ZA200409527B - Pyranoindazoles and their use for the treatment of glaucoma. - Google Patents

Description

PYRANOINDAZOLES AND THEIR USE FOR THE TREATMENT OF

GLAUCOMA

This application is a continuation-in-part of PCT application Serial No. 5s PCT/US02/16861, filed May 30, 2002, which claims the benefit of U.S. Provisional Patent

Application No. 60/295.429 filed June 1, 2001, both of which are Mecomoraied in their entirety by reference herein.

BACKGROUND OF THE INVENTION

’ The present invention relates to various pyranoindazoles. These novel compounds are useful for lowering and controlling normal or elevated intraocular pressure (IOP) and for treating glaucoma.

The disease state referred to as glaucoma is characterized by a permanent loss of 1s visual function due to irreversible damage to the optic nerve. The several morphologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease. Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be at high risk for the eventual development of the visual loss associated with glaucoma. If glaucoma or ocular hypertension is detected early and treated promptly with medications that effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated.” Drug therapies that have proven to be effective for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents 2s that increase the outflow facility. Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.

There are some individuals who do not respond well when treated with certain existing glaucoma therapies. There is, therefore, a need for other topical therapeutic agents that control IOP.

Serotonergic 5-HT,, agonists have been reported as being neuroprotective in animal models and many of these agents have been evaluated for the treatment of acute stroke among other indications. This class of compounds has been mentioned for the treatment of glaucoma (lowering and controlling IOP), see e.g., WO 98/18458 (DeSantis, et al.) and EP 0771563A2 (Mano, et al.). Osborne, et al. (Ophthalmologica, Vol. 210:308-314, 1996) teach that 8-hydroxydipropylaminotetralin (8-OH-DPAT) (a 5-HT,, agonist) reduces IOP in rabbits. Wang, et al. (Current Eye Research, Vol. 16(8):769-775, August 1997, and 1VOS,

Vol. 39(4), S488, March, 1998) indicate that 5-methylurapidil, an a,, antagonist and 5-HT,, agonist lowers IOP in the monkey, but due to its 0,5 receptor activity. Also, 5-HT,, antagonists are disclosed as being useful for the treatment of glaucoma (elevated 10P) (eg.

WO 92/0338, McLees). Furthermore, DeSai, et al. (WO 97/35579) and Macor, et al. (U.S. 15s 5,578,612) relate to the use of 5-HT, and 5-HT, j. agonists for the treatment of glaucoma (elevated IOP). These anti-migraine compounds, e.g., sumatriptan and naratriptan and related compounds, are 5-HT , ¢ - agonists.

It has been found that serotonergic compounds which possess agonist activity at 5-

HT, receptors effectively lower and control normal and elevated I0P and are useful for treating glaucoma, see commonly owned co-pending application, PCT/US99/ 19888, incorporated in its entirety by reference herein. Compounds that act as agonists at 5-HT, receptors are well known and have shown a variety of utilities, primarily for disorders or conditions associated with the central nervous system (CNS). U.S. Patent No. 5,494,928 relates to certain 2-(indol-1-yl)-ethylamine derivatives that are 5-HT,. agonists for the treatment of obsessive compulsive disorder and other CNS derived personality disorders.

U.S. Patent No. 5,571,833 relates to tryptamine derivatives that are 5-HT, agonists for the treatment of portal hypertension and migraine. U.S. Patent No. 5,874,477 relates to a method for treating malaria using 5-HT,,,. agonists. U.S. Patent No. 5,902,815 relates to the use of 5-HT,, agonists to prevent adverse effects of NMDA receptor hypo-function. WO 98/31354 relates to 5-HT,p agonists for the treatment of depression and other CNS conditions. WO 00/12475 relates to indoline derivatives and WO 00/12510 and WO 00/44753 relate to certain indole derivatives as 5-HT,; and 5-HT,¢ receptor agonists for the treatment of a variety of disorders of the central nervous system, but especially for the io treatment of obesity. WO 00/35922 relates to certain pyrazino[1,2-a]quinoxaline derivates as 5-HT), agonists for the treatment of obsessive compulsive disorder, depression, eating disorders, and other disorders involving the CNS. WO 00/77002 and WO 00/77010 relate to certain substituted tetracyclic pyrido[4,3-b]indoles as 5-HT,; agonists with utility for the treatment of central nervous system disorders including obesity, anxiety, depression, sleep 15. disorders, cephalic pain, and social phobias among others. Agonist response at the 5-HT,, receptor is reported to be the primary activity responsible for hallucinogenic activity, with some lesser involvement of the 5-HT,c receptor possible [Psychopharmacology, Vol. 121:357, 1995].

Few furan or pyran containing fused indazoles have been reported. The chemical synthesis of 7-methyl- and 1,7-dimethyl-1H-furo[2,3-g}indazole [Gazz. Chim Ital 106, 1083 (1976)] as well as that of 3-methyl- and 1-(4-aminophenyl)-3-methyl-1 4- benzo[b]furo[2,3-glindazole [An. Asoc. Quim. Argent. 59, 69 (1971)] has been reported without discussion of their utility. European Patent Application EP 990,650 (Intnl.

Publication Number WO 98/56768) relates to substituted 2-(furo[2,3-glindazol-1-y1)-

ethylamines, such as (S)-2-(furo[2,3-glindazol-1-yl)-1-methylethylamine, which are reported to have high selectivity and affinity for 5-HT,. receptors and are potentially useful for treating a variety of central nervous system disorders. The chemical synthesis of 9-methyl-1H- pyrano[2,3-glindazol-7-one and the corresponding non-methylated compound was reported [Indian J. Chem. 26B, 436 (1987)] with no mention of utility.

U.S. Patent Nos. 5,561,150 and 5,646,173 relate to certain tricyclic pyrazole derivative compounds which are identified as being 5-HT,. agonists for the treatment of CNS diseases and are primarily directed to lipophilic analogs that have a high probability of entering the brain. Similarly, WO 98/56768 relates to tricyclic 5-HT,. agonists for the to treatment of CNS diseases. All the patents and publications mentioned above and throughout are incorporated in their entirety by reference herein. 5-Hyroxytryptamine (serotonin) does not cross the blood-brain barrier and enter the brain. However, in order to increase brain serotonin levels the administration of 5-hydroxy- tryptophan can be employed. The transport of 5-hydroxy-tryptophan into the brain readily 1s occurs, and once in the brain 5-hydroxy-tryptophan is rapidly decarboxylated to provide serotonin.

Accordingly, there is a need to provide new compounds which avoid the disadvantages described above and which provide increased chemical stability and a desired length of therapeutic activity, for instance, in decreasing intraocular pressure and treating glaucoma.

SUMMARY OF THE PRESENT INVENTION

A feature of the present invention is to provide novel compounds which are 5-HT, agonists.

Another feature of the present invention is to provide compounds which have increased chemical stability and which are useful in lowering and controlling normal or elevated intraocular pressure and/or treating glaucoma.

Another feature of the present invention is to provide compounds which provide a s desired level of therapeutic activity in lowering and controlling normal or elevated intraocular pressure and/or treating glaucoma.

Additional features and advantages of the present invention will be set forth in part in the description that follows, and in part will be apparent from the description, or may be learned by practice of the present invention. The objectives and other advantages of the lo present invention will be realized and attained by means of the elements and combinations particularly pointed out in the description and appended claims.

To achieve these and other advantages, and in accordance with the purposes of the present invention, as embodied and broadly described herein, the present invention relates to a compound having the Formula I:

B RS

R te 0 y R' “\ “N , <

R

8 \ 5

R R or pharmaceutically acceptable salts or solvates or prodrug forms of the compounds of

Formula I. In the formula, R' and R? are independently chosen from hydrogen or an alkyl group, such as C, alkyl;

R® and R* are independently chosen from hydrogen or an alkyl group, such as C, alkyl or;

R’ and R* and the carbon atom to which they are attached can form a cycloalkyl ring, or furthermore,

R?and R? together can be (CH,),, to form a saturated heterocycle;

R’ is chosen from hydrogen, halogen, an alkyl group, such as Cis alkyl or C alkyl substituted by halogen;

R® and R’ are independently chosen from hydrogen, halogen, cyano, an alkylthio such as

C, , alkylthio, an alkyl such as C,, alkyl, or a substituted alkyl such as C, , alkyl! substituted by halogen;

R® and R® are independently chosen from hydrogen, hydroxyl, an alkyl such as C, alkyl, to an alkoxy such as C, alkoxy, =O, NR'"R", OC(=0)NR'R?, OC(=0)C, jalkyl, an alkylthiol such as C,, alkylthiol, a substituted alkyl such as C, alkyl substituted with halogen, or

NR'R", OR"?, CO,R", or CONR"RY, and further R® and R® can be chosen from Z- (CH,),-NR"R", Z-(CH,),-OR", Z-(CH,),-C(=0)OR", or Z-(CH,),-C(=O)NR"R";

R' and R" are independently chosen from hydrogen, an alkyl group such as C, alkyl, 1s C(=0)C,, alkyl, C(=0)OC, alkyl, C(=0)NR'R?, or a substituted alkyl such as C, alkyl substituted with halogen, hydroxyl, NR'R? or R" and R"' together can complete a saturated > or 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S when a 6-membered ring;

R" is hydrogen, C, alkyl, C(=0)C, calkyl, or C(=0)C, 4alkyi substituted by hydroxyl, C. ,alkoxide, or halide;

R" is hydrogen, C, alkyl, C, alkyl substituted by hydroxyl, C, salkoxy, or halide;

R'" and R" are independently chosen from hydrogen, hydroxyl, C, alkoxy, C,4alkyl,

C,4alkyl substituted by hydroxyl, C, alkoxy, halide, or R" and R'S can be combined to form a saturated heterocyclic ring selected from pyrrolidine, piperidine, piperazine, or morpholine;

Ais (CH,),, C=0, or CHC, alkyl;

B is either a single or a double bond, wherein when B is a double bond, R® and R’ are selected from hydrogen, an alkyl group, such as C, alkyl, or a substituted alkyl group, such as a C, alkyl substituted by halogen, hydroxyl, or NR'’R'': s when A is (CH,), and n is 0, R® is chosen from CO,R", C, alkyl substituted with OR",

NR"R", CO,R" or CONR"R" and R’ is selected from hydrogen or C, ,alkyl and Bisa single bond;

Zis O or S(0),; m= 2-4; n=0-2; : p=12;

X and Y are either N or C, wherein X and Y are different from each other; and the dashed bonds denote a suitably appointed single and double bond.

In another preferred embodiment of the formula, R' and R? are independently 1s chosen from hydrogen or an alkyl group, such as C, , alkyl;

R® and R* are independently chosen from hydrogen or an alkyl group, such as C,_, alkyl or;

R’ and R* and the carbon atom to which they are attached can form a cycloalkyl ring (e.g. cyclopropyl ring), or furthermore,

R? and R’ together can be (CH,),, to form a saturated heterocycle; . R*® is chosen from hydrogen, halogen, a substituted or unsubstituted alkyl group, such as

Cisalkyl or C, jalkyl substituted by halogen;

R® and R’ are independently chosen from hydrogen, halogen, cyano, an alkylthio such ag

C,4 alkylthio, an alkyl such as C,, alkyl, or a substituted alkyl such as C, , alkyl substituted by halogen;

R® and R® are independently chosen from hydrogen, hydroxyl, an alkyl such as C,4 alkyl, an alkoxy such as C, salkoxy, =O, NR'R", OC(=0)NR'R?, OC(=0)C, alkyl, an alkylthiol such as C, alkylthiol, a substituted alkyl such as C, alkyl substituted with halogen,

NR"R", OR", CO,R", or CONR"R¥, and further R® and R® can be chosen from Z- 5s (CHp,-OR", Z-(CH,),-C(=O)OR", or Z-(CH,),-NR"R";

R' and R" are independently chosen from hydrogen, an alkyl group such as C,, alkyl,

C(=0)C,, alkyl, C(=0)0C, , alkyl, C(=O)NR'R?, or a substituted alky] group such as C, alkyl substituted with halogen, hydroxyl, or NR'R?, or R" and R"' together can complete a saturated 5 or 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S when a 6-membered ring;

R" is C, qalkyl, C(=0)C, calkyl, or C(=0)C, alkyl substituted by hydroxyl, C, jalkoxide, or halide;

R" is hydrogen, C, zalkyl, C,alkyl substituted by hydroxyl, C, alkoxy, or halide;

R'" and R" are independently chosen from hydrogen, hydroxyl, C, alkoxy, C, alkyl, 1s C,qalkyl substituted by hydroxyl, C,_,alkoxy, halide, or R' and R® can be combined to form a saturated heterocyclic ring selected from pyrrolidine, piperidine, piperazine, or morpholine;

A 1s (CH,),, C=0, or CHC, alkyl;

B is either a single or a double bond, wherein when B is a double bond, R* and R® are selected from hydrogen, an alkyl group, such as C, alkyl, or a substituted alkyl group, suchas a C, ,alkyl substituted by halogen, hydroxyl, or NR"R": when A is (CH,), and n is 0, R® is chosen from C, ,alkyl substituted by hydroxyl or OR" and R’ is selected from hydrogen or C, ,alkyl and B is a single bond;

X and Y are either N or C, wherein X and Y are different from each other; and the dashed bonds denote a suitably appointed single and double bond.

Zis O or (0); m= 2-4; n=0-2; and p=1-2.

The present invention further relates to pharmaceutical compositions containing at least one compound of Formula I.

The present invention further relates to methods to lower and/or control normal or elevated intraocular pressure by administering an effective amount of a composition containing a compound having Formula I as described above.

The present invention also relates to a method for treating glaucoma which involves administering an effective amount of a composition containing a compound having Formula

I as described above.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are intended to provide a further is explanation of the present invention, as claimed.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

— = NUT HE PRESENT INVENTION

The present invention relates to a variety of compounds which are useful according to the present invention. These compounds are generally represented by the following

Formula ll. . ° 8 , R2

R

TC Ee [e} Y rR \

EN

Rr’ x (] \ 5

R R

In the formula, R' and R? are independently chosen from hydrogen or an alkyl group, such as C,_ alkyl;

R* and R* are independently chosen from hydrogen or an alkyl group, such as C,, alkyl or;

R’ and R* and the carbon atom to which they are attached can form a cycloalkyl ring (e.g., s cyclopropyl ring), or furthermore,

R? and R’ together can be (CH,)_. to form a saturated heterocycle;

R’ is chosen from hydrogen, halogen, a substituted or unsubstituted alkyl group, such as

C,salkyl or C, alkyl substituted by halogen;

R® and R’ are independently chosen from hydrogen, halogen, cyano, an alkylthio such as

C,, alkylthio, an alkyl such as C, alkyl, or a substituted alkyl such as C, alkyl substituted by halogen;

R?® and R® are independently chosen from hydrogen, hydroxyl, an alkyl such as C,, alkyl, an alkoxy such as C, alkoxy, =O, NR'’R"", OC(=0)NR'R?, OC(=0)C, ;alkyl, an alkylthiol such as C, alkylthiol, a substituted alkyl such as C,, alkyl substituted with halogen, or 1s NR'R'", OR", CO,R", or CONR"“R", and further R® and R’ can be chosen from Z- (CH,),-NR"R", Z-(CH,),-OR", Z-(CH,),-C(=0)OR", or Z-(CH,),-C(=O)NR"R"*;

R'” and R" are independently chosen from hydrogen, an alkyl group such as C,, alkyl,

C(=0)C,, alkyl, C(=0)0OC, , alkyl, C(=O)NR'R?, or a substituted alkyl group such as C, alkyl substituted with halogen, hydroxyl, or NR'R?, or R" and R"' together can complete a saturated 5 or 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S when a 6-membered ring; }

R' is hydrogen, C, salkyl, C(=0)C, (alkyl, or C(=0)C, calkyl substituted by hydroxyl, C,. «alkoxide, or halide;

R" is hydrogen, C, alkyl, C, salkyl substituted by hydroxyl, C, alkoxy, or halide;

R™ and R'® are independently chosen from hydrogen, hydroxyl, C, alkoxy, C, alkyl,

C,salkyl substituted by hydroxyl, C, alkoxy, halide, or R* and RS can be combined to form a saturated heterocyclic ring selected from pyrrolidine, piperidine, piperazine, or morpholine;

Ais (CH,),, C=0, or CHC 1salkyl; 5s Bis either a single or a double bond, wherein when B is a double bond, R® and R’ are selected from hydrogen, an alkyl group, such as C, alkyl, or a substituted alkyl group, such as a C, ,alkyl substituted by halogen, hydroxyl, or NR"R"!; when A is (CH,), and n is 0, R® is chosen from COR", C, (alkyl substituted with OR",

NR"R", CO,R" or CONR"R" and R® is selected from hydrogen or C, alkyl and B is a single bond;

ZisO or S(0),; m = 2-4; n=0-2; p=1-2; 1s XandY are either N or C, wherein X and Y are different from each other; and the dashed bonds denote a suitably appointed single and double bond.

In another preferred embodiment of Formula 1, R' and R? are independently chosen from hydrogen or an alkyl group, such as C,_, alkyl;

R* and R* are independently chosen from hydrogen or an alkyl group, such as C, , alkyl or;

R’and R* and the carbon atom to which they are attached can form a cycloalkyl ring (e.g, cyclopropyl ring), or furthermore,

R? and R® together can be (CH,), to form a saturated heterocycle;

R® is chosen from hydrogen, halogen, a substituted or unsubstituted alkyl group, such as

C,salkyl or C,, alkyl substituted by halogen;

R® and R are independently chosen from hydrogen, halogen, cyano, an alkylthio such as

C,.s alkylthio, an alkyl such as C,. alkyl, or a substituted alkyl such as C, , alkyl substituted by halogen;

R® and R® are independently chosen from hydrogen, hydroxyl, an alkyl such as C,, alkyl, an alkoxy such as C, salkoxy, =O, NR'°R"', OC(=O)NR'R?, OC(=0)C, alkyl, an alkylthiol such as C,¢ alkylthiol, a substituted alkyl such as C,; alkyl substituted with halogen,

NR'R", OR", COR", or CONR™R", and further R* and R® can be chosen from Z- (CH,),-OR", Z-(CH,),-C(=0)OR", or Z-(CH,),-NR"R";

R'® and R" are independently chosen from hydrogen, an alkyl group such as C, , alkyl,

C(=0)C,, alkyl, C(=0)OC,_, alkyl, C(=O)NR'R?, or a substituted alkyl group such as C, alkyl substituted with halogen, hydroxyl, or NR'R?, or R' and R"' together can complete a saturated 5 or 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S when a 6-membered ring;

R'? is C,galkyl, C(=0)C, alkyl, or C(=0)C,_ alkyl substituted by hydroxyl, C,_ alkoxide, or halide;

R" is hydrogen, C, salkyl, C,.salkyl substituted by hydroxyl, C, ,alkoxy, or halide;

R' and R" are independently chosen from hydrogen, hydroxyl, C, alkoxy, C, alkyl,

C, salkyl substituted by hydroxyl, C, ,alkoxy, halide, or R" and R" can be combined to form a saturated heterocyclic ring selected from pyrrolidine, piperidine, piperazine, or morpholine;

Ais (CH, C=0, or CHC, alkyl;

B is either a single or a double bond, wherein when B is a double bond, R® and R® are selected from hydrogen, an alkyl group, such as C, alkyl, or a substituted alkyl group, such as a C, jalkyl substituted by halogen, hydroxyl, or NR'°R'!; when A is (CH,), and n is 0, R® is chosen from C, alkyl substituted by hydroxyl or OR?

and R’ is selected from hydrogen or C, ,alkyl and B is a single bond;

X and Y are either N or C, wherein X and Y are different from each other; and the dashed bonds denote a suitably appointed single and double bond;

ZisOor S(0),; m=2-4; n= 0-2; and p=1-2.

Pharmaceutically acceptable salts and solvates, and prodrug forms of the compounds of Formula I are also part of the present invention.

Preferred compounds are:

Wherein R' and R? are independently chosen from hydrogen or C, jalkyl;

R’ and R* are independently chosen from hydrogen, C, jalkyl, or R? and R® together can be (CH,),, to form a saturated heterocycle;

R’ is chosen from hydrogen, halogen, or C, alkyl;

R® and R’ are independently chosen from hydrogen, halogen, cyano, C,.alkylthio, C,. «alkyl, or C, alkyl substituted by halogen;

R® and R’ are chosen from hydrogen, hydroxyl, C, calkyl, C, alkoxy, NR'R"", or C, salkyl substituted with halogen, hydroxyl, or NR'°R'!;

R' and R" are independently chosen from hydrogen, C, alkyl, C(=0)C, alkyl,

C(=0)OC,, alkyl, C(=O)NR'R’, or R" and R" together can complete a saturated 6. membered heterocyclic ring, which can include an additional heteroatom selected from N,

O,orS;

A 1s (CH,), or CHC, alkyl;

B is either a single or double bond, wherein when B is a double bond, R® and R® are selected from hydrogen, C, salkyl, or C, alkyl substituted by halogen, hydroxy, or

NR'"R'; m = 3-4; s n=1-2;

X and Y are either N or C, wherein X and Y are different; and the dashed bonds denote a suitably appointed single and double bond;

Most preferred compounds are:

Wherein R' and R? are independently chosen from hydrogen or C, jalkyl;

R'is C, alkyl, or R? and R® together can be (CH,), to form pyrrolidine;

R* is hydrogen;

R’ is chosen from hydrogen or C, alkyl;

R® and R are independently chosen from hydrogen, halogen, or C, ,alkyl;

R’® and R® are independently chosen from hydrogen, hydroxyl, C,_ alkoxy, NR"R" or

C, alkyl substituted with hydroxyl or NR'R"";

R'® and R'" are independently chosen from hydrogen, C, jalkyl, C(=0)C, alkyl, or R" and

R'' together can complete a saturated 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S;

Ais (CH,),;

Bisa single bond; n=1;

XisCand YisN; and the dashed bonds denote a suitably appointed single and double bond. :

Representative examples of preferred compounds of Formula I are:

1-(2-Aminopropyl)-1 ,7,8,9-tetrahydro-pyrano(2,3-gJindazol-8-ol ; 1-((8)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano|2,3-glindazol-8-ol; (R)-1 -((S)-2-Aminopropyl)-1 »1,8,9-tetrahydro-pyrano(2,3-glindazol-8-ol: (S)-1 -((S)-2-Aminopropyl)-1 »7.8,9-tetrahydro-pyrano|2,3-glindazol-8-ol; 1-((8)-2-Aminopropyl)-3-methyl-1,7,8,9-tetrahydro-pyrano[2,3-gJindazol--ol: 1-(S)-1 -Pyrrolidin-2-ylmethyl-1 ,7,8,9-tetrahydro-pyrano([2,3-glindazol-8-ol; 1-((S)-2-Aminopropyl)-5-fluoro-1 ,7,8,9-tetrahydro-pyrano[2,3-gJindazol-8-ol; (R)-1 -((S)-2-Aminopropyl)-1 ,1,8,9-tetrahydro-pyrano|[2,3-gJindazol-8-ylamine; [1 -((5)-2-Aminopropyl)-1 7,8,9-tetrahydro-pyrano [2,3-glindazol-8-yl]-dimethylamine; [1-((S)-2-Aminopropyl)-1 ,7,8,9-tetrahydro-pyrano [2,3-g]indazol-8-y1}-methanol : 1-((S)-2-Aminopropyl)-1 ,7,8,9-tetrahydro-pyrano [2,3-glindazole-8,9-diol; 1 -((5)-2-Aminopropyl)-9-methoxy-1 »1,8,9-tetrahydro-pyrano [2,3-glindazol-8-0l;

I-(2-Aminopropyl)-3,7,8 9-tetrahydro-pyrano[3,2-¢]indazol-8-ol; 1 -(Pyrrolidin-2-ylmethyl)-3,7,8,9-tetrahydro-pyrano[3 ,2-e]indazol-8-ol; 1-((S)-2-Aminopropy)-3,7,8,9-tetrahydro-pyrano[3,2-e}indazol-8-ol: 1-((S)-2-Aminopropyl)-3 -methyl-3,7,8,9-tetrahydro-pyrano[3 ,2-ejindazol-8-ol;

N-[2-[(R)-1-((S)-2-amino-propyl)-1 »7,8,9-tetrahydro-pyrano[2,3-glindazol-8-yloxyJethy1]- acetamide; 2-[(R)-1-((S)-2-amino-propyl)-1 ,7,8,9-tetrahydro-pyrano[2,3-gJindazol-8-yloxy]-ethanol R 2-[(R)-1-((S)-2-amino-propyl)-1 ,7,8,9-tetrahydro-pyrano{2,3-glindazol-8-yloxy]- acetamide; [(R)-1-((S)-2-amino-propyl)-1 ,1,8,9-tetrahydro-pyrano|2,3-glindazol-8-yloxy]-acetic acid tert-butyl ester;

N-[2-[(R)-1-((S)-2-Aminopropy])-1 ,7,8,9-tetrahydropyrano[2,3-gJindazol-8-yloxy)- ethyljacetamide; 2-[(R)-1 -((S)-2-Aminopropyl)-1 ,7,8,9-tetrahydro-pyrano([2,3-glindazol-8-yloxy]-ethanol; (S)-2-[(R)-8-(2-Methoxyethoxy)-8,9-dihydro-7H-pyrano[2,3-glindazol-1 -yl]-1-methyl- 5s ethylamine; 2-[(R)-1-((S)-2- Aminopropyl)-1 »7,8,9-tetrahydro-pyrano(2,3-glindazol-8-yloxy]-acetamide: 2-[(R)-1-((S)-2-Aminopropyl)-1 ,7,8,9-tetrahydro-pyrano[2 »3-glindazol-8-yloxy]-N-hydroxy- acetamide; 1-[(R)-1 -((S)-2-Aminopropyl)-1 ,7,8,9-tetrahydro-pyrano[2,3-glindazol-8-y1]-3-ethyl-1 - methylurea; (S)-1-Methyl-2-(3 ,7,8,9-tetrahydro-pyrano[3,2-e]indazol-1 -yl)-ethylamine; 2-[(R)-1 -((S)-2-Aminopropyl)-3,7,8,9-tetrahydro-pyrano[3 ,2-e]indazol-8-yloxy]-ethanol; [1-((S)-2-Aminopropy)-7,8-dihydro-1H-furof2,3-g]indazol-7-yl}- methanol: 2-[(S)-1 -((S)-2-Aminopropyl)-7,8-dihydro-3 H-furo[3,2-¢]indazol-7-yl]-acetamide; 1s or combinations thereof.

Certain compounds of Formula I can contain one or more chiral centers. The present invention contemplates all enantiomers, diastereomers, and mixtures thereof.

In the above definitions, the total number of carbon atoms in a substituent group is indicated by the C;; prefix where the numbers i and J define the number of carbon atoms.

This definition includes straight chain, branched chain, and cyclic alkyl or (cyclic alkylalky! groups. A substituent may be present either singly or multiply when incorporated into the indicated structural unit. For example, the substituent halogen, which means fluorine, chlorine, bromine, or iodine, would indicate that the unit to which it is attached may be : substituted with one or more halogen atoms, which may be the same or different.

Claims (24)

WHAT IS CLAIMED IS:

1. A compound represented by Formula I: I Nr ae t rR? Oo Y R* \ rf R cL R R wherein R' and R? are independently chosen from hydrogen or an alkyl group; sR? and R* are independently hydrogen or an alkyl group or; R? and R* and the carbon atom to which they are attached form a cycloalkyl ring, or; R? and R® together form a saturated (CH;)m heterocycle; R® is hydrogen, halogen, or a substituted or unsubstituted alkyl group; RS and R’ are independently hydrogen, halogen, cyano, an alkylthio, or a substituted or unsubstituted alkyl group; R® and R’ are independently hydrogen, hydroxyl, an alkyl group, an alkoxy, =O, NR!R!, OC(=O)NR'R? , OC(=0)C.4alkyl, an alkylthiol, or an alkyl substituted with halogen, NR°R!!, OR'%, CO,R", or CONR"R", or R® and R® can be chosen from Z-(CHz)x- NR!°R"!, Z-(CH;)m-OR 2, Z-(CH,),-C(=0)OR?, or Z-(CH,),-C(=O)NR'“R"*; Rand R' are independently hydrogen, a substituted or unsubstituted alkyl group, C(=0)C,4 alkyl, C(=0)OC;.4 alkyl, or C(=O)NR'R? or R'” and R"' together complete a saturated 5 or 6-membered heterocyclic ring, which optionally includes an additional heteroatom selected from N, O, or S when a 6-membered ring wherein at least one of R® or R’is an alkyl substituted with OR'?, COR", or CONRMR', or at least one of R8or Ris 2 chosen from Z-(CH2)m-NR'’R"", Z-(CH;)m-OR'2, Z-(CH,),-C(=0)OR ">, or Z~(CHa),- C(=0)NR"R"; R'? is hydrogen, C;.salkyl, C(=0)Ci.salkyl, or C(=O)Cisalkyl substituted with hydroxyl, Cialkoxide, or halide except R'? is not hydrogen when R® or R®is OR'%; AMENDED SHEET

R" is hydrogen, Ci.salkyl, C.¢alkyl substituted with hydroxyl, C;_4alkoxy, or halide; R' and R" are independently chosen from hydrogen, hydroxyl, C;.salkoxy, C;.¢alkyl, Ca. salkyl substituted by hydroxyl, Ci4alkoxy, halide, or R'* and R"* can be combined to form saturated heterocyclic ring selected from pyrrolidine, piperidine, piperazine, or s morpholine; A is (CHy),, C=0, or CHC, 4alkyl; B is either a single or a double bond, wherein when B is a double bond, R® and R® are selected from hydrogen, or a substituted or unsubstituted alkyl group; wherein when A is (CH), and nis 0, R® is chosen from COR", Ci-salkyl substituted with OR!2Z NR'"R!, CO,R" or CONR"R'® and R’ is selected from hydrogen or C;.;alkyl and B is a single bond; Z is O or S(O)y; m=2-4; n=0-2; p=1-2; X and Y are either N or C, wherein X and Y are different; and the dashed bonds denote a suitably appointed single and double bond; or pharmaceutically acceptable salts, solvates or prodrugs thereof.

2. The compound of claim 1, wherein R? and R? form a saturated (CHy)m heterocycle.

3. The compound of claim 1, wherein said R® and R* together form a cyclopropyl ring.

4. The compound of claim 1, wherein R! and R? are independently chosen from hydrogen or Ci 4alkyl; AMENDED SHEET

R’ and R* are independently chosen from hydrogen or C; alkyl, or R? and R® together form a saturated (CH,),, heterocycle; R’ is chosen from hydrogen, halogen, or C;.alkyl; R® and R7 are independently chosen from hydrogen, halogen, cyano, C;_4alkylthio, Cjaalkyl, or C;_salkyl substituted by halogen; R® and R° are chosen from hydrogen, hydroxyl, C;.salkyl, C,.salkoxy, NR'R! ! or Ci.¢alkyl substituted with halogen, hydroxyl, NR!°R", Z-(CH,)m-OR"?, or Z- (CH,),C(=0 NR'"R'® wherein at least one of R® or R’ is an alkyl substituted with OR", CO,RY, or CONRMRY, or at least one of R?® or R’ is chosen from Z~(CHy)m-NR'’R"!, Z- (CHp)m-OR'?, Z-(CH,),-C(=0)OR", or Z-(CH,),-C(=0)NR'R'” except R'? is not hydrogen when R® or R? is OR'?); R'* and R"! are independently chosen from hydrogen or C; 4alkyl or C(=0)C. salkyl or R' and R'' together complete a saturated 5 or 6-membered heterocyclic ring, which optionally includes an additional heteroatom selected from N, O, or S when a 6- membered ring; A is (CH), or CHC, salkyl; B is either a single or double bond, wherein when B is a double bond, R® and R’ are selected from hydrogen, C4alkyl, or C;_4alkyl substituted by halogen, hydroxy, or NR!’R': m = 3-4; n=1-2; and X and Y are either N or C, wherein X and Y cannot be the same; and the dashed bonds denote a suitably appointed single and double bond.

5. The compound of claim 1, wherein R' and R* are independently chosen from hydrogen or C;_salkyl; AMENDED SHEET

R? is C1.,alkyl, or R? and R? together are (CH,)3 to form pyrrolidine; R* is hydrogen; R’ is chosen from hydrogen or C,.salkyl; R® and R’ are independently chosen from hydrogen, halogen, or C;alkyl; R® and R® are independently chosen from hydrogen, hydroxyl, C;_salkoxy, NR'R", or C,.¢alkyl substituted with hydroxyl, NR'’R"!, Z-(CH,)m-OR"?, or Z- (CH,),C(=0) NR'“R'® wherein at least one of R® or R’ is an alkyl substituted with OR", COR" , Or CONR'R"P , or at least one of R® or R® is chosen from Z-(CHa)m-NR'R!}, Z- (CH2)m-OR'2, Z-(CH,),-C(=0)OR", or Z-(CH),-C(=0)NR“R'® except R'? is not hydrogen when R® or R’ is OR'?; R'? and R'! are independently chosen from hydrogen, C;4alkyl or C(=0)C; alkyl or R'® and R"! together complete a saturated 5 or 6-membered heterocyclic ring, which optionally includes an additional heteroatom selected from N, O, or S when a 6-membered ring; Ais (CHa)p; B is a single bond; n=1; Xis Cand Y is N; and the dashed bonds denote a suitably appointed single and double bond.

6. The compound of claim 1, wherein said compound is: N-[2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydropyrano[2,3-g]indazol-8-yloxy]- ethyl]acetamide; 2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-gJindazol-8-yloxy]-ethanol, (S)-2-[(R)-8-(2-Methoxyethoxy)-8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl]-1-methyl- ethylamine; AMENDED SHEET

2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-gindazol-8-yloxy]-acetamide; 2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-gJindazol-8-yloxy]-N-hydroxy- acetamide; 1-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yl]-3-ethyl-1- methylurea; (S)-1-Methyl-2-(3,7,8,9-tetrahydro-pyrano([3,2-elindazol- 1-yl)-ethylamine; 2-[(R)-1-((S)-2-Aminopropyl)-3,7,8,9-tetrahydro-pyrano( 3,2-e]indazoi-8-yloxy]-ethanol, [1-((S)-2-Aminopropyl)-7,8-dihydro-1H-furo[2,3-g]indazol-7-yl]-methanol; 2-[(S)-1-((S)-2-Aminopropyl)-7,8-dihydro-3 H-furo[3,2-e]indazol-7-yl]-acetamide; or combinations thereof.

7. The compound of claim 1, wherein said X is N.

8. The compound of claim 1, wherein said X is C.

9. A method of controlling normal or elevated intraocular pressure comprising administering a pharmaceutically effective amount of a composition comprising at least one compound of claim 1.

10. The method of claim 9, wherein R? and R® form a saturated (CHy)m heterocycle.

11. The method of claim 9, wherein said R*> and R* together form a cyclopropyl ring.

12. The method of claim 9, wherein R' and R? are independently chosen from hydrogen or C;alkyl; R? and R* are independently chosen from hydrogen or C;.salkyl, or R? and R® together form a saturated (CHa) heterocycle; R’ is chosen from hydrogen, halogen, or Cjalkyl; AMENDED SHEET

R® and R are independently chosen from hydrogen, halogen, cyano, C;4alkylthio, Ci4alkyl, or Cy salkyl substituted by halogen; R® and R? are chosen from hydrogen, hydroxyl, C,_salkyl, C;.salkoxy, NR!R!!, or Cy.¢alkyl substituted with halogen, hydroxyl, NR'R!, Z-(CH3)m-OR'?, or Z- (CH,),C(=O)NR"R" wherein at least one of R® or R’ is an alkyl substituted with OR"? COR", or CONR'“R"® , or at least one of R® or R® is chosen from Z-(CHz)m-NR!°R"!, Z- (CH)m-OR'%, Z-(CHy),-C(=0)OR", or Z-(CH,),-C(=0)NR'*R"® except R'? is not hydrogen when R® or R® is OR'?; R'? and R"" are independently chosen from hydrogen or C;_salkyl or C(=0)C1. alkyl or Rand R" together can complete a saturated 5 or 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S when a 6-membered ring; A is (CH;), or CHC, 4alkyl; B is either a single or double bond, wherein when B is a double bond, R® and R’ are selected from hydrogen, C;_jalkyl, or C,.salkyl substituted by halogen, hydroxy, or NRI°R'!, m = 3-4; n=1-2; and X and Y are either N or C, wherein X and Y cannot be the same; and the dashed bonds denote a suitably appointed single and double bond.

13. The method of claim 9, wherein R' and R? are independently chosen from hydrogen or C,.salkyl; R’ is C,.zalkyl, or R? and R? together are (CH,)s3 to form pyrrolidine; Ris hydrogen; R’ is chosen from hydrogen or C;_salkyl; AMENDED SHEET

R® and R’ are independently chosen from hydrogen, halogen, or Ciaalkyl; R® and R’ are independently chosen from hydrogen, hydroxyl, C,.¢alkoxy, NR'R"!, or C,.salkyl substituted with hydroxyl, NR'R", Z-(CH,)m-OR"?, or Z- (CH,),C(=O)NR'“R'® wherein at least one of R® or R’ is an alkyl substituted with OR'?, s CORP , Or CONRMR", or at least one of R® or R? is chosen from Z-(CHy)m-NR'R", Z- (CH2)m-OR'2, Z-(CH,),-C(=0)OR", or Z-(CH,),-C(=0)NR'*R"’ except R'? is not hydrogen when R® or R? is OR'?; R'? and R" are independently chosen from hydrogen, C1alkyl or C(=0)C.salkyl or R'® and R! together complete a saturated 5 or 6-membered heterocyclic ring, which optionally includes an additional heteroatom selected from N, O, or S when a 6-membered ring; Ais (CHa); B is a single bond, n=1; X is C and Y is N; and the dashed bonds denote a suitably appointed single and double bond.

14. The method of claim 9, wherein said compound is: N-[2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydropyrano[2,3-g]indazol-8-yloxy]- ethylJacetamide; 2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yloxy]-ethanol; (S)-2-[(R)-8-(2-Methoxyethoxy)-8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl]-1-methyl- ethylamine; 2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[ 2,3-glindazol-8-yloxy]-acetamide; 2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yloxy]-N-hydroxy- acetamide; 1-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yl]-3-ethyl-1- AMENDED SHEET methylurea; (S)-1-Methyl-2-(3,7,8,9-tetrahydro-pyrano( 3,2-e]indazol-1-yl)-ethylamine; 2-[(R)-1-((S)-2-Aminopropyl)-3,7,8,9-tetrahydro-pyrano[ 3,2-e]indazol-8-yloxy]-ethanol; [1-((S)-2-Aminopropyl)-7,8-dihydro-1H-furo[2,3-g]indazol-7-yl]-methanol; 2-[(S)-1-((S)-2-Aminopropyl)-7,8-dihydro-3 H-furo[3,2-e]indazol-7-yl]-acetamide; or combinations thereof.

15. The method of claim 9, wherein said X is N.

16. The method of claim 9, wherein said X is C.

17. At least one compound of claim 1 for use in the manufacture of a medicament for use in a method for the treatment of glaucoma comprising administering a pharmaceutically effective amount of said medicament to a person in need thereof.

18. Use of a compound according to claim 17, wherein R! and R® are independently chosen from hydrogen or C;4alkyl; R> and R* are independently chosen from hydrogen or Ci 4alkyl, or R? and R® together form a saturated (CH,)m heterocycle; R’ is chosen from hydrogen, halogen, or Cj.salkyl; R® and R’ are independently chosen from hydrogen, halogen, cyano, Ci.salkylthio,

Ci.4alkyl, or C,_4alkyl substituted by halogen; R® and R’ are chosen from hydrogen, hydroxyl, C,alkyl, C;.salkoxy, NR'R', or Cialkyl substituted with halogen, hydroxyl, NR'R!, Z-(CH;)m-OR", or Z- (CH,),C(=O)NR'“R" wherein at least one of R® or R’ is an alkyl substituted with OR"? CO,R", or CONR'R" , or at least one of R® or R’ is chosen from Z-(CHy)m-NR'R!, Z- (CH,)m-OR'?, Z-(CH,),-C(=0)OR"?, or Z-(CH,),-C(=O)NR'‘R'” except R'? is not hydrogen when R¥orR%is OR'%; AMENDED SHEET

R' and R"! are independently chosen from hydrogen or C4alkyl or C(=0)C;- salkyl or R'% and R'! together can complete a saturated 5 or 6-membered heterocyclic ring, which can include an additional heteroatom selected from N, O, or S when a 6-membered ring; A is (CHy), or CHC, jalkyl; B is either a single or double bond, wherein when B is a double bond, R® and R’ are selected from hydrogen, Ci.salkyl, or C;_4alkyl substituted by halogen, hydroxy, or NR''R'!; m = 3-4; n=1-2; and X and Y are either N or C, wherein X and Y cannot be the same; and the dashed bonds denote a suitably appointed single and double bond.

19. Use of a compound according to claim 17, wherein R' and R? are independently chosen from hydrogen or C;.salkyl; R? is Cyalkyl, or R? and R? together are (CH,)3 to form pyrrolidine; R* is hydrogen; R’ is chosen from hydrogen or C_galkyl; R® and R’ are independently chosen from hydrogen, halogen, or C;.4alkyl; R® and R? are independently chosen from hydrogen, hydroxyl, Ci.salkoxy, NR!"R'! or Calkyl substituted with hydroxyl, NR'R'!, Z-(CH2)m-OR'2, or Z- (CH2),C(=0)NR'“R"’ wherein at least one of R® or R’ is an alkyl substituted with OR'2, CO,R", or CONR'"RY, or at least one of R® or R’ is chosen from Z-(CHz)m-NR'’R', Z- (CH2)m-OR'%, Z-(CH,),-C(=0)OR"3, or Z-(CH2),-C(=0)NR"R"’ except R'? is not hydrogen when R® or R’ is OR'?; AMENDED SHEET

R'" and R'' are independently chosen from hydrogen, C alkyl or C(=0)C;.4alkyl or R'’ and R!! together complete a saturated 5 or 6-membered heterocyclic ring, which optionally includes an additional heteroatom selected from N, O, or S when a 6-membered ring; A is (CHa)y; B is a single bond; n=1; Xis Cand Y is N; and the dashed bonds denote a suitably appointed single and double bond.

20. Use of a compound according to claim 17, wherein said compound is: N-[2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydropyrano[2,3-g]Jindazol-8-yloxy]- ethyl]acetamide; 2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yloxy]-ethanol; (S)-2-[(R)-8-(2-Methoxyethoxy)-8,9-dihydro-7H-pyrano[2,3-g]indazol-1-yl]- 1-methyl- ethylamine; 2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yloxy]-acetamide; 2-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yloxy]-N-hydroxy- acetamide; 1-[(R)-1-((S)-2-Aminopropyl)-1,7,8,9-tetrahydro-pyrano[2,3-g]indazol-8-yl]-3-ethyl-1- methylurea; (S)-1-Methyl-2-(3,7,8.,9-tetrahydro-pyrano[ 3,2-e]indazol-1-yl)-ethylamine; 2-[(R)-1-((S)-2-Aminopropyl)-3,7,8,9-tetrahydro-pyrano( 3,2-e]indazol-8-yloxy]-ethanol; [1-((S)-2-Aminopropyl)-7,8-dihydro-1H-furo[2,3-g]indazol-7-yl]-methanol; 2-[(S)-1-((S)-2-Aminopropyl)-7,8-dihydro-3H-furo[ 3,2-e]indazol-7-yl]-acetamide; or combinations thereof. AMENDED SHEET

21. A pharmaceutical composition comprising the compound of claim 1 and at least one carrier.

22. At least one compound of claim 1 for use in the manufacture of a medicament for use in a method to block or bind to serotonin receptors comprising administering an effective amount of said medicament to a patient.

23. A compound as claimed in claim 1 substantially as described herein with reference to Tables 1 to 3.

24. A compound as claimed in claim 1 produced according to a method substantially as described herein with reference to examples 4, 5 and 13. AMENDED SHEET