HYDROXY-SUBSTITUTED ARYL SULFAMIDE DERIVATIVES AND METHODS OF THEIR USE

1 . A compound of formula I:

or a tautomer or pharmaceutically acceptable salt thereof;

wherein:

n is an integer from 0 to 4;

m is an integer from 1 to 6;

X is —CH 2 —;

R 1 is, independently at each occurrence, H, alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or arylamido; wherein each aryl or heteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido is independently substituted with 0-3 alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido groups;

R 2 is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl;

R 3 and R 4 are, independently, H, alkyl, arylalkyl or heteroarylmethyl, wherein each of alkyl, arylalkyl or heteroarylmethyl are indepentyl substituted with 0-3 alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided that neither R 3 or R 4 contain an aminoalkyl group;

represents an S-isomer, R-isomer or racemate; and

wherein 1-3 carbon atoms in ring A may optionally be replaced with N.

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

3 . The compound of claim 1 , wherein R 2 is:

wherein,

each R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from the group consisting of H, alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl substituted, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, or arylamido.

4 . The compound of claim 3 , wherein R 9 is F.

5 . The compound of claim 4 , wherein R 5 , R 6 , R 7 and R 8 are H.

6 . The compound of claim 3 , wherein R 5 , R 6 , R 7 , R 8 and R 9 are H, halo, alkyl or alkoxy.

7 . The compound of claim 1 , wherein R 3 is methyl.

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

9 . The compound of claim 1 , wherein m is an integer from 2 to 6.

10 . The compound of claim 1 , wherein m is 2.

11 . The compound of claim 1 , wherein ring A comprises all carbon atoms.

12 . The compound of claim 1 , wherein R 2 is pyridinyl, methyl-pyridinyl, ethyl-pyridinyl, methoxy-pyridinyl, or quinolinyl.

13 . The compound of claim 1 , wherein R 2 is phenyl, fluoro-phenyl, difluoro-phenyl, trifluoro-phenyl, chloro-phenyl, fluoro-chloro-phenyl, bromo-phenyl, trifluoromethyl-phenyl trifluoromethoxy-phenyl, methyl-fluoro-phenyl, methoxy-fluoro-phenyl, or naphthyl.

14 . The compound of claim 1 , wherein represents an S-isomer.

15 . The compound of claim 1 , wherein represents an R-isomer.

16 . The compound of claim 3 , wherein:

R 1 is H;

R 9 is F;

R 5 , R 6 , R 7 and R 3 are H;

R 3 is methyl;

R 4 is H;

m is 2; and

represents an S-isomer.

17 . The compound of claim 1 , selected from the group consisting of:

18 . The compound of claim 1 , selected from the group consisting of:

1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;

(2R)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

3-fluoro-4-{3-[(3S)-3-hydroxy-4-(methylamino)butyl]-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl}phenol:

4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)pentan-2-ol;

(2S)-1-amino-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;

(2S)-5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)pentan-2-ol;

(2R)-5-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)pentan-2-ol;

4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)butan-2-ol;

1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;

4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino)butan-2-ol;

1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;

1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;

4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol;

(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol;

(2S)-1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;

(2R)-1-(dimethylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;

(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino)butan-2-ol;

(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(isopropylamino)butan-2-ol;

(2S)-1-(cyclopropylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;

(2S)-1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;

(2R)-1-(tert-butylamino)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)butan-2-ol;

(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)butan-2-ol;

(2R)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(ethylamino)butan-2-ol;

(2S)-1-(cyclopropylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;

(2S)-1-(cyclopropylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;

(2S)-1-(cyclopropylamino)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;

(2S)-1-(cyclopropylamino)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;

(2S)-1-(cyclopropylamino)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;

(2S)-1-(cyclopropylamino)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;

(2S)-4-(2,2-dioxido-3-phenyl-2,1,3-benzothiadiazol-1(3H)-yl)-1-(methylamino)butan-2-ol;

(2S)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2S)-4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2S)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2S)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2S)-4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2S)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;

(2S)-4-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2S)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2R)-4-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2R)-4-[3-(3,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2R)-4-[3-(2,5-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2R)-4-[3-(2,4-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2R)-4-[3-(4-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2R)-1-(methylamino)-4-[3-(2-methylphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;

(2R)-4-[3-(2-chlorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2R)-4-[3-(3-methoxyphenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(methylamino)butan-2-ol;

(2S)-1-(cyclobutylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;

(2S)-1-(cyclopentylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;

(2S)-1-(cyclohexylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol;

(2S)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]-1-(isopropylamino)butan-2-ol;

(2S)-1-(ethylamino)-4-[3-(2-fluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]butan-2-ol; and

pharmaceutically acceptable salts thereof.

19 . The compound of claim 1 ,

wherein said pharmaceutically acceptable salt is a hydrochloride or dihydrochloride.

20 . A composition, comprising:

a. at least one compound of formula I:

or a tautomer or pharmaceutically acceptable salt thereof;

wherein:

n is an integer from 0 to 4;

m is an integer from 1 to 6;

X is —CH 2 —;

R 1 is, independently at each occurrence, H, alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or arylamido; wherein each aryl or heteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido is independently substituted with 0-3 alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido groups;

R 2 is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl;

R 3 and R 4 are, independently, H, alkyl, arylalkyl or heteroarylmethyl, wherein each of alkyl, arylalkyl or heteroarylmethyl are indepentyl substituted with 0-3 alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided that neither R 3 or R 4 contain an aminoalkyl group;

represents an S-isomer, R-isomer or racemate; and

wherein 1-3 carbon atoms in ring A may optionally be replaced with N; and

b. at least one pharmaceutically acceptable carrier.

21 . A method for treating or preventing a condition selected from the group consisting of a vasomotor symptom, sexual dysfunction, gastrointestinal disorder, genitourinary disorder, chronic fatigue syndrome, fibromyalgia syndrome, depression disorder, endogenous behavioral disorder, cognitive disorder, diabetic neuropathy, pain, and combinations thereof in a subject in need thereof, comprising the step of:

administering to said subject an effective amount of a compound of formula I:

or a tautomer or pharmaceutically acceptable salt thereof;

wherein:

n is an integer from 0 to 4;

m is an integer from 1 to 6;

X is —CH 2 —;

R 1 is, independently at each occurrence, H, alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, aryl, heteroaryl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide alkylamido, or arylamido; wherein each aryl or heteroaryl is independently substituted with 0-3 alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups; and each arylsulfonamide or arylamido is independently substituted with 0-3 alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, or alkylamido groups;

R 2 is aryl or heteroaryl substituted with 0-4 alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, alkynyl, alkylsulfoxide, alkylsulfone, alkylsulfonamide, arylsulfonamide, alkylamido, arylamido, or aryl or heteroaryl optionally substituted with alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl;

R 3 and R 4 are, independently, H, alkyl, arylalkyl or heteroarylmethyl, wherein each of alkyl, arylalkyl or heteroarylmethyl are indepentyl substituted with 0-3 alkyl, alkoxy, halo, CF 3 , OCF 3 , hydroxy, alkanoyloxy, nitro, nitrile, alkenyl, or alkynyl groups, provided that neither R 3 or R 4 contain an aminoalkyl group;

represents an S-isomer, R-isomer or racemate; and

wherein 1-3 carbon atoms in ring A may optionally be replaced with N.

22 . The method of claim 21 ,

wherein said vasomotor symptom is hot flush.

23 . The method of claim 21 ,

wherein said sexual dysfunction is desire-related or arousal-related.

24 . The method of claim 21 ,

wherein said gastrointestinal disorder or said genitourinary disorder is stress incontinence or urge incontinence.

25 . The method of claim 21 ,

wherein said condition is chronic fatigue syndrome or fibromyalgia syndrome.

26 . The method of claim 20 ,

wherein said condition is a depression disorder selected from the group consisting of major depressive disorder, generalized anxiety disorder, panic disorder, attention deficit disorder with or without hyperactivity, sleep disturbance, social phobia, and combinations thereof.

27 . The method of claim 21 ,

wherein said condition is diabetic neuropathy.

28 . The method of claim 21 ,

wherein said condition is pain.

29 . The method of claim 28 ,

wherein said pain is acute centralized pain, acute peripheral pain, or a combination thereof.

30 . The method of claim 28 ,

wherein said pain is chronic centralized pain, chronic peripheral pain, or a combination thereof.

31 . The method of claim 28 ,

wherein said pain is neuropathic pain, visceral pain, musculoskeletal pain, bony pain, cancer pain, inflammatory pain, or a combination thereof.

32 . The method of claim 31 ,

wherein said neuropathic pain is associated with diabetes, post traumatic pain of amputation, lower back pain, cancer, chemical injury, toxins, major surgery, peripheral nerve damage due to traumatic injury compression, post-herpetic neuralgia, trigeminal neuralgia, lumbar or cervical radiculopathies, fibromyalgia, glossopharyngeal neuralgia, reflex sympathetic dystrophy, casualgia, thalamic syndrome, nerve root avulsion, reflex sympathetic dystrophy or post thoracotomy pain, nutritional deficiencies, viral infection, bacterial infection, metastatic infiltration, adiposis dolorosa, burns, central pain conditions related to thalamic conditions, or a combination thereof.

33 . The method of claim 32 ,

wherein said neuropathic pain is post-herpetic neuralgia.

34 . The method of claim 31 ,

wherein said visceral pain is associated with ulcerative colitis, irritable bowel syndrome, irritable bladder, Crohn's disease, rheumatologic (arthralgias), tumors, gastritis, pancreatitis, infections of the organs, biliary tract disorders, or a combination thereof.

35 . The method of claim 28 ,

wherein said subject is female; and

the pain is female-specific pain.