro or thio;
R ^{4 "} is substituted alkyl, methyl, halo, substituted sulfonyl, alkoxy, or amino;
Each of R ⁵ and R ⁶ is independently H, halo, or substituted or unsubstituted C ₁ -C ₆ alkyl;
R ^{4 ′} is substituted or unsubstituted C ₁ -C ₆ alkyl; and
R ^{6 ′} is hydrogen, halo or substituted or unsubstituted C ₁ -C ₆ alkyl;
Each of R ⁷ and R ⁸ is independently halo or substituted or unsubstituted C ₁ -C ₆ alkyl; or R ⁷ and R ⁸ together are substituted or unsubstituted C ₃ -C ₈ cyclo An alkyl ring is formed. ).

R ^{4 "is} methyl, chloro, trifluoromethyl, fluoro or SO ₂ Me, claim 37 A compound according.

Each R ⁴ is H, 37. A compound according.

R ^{4 'is} a hydroxyl-substituted C ₁ -C ₆ alkyl, claim 37 A compound according.

R ^{4 'is} - (CH ₂₎ be _n -OH; and wherein n is selected from 1-6, Claim 37 A compound according.

R ^{4 'is} a CH ₂ OH, 37. A compound according.

43. A pharmaceutical composition comprising a compound according to any one of claims 1-42 or a pharmaceutically acceptable salt, solvate or composition thereof.

44. The pharmaceutical composition according to claim 43, further comprising a pharmaceutically acceptable carrier, wherein the carrier is a parenteral carrier, an oral or topical carrier.

Contacting a compound of formula R ³ -L-Cy-COCl with a compound of formula R ¹ R ² NH under conditions sufficient to form a compound of any one of claims 1-42. 43. A process for preparing a compound according to any one of claims 1 to 42, wherein Cy is aryl or heteroaryl; and R ² is H.

43. A compound according to any one of claims 1-42 or a pharmaceutically acceptable salt or solvate thereof for use as a medicament or medicament.

45. The pharmaceutical composition according to claim 43 or 44, wherein the disease to be treated is a disease for which a VR1 antagonist is indicated.

The disease is acute cerebral ischemia, pain, chronic pain, acute pain, nociceptive pain, neuropathic pain, inflammatory pain, postherpetic neuralgia, neuropathy, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve Injury, rheumatoid arthritis pain, osteoarthritic pain, burns, back pain, visceral pain, cancer pain, toothache, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity Pelvic hypersensitivity, pelvic pain, menstrual pain; bladder diseases including incontinence, dysuria, renal colic and cystitis; inflammation including burns, rheumatoid arthritis and osteoarthritis; stroke, post-stroke pain and multiple sclerosis Neurodegenerative diseases, including asthma; lung disease including asthma, cough, chronic obstructive pulmonary disease (COPD) and bronchoconstriction; gastroesophageal reflux disease (GERD), difficulty swallowing, ulcers, irritable bowel syndrome (IBS), inflammation Reproductive bowel disease (IBD), colitis and Crohn's disease No gastrointestinal disorders; ischemia including cerebrovascular ischemia; emesis, including emesis cancer chemotherapy-induced, and is selected from the group consisting of obesity, the pharmaceutical composition of claim 47.

43. An effective amount of a compound according to any one of claims 1 to 42, or a pharmaceutically acceptable salt, solvate or composition thereof for use in the treatment of a disease for which a VR1 antagonist is indicated.

43. A combination of the compound according to any one of claims 1-42 and another pharmacologically active substance.

2. The compound of claim 1, wherein the compound is selected from the following group:

.

2. The compound of claim 1, wherein the compound is selected from the following group:
(E) -N- (isoquinolin-5-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -N- (3,4-Dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -2-methyl-4- (3,3,3-trifluoroprop-1- Enyl) benzamide;
(Z) -N- (3,4-Dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -2-methoxy-4- (3,3,3-trifluoroprop-1- Enyl) benzamide;
(Z) -N- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methoxy-4- (3,3,3-trifluoroprop-1-enyl) benzamide ;
(E) -N- (3,4-Dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -2-methoxy-4- (3,3,3-trifluoroprop-1- Enyl) benzamide;
(E) -N- (2,3-Dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methoxy-4- (3,3,3-trifluoroprop-1-enyl) benzamide ;
4- (cyclopropylethynyl) -N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -2-methylbenzamide;
4- (cyclopentylethynyl) -N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -2-methylbenzamide;
4- (cyclopentylethynyl) -2-fluoro-N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) benzamide;
4- (cyclopropylethynyl) -2-fluoro-N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) benzamide;
N- (3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -4- (3,3-dimethylbut-1-ynyl) -2-methoxybenzamide;
4- (cyclopropylethynyl) -2,6-difluoro-N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) benzamide;
4- (cyclopropylethynyl) -N- (3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -2,6-difluorobenzamide;
(E) -N- (3- (Hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -2-methyl-4- (3,3,3 -Trifluoroprop-1-enyl) benzamide;
4- (cyclopentylethynyl) -N- (2-((cyclopropylmethoxy) methyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methylbenzamide;
N- (2-((Cyclopropylmethoxy) methyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -4- (3,3-dimethylbut-1-ynyl)- 2-methylbenzamide;
(E) -N- (3,4-Dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -2-fluoro-4- (3,3,3-trifluoroprop-1- Enyl) benzamide;
(Z) -N- (3,4-Dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -2-fluoro-4- (3,3,3-trifluoroprop-1- Enyl) benzamide;
N- (3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -4- (3,3-dimethylbut-1-ynyl) -2-fluorobenzamide;
4- (3,3-Dimethylbut-1-ynyl) -2-fluoro-N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazine-7- Il) benzamide;
4- (cyclopentylethynyl) -N- (3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -2-methylbenzamide;
4- (cyclopentylethynyl) -N- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methylbenzamide;
4- (cyclopentylethynyl) -N- (2- (hydroxymethyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methylbenzamide;
(E) -N- (2,3-Dihydrobenzo [b] [1,4] dioxin-6-yl) -2-fluoro-4- (3,3,3-trifluoroprop-1-enyl) benzamide ;
4- (cyclopropylethynyl) -N- (3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -2-fluorobenzamide;
(E) -2-Fluoro-N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -4- (3,3,3 -Trifluoroprop-1-enyl) benzamide;
4- (cyclopropylethynyl) -N- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2-fluorobenzamide;
2-chloro-N- (3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -4- (3,3-dimethylbut-1-ynyl) benzamide;
2-chloro-4- (cyclopropylethynyl) -N- (3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) benzamide;
(E) -2-Chloro-N- (3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -4- (3,3,3-trifluoroprop-1- Enyl) benzamide;
(E) -2-Fluoro-N- (2- (hydroxymethyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -4- (3,3,3-trifluoro Prop-1-enyl) benzamide;
4- (cyclopropylethynyl) -2-fluoro-N- (2- (hydroxymethyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) benzamide;
4- (cyclopropylethynyl) -N- (2- (hydroxymethyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methylbenzamide;
4- (cyclopropylethynyl) -N- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methylbenzamide;
4- (cyclopropylethynyl) -N- (3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -2-methylbenzamide;
4- (3,3-Dimethylbut-1-ynyl) -2-fluoro-N- (2- (hydroxymethyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) benzamide ;
N- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -4- (3,3-dimethylbut-1-ynyl) -2-fluorobenzamide;
2-chloro-4- (cyclopropylethynyl) -N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) benzamide;
(E) -2-Chloro-N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -4- (3,3,3 -Trifluoroprop-1-enyl) benzamide;
2-Chloro-4- (3,3-dimethylbut-1-ynyl) -N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazine-7- Il) benzamide;
4- (cyclopentylethynyl) -N- (2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2- (methylsulfonyl) benzamide;
(E) -2-Fluoro-N- (isoquinolin-5-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide;
2-chloro-4- (3,3-dimethylbut-1-ynyl) -N- (isoquinolin-5-yl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -2-methyl-N- (2-methylbenzo [d] thiazol-5-yl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -N- (isoquinolin-5-yl) -2-methylbenzamide;
2-chloro-4- (3,3-dimethylbut-1-ynyl) -N- (quinolin-3-yl) benzamide;
2-chloro-4- (3,3-dimethylbut-1-ynyl) -N- (2-methylbenzo [d] thiazol-5-yl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -2,6-difluoro-N- (isoquinolin-5-yl) benzamide;
4- (3,3-Dimethylbut-1-ynyl) -N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -2 -Methylbenzamide;
4- (3,3-Dimethylbut-1-ynyl) -2,6-difluoro-N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazine- 7-yl) benzamide;
(R) -4- (Cyclopropylethynyl) -2-fluoro-N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) benzamide ;
(R) -4- (3,3-Dimethylbut-1-ynyl) -2-fluoro-N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] Oxazin-7-yl) benzamide;
(S) -4- (Cyclopropylethynyl) -2-fluoro-N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) benzamide ;
(S) -4- (3,3-Dimethylbut-1-ynyl) -2-fluoro-N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] Oxazin-7-yl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N- (2-methylbenzo [d] thiazol-5-yl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N- (quinolin-3-yl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N- (isoquinolin-5-yl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -2-fluoro-N- (isoquinolin-5-yl) -3-methoxybenzamide;
(E) -2-Fluoro-N- (2-methylbenzo [d] thiazol-5-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -2-Fluoro-N- (quinolin-3-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -2,6-difluoro-N- (quinolin-3-yl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -2,6-difluoro-N- (2-methylbenzo [d] thiazol-5-yl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -2-methyl-N- (quinolin-3-yl) benzamide;
(S) -2-Chloro-4- (3,3-dimethylbut-1-ynyl) -N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] Oxazin-7-yl) benzamide;
(R) -2-Chloro-4- (3,3-dimethylbut-1-ynyl) -N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] Oxazin-7-yl) benzamide;
(R) -4- (3,3-Dimethylbut-1-ynyl) -N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazine-7- Yl) -2-methylbenzamide;
(E) -N- (2- (hydroxymethyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methyl-4- (3,3,3-trifluoro Prop-1-enyl) benzamide;
4- (3,3-Dimethylbut-1-ynyl) -N- (2- (hydroxymethyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methylbenzamide ;
(E) -2-Methyl-N- (quinolin-3-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -2-Methyl-N- (2-methylbenzo [d] thiazol-5-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -N- (3-hydroxy-2,3,4,5-tetrahydrobenzo [b] [1,4] oxazepin-8-yl) -2-methyl-4- (3,3,3-tri Fluoroprop-1-enyl) benzamide;
(E) -N- (2,3-Dihydrobenzo [b] [1,4] dioxin-6-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide ;
2-Chloro-4- (3,3-dimethylbut-1-ynyl) -5-fluoro-N- (2- (hydroxymethyl) -2,3-dihydrobenzo [b] [1,4] dioxin-6 -Yl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -N- (1H-indol-7-yl) -2-methylbenzamide;
(S, E) -2-Fluoro-N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -4- (3,3 , 3-trifluoroprop-1-enyl) benzamide;
(S) -4- (3,3-Dimethylbut-1-ynyl) -N- (3- (hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazine-7- Yl) -2-methylbenzamide;
(S, E) -N- (3- (Hydroxymethyl) -3,4-dihydro-2H-benzo [b] [1,4] oxazin-7-yl) -2-methyl-4- (3,3 , 3-trifluoroprop-1-enyl) benzamide;
(E) -2-Methyl-N- (3-methylisoquinolin-5-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -N- (2- (hydroxymethyl) benzo [d] thiazol-5-yl) -2-methylbenzamide;
N- (benzo [d] thiazol-5-yl) -4- (3,3-dimethylbut-1-ynyl) -2-methylbenzamide;
N- (1-chloroisoquinolin-5-yl) -4- (3,3-dimethylbut-1-ynyl) -2-methylbenzamide;
(E) -N- (1-chloroisoquinolin-5-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -4- (3,3-Dimethylbut-1-enyl) -2-methyl-N- (quinolin-3-yl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -2-methyl-N- (1H-pyrrolo [2,3-b] pyridin-5-yl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -N- (1,3-dioxoisoindoline-5-yl) -2-methylbenzamide;
N- (1H-benzo [d] imidazol-5-yl) -4- (3,3-dimethylbut-1-ynyl) -2-methylbenzamide;
4- (3,3-dimethylbut-1-ynyl) -2-methyl-N- (2-methyl-1H-benzo [d] imidazol-5-yl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -N- (7- (hydroxymethyl) quinolin-3-yl) -2-methylbenzamide;
4- (3,3-dimethylbut-1-ynyl) -2-methyl-N- (2-oxo-2,3-dihydrobenzo [d] oxazol-6-yl) benzamide;
4- (3,3-dimethylbut-1-ynyl) -N- (2- (hydroxymethyl) -3H-imidazo [4,5-b] pyridin-6-yl) -2-methylbenzamide;
(E) -2-Methyl-N- (quinolin-8-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -2-Methyl-N- (quinolin-6-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -2-Methyl-N- (quinolin-5-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -2-Methyl-N- (quinolin-7-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -N- (2- (hydroxymethyl) benzo [d] thiazol-5-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -N- (3- (hydroxymethyl) quinolin-7-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -2-Methyl-N- (5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide ;
(E) -2-Methyl-N- (1H-pyrrolo [2,3-b] pyridin-5-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -N- (3- (hydroxymethyl) -1H-indazol-6-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -N- (1H-indol-6-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -N- (3- (Hydroxymethyl) -3,4-dihydro-2H-pyrido [3,2-b] [1,4] oxazin-7-yl) -2-methyl-4- (3 , 3,3-trifluoroprop-1-enyl) benzamide;
(E) -N- (3- (hydroxymethyl) -1H-indazol-5-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -N- (2- (hydroxymethyl) -1H-indol-5-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -N- (2,3-dihydro-1H-inden-4-yl) -2-methyl-4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -2-Methyl-N- (5,6,7,8-tetrahydronaphthalen-1-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide;
(E) -2-Methyl-N- (2-methylquinolin-6-yl) -4- (3,3,3-trifluoroprop-1-enyl) benzamide.

53. A pharmaceutical composition comprising a compound according to claim 51 or 52, or a pharmaceutically acceptable salt, solvate or composition thereof.

Contacting a compound of formula R ³ -L-Cy-COCl with a compound of formula R ¹ R ² NH under conditions sufficient to form a compound of claim 51 or 52, wherein 53. The method for producing a compound according to claim 51 or 52, wherein Cy is aryl or heteroaryl; and R ² is H.

53. A compound according to claim 51 or 52 or a pharmaceutically acceptable salt or solvate thereof for use as a medicament or medicament.

54. An effective amount of a compound of claim 51 or 52, or a pharmaceutically acceptable salt, solvate or composition thereof, for use in the treatment of a disease for which a VR1 antagonist is indicated.

53. A combination of the compound of claim 51 or 52 and another pharmacologically active substance.