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WO2015095515A1 - Sgc activators for the treatment of glaucoma - Google Patents

Sgc activators for the treatment of glaucoma Download PDF

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Publication number
WO2015095515A1
WO2015095515A1 PCT/US2014/071150 US2014071150W WO2015095515A1 WO 2015095515 A1 WO2015095515 A1 WO 2015095515A1 US 2014071150 W US2014071150 W US 2014071150W WO 2015095515 A1 WO2015095515 A1 WO 2015095515A1
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WIPO (PCT)
Prior art keywords
trifluoromethyl
phenyl
carboxylic acid
alkyl
pyrazole
Prior art date
Application number
PCT/US2014/071150
Other languages
French (fr)
Inventor
Christopher Adams
David B. Belanger
Takeru Ehara
Luciana Ferrara
Toshio Kawanami
Muneto Mogi
Ganesh Prasanna
Original Assignee
Novartis Ag
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Publication of WO2015095515A1 publication Critical patent/WO2015095515A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention is related generally to treatments for glaucoma and more specifically to agents which activate soluble guanylate cyclase (sGC) thereby lowering intraocular pressure such as that associated with glaucoma and ocular hypertension.
  • sGC soluble guanylate cyclase
  • the eye disease glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve.
  • the several morphologically or functionally distinct types of glaucoma are typically characterized by an undesirable elevation of intraocular pressure (IOP), which is considered to be causally related to the pathological course of the disease.
  • IOP intraocular pressure
  • Continuously elevated IOP has been associated with the progressive loss of retinal ganglion cells, optic nerve damage ultimately resulting in the loss of visual function.
  • ocular hypertension a condition in which IOP is elevated, can present without apparent loss of visual function.
  • patients with ocular hypertension are considered to be at a high risk for eventually developing the visual loss associated with glaucoma.
  • lowering IOP is the current treatment objective for the of glaucoma patients and for patients with ocular hypertension in order to decrease the potential for, or severity of, glaucomatous retinopathy.
  • many individuals do not respond well when treated with existing glaucoma therapies.
  • Glaucoma patients have relatively low IOP, yet present with glaucomatous visual field loss. These patients may benefit from agents that lower and control IOP, because glaucoma that is detected early and treated promptly may have reduced or delayed loss of visual function.
  • Conventional therapeutic agents that have proven to be effective for the reduction of IOP include both agents that decrease aqueous humor production and agents that increase the uveoscleral outflow. There are currently no approved agents that directly increase conventional outflow facility via trabecular meshwork and Schlemm's canal. Such agents are in general administered by one of two routes; topically by direct application to the eye, or orally.
  • Soluble guanylate cyclase is a receptor enzyme for the second messenger, nitric oxide (NO) in several cell types including muscle, epithelia, neuronal, and endothelial cells.
  • NO nitric oxide
  • functional sGC is a heterodimer composed of either an alpha 1 or alpha 2 subunit combined with the beta 1 subunit which has a heme prosthetic group.
  • NO binds to the prosthetic heme of sGC which activates the enzyme to catalyze the conversion of guanosine-5'-triphosphate (GTP) to cyclic guanosine monophosphate (cGMP).
  • GTP guanosine-5'-triphosphate
  • cGMP cyclic guanosine monophosphate
  • cGMP is a second messanger which in turn exerts its effects by activating cGMP dependent protein kinase (PKG) isoforms, phosphodiesterases, and cGMP gated ion channels.
  • PKG cGMP dependent protein kinase
  • sGC can thus modulate numerous pathways associated with diseases including hypertension (arterial and pulmonary), heart failure, atherosclerosis, erectile dysfunction, liver cirrhosis, and renal fibrosis.
  • oxidative stress can cause the oxidation of the heme group of sGC (from ferrous to ferric state) which is incapable of being activated by NO and can contribute to exacerbation of disease processes.
  • sGC oxidation and unresponsiveness to NO
  • endothelial dysfunction As a consequence of sGC oxidation and unresponsiveness to NO, endothelial dysfunction, atherosclerosis, hypertension, stable or unstable angina pectoris, thromboses, myocardial infarction, strokes or erectile dysfunction are worsened. Therefore, pharmacological stimulation or activation of sGC offers a possibility to normalize cGMP production and therefore makes possible the treatment and/or prevention of such disorders.
  • sGC stimulators are dependent on heme, but they are not active once sGC become oxidized.
  • sGC activators on the other hand can still activate the enzyme to generate cGMP even in the absence of nitric oxide (NO) synthesis, NO availability and oxidative stress induced heme iron oxidation of sGC in disease pathology.
  • NO nitric oxide
  • the present invention in part relates to methods of treating glaucoma in human patients or other mammals.
  • the present invention also relates to methods of lowering or controlling normal or elevated IOP in a human patient or other mammals.
  • the invention provides methods of treating and/or preventing glaucoma by administration of an sGC activator compound described infra.
  • Oxidative stress is thought to be an underlying factor that can adversely affect trabecular meshwork function, resulting from/in IOP elevation in POAG.
  • Reactive oxygen species ROS not only decrease the bioavailability of nitric oxide (NO) but also shift the sGC redox equilibrium to its oxidized form, which as mentioned before is unresponsive to NO.
  • Selective activation of the oxidized form of sGC should target only the diseased state of the target enzyme in the putative target tissue, trabecular
  • Certain embodiments of the present invention comprise compositions or methods which include or use compounds capable of activating sGC thereby modulating intraocular pressure in the eye.
  • sGC receptor activity By activating sGC receptor activity, subject compounds according to certain embodiments of the present invention are accordingly useful for lowering and/or controlling IOP associated with normal-tension glaucoma, ocular hypertension, and glaucoma, including primary open-angle glaucoma in humans and other warm-blooded animals.
  • the compounds may be formulated in pharmaceutical compositions suitable for topical delivery to the eye.
  • Certain sGC activators which are contemplated for use in the methods of the instant invention include those compounds prepared and disclosed by WO2009/032249, WO2012/058132, WO2010/099054, WO2009/071504, WO2012/122340, WO2013/025425 and WO2009/068652, each of which is incorporated by reference.
  • the present invention relates to a method of treating or preventing glaucoma or reducing intraocular pressure comprising administering to a subject in need thereof a sGC activator.
  • the invention has surprisingly shown, in a clinically relevant animal model, that administration of certain classese of sGC activators provides desirable sustained efficacy in reducing intraocular pressure (IOP) that is superior to reduction observed by administration of sGC stimulators.
  • IOP intraocular pressure
  • sGC activators are useful in the treatment of glaucoma and ocular hypertension.
  • sGC activator is a compound capable of modulating sGC activity in pathologically changed heme-free sGC (i.e., following heme oxidation) to generate cGMP signaling which would otherwise be unresponsive to nitric oxide.
  • sGC stimulators refers to compounds that are capable of synergizing with nitric oxide and can directly stimulate cGMP production so long as the heme domain is present in the enzyme.
  • the invention provides methods of treating or preventing glaucoma or reducing intraocular pressure according to the first embodiment in which the method comprises administering to a subject in need of such therapy a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2009/032249 which is incorporated by reference for the compounds disclosed therein.
  • the second embodiment provides for the administration of a sGC activator of formula (I):
  • Z 1 is selected from the group consisting of CH and N;
  • Dl is CH, CR4 or N
  • R7 is selected from the group consisting of
  • Ci-6 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms and unsubstituted or monosubstituted with OC 1-3 alkyl,
  • Ci-4 alkyl and -OC1-4 alkyl are unsubstituted or substituted with 1-3 flourine atoms;
  • Li is selected from the group consisting of O, S, C(Rl )2; and CF2;
  • L2 is selected from the group consisting of (CH2>2-4, -C(Rl2)2, -CF2- O, and S, provided that when Ll is 0 or S, L2 is not O or S;
  • Rl2 is independently selected from the group consisting of hydrogen and C 1.3 alkyl, wherein C
  • 1-3 alkyl is unsubstituted or substituted with 1-3 flourine atoms
  • E is a ring selected from the group consisting of
  • a 5-10 membered heteroaryl ring having 1, 2 or 3 heteroatoms independently selected from the group consisting of 0, 1, 2, and 3 N atoms, 0 or 1 O atoms, and 0 or 1 S atoms,
  • aryl, heteroaryl, and C - j _g cycloalkyl are unsubstituted or monosubstituted with R-*, and unsubstituted, monosubstituted or independently disubstituted with R ⁇ ; in each instance in which it occurs, is independently selected from the group consisting of halogen,
  • alkyl group may be unsubstituted or substituted with 1-3
  • O-Ci-6 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, and unsubstituted or monosubstituted with a group independently selected from C3.6 cycloalkyl and R6,
  • KG is selected from the group consisting of
  • a phenyl ring which is unsubstituted, monosubstituted or disubstituted with a group independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, OC]-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, NO2, S(O)0-2Q-4 alkyl, C2-4 alkenyl, O-C2-4 alkenyl, NR9R10, and COOH, and
  • heteroaryl ring containing 1-2 heteroatoms which are independently selected from N, O and S, wherein the heteroaryl ring is unsubstituted, monosubstituted or disubstituted with a group independently selected from: halogen, OH, CN, C1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, OC1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, NO2, S(O)0-2Cl-6 alkyl, S(O)0-2 aryl, C2-6 alkenyl, OC2-6 alkenyl, NR9R10, and COOH;
  • R8 is selected from the group consisting of
  • cycloalkyl group may be unsubstituted or substituted with 1- 3 fluorine atoms OCj_4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms *
  • R9 and RlO are independently selected from the group consisting of hydrogen and Ci-6 alkyl
  • R1 1 is selected from the group consisting of hydrogen and Ci-6 alkyl.
  • the sGC activator of Formula (I) is selected from
  • a preferred sGC activator compound of Formula I which is suitable for use in the methods for the treatment or prevention of glaucoma or in the reduction of intraocular pressure provided in the second embodiment is 1- ⁇ 6-[5-chloro-2-( ⁇ 4-[frans-4-
  • the invention provides methods of treating or preventing glaucoma or reducing intraocular pressure according to the first embodiment in which the method comprises administering to a subject in need of such therapy a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2012/058132 which is incorporated by reference for the compounds disclosed therein.
  • the third embodiment provides for the administration of a sGC activator of formula (II):
  • X is selected from the group consisting of CH, CR.2 and N;
  • la and Rib are independently selected from the group consisting of -H, -F, -Cl, -Br, -CN ? cyclopropyl, -Ci ⁇ alkyl optionally substituted with one to six of-F, and -0-C]-3alkyl optionally substituted with one to six of -F;
  • R2 is selected from the group consisting of -F, -CI, -Br, -CN, cyclopropyl, -Chalky! optionally substituted with one to six of -F, and -0-Ci_3alkyl optionally substituted with one to six of-F;
  • R4 is selected from the group consisting of:
  • phenyl optionally substituted with one to three substituents independently- selected from the group consisting of -OH, -CN, -CI, -F, -Ci-.3a.kyi optionally substituted with one to six of-F, and -0-C] -3alkyl optionally substituted with one to six of-F; and optionally substituted with one of oxo,
  • -C3-6cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of -F, -OH, -CF3, and -OC1 -3alkyl; and optionally substituted with one of oxo ;
  • R5 is selected from the group consisting of ⁇ H, -F, -OH, -CF3, -OCj -3alkyi and -OCF3;
  • j is an integer selected from 0 and 1 ;
  • k is an integer selected from 0 and 1 ;
  • W is selected from the group consisting of CR& and N;
  • R7 is selected from the group consisting of (a) -H, (b) -Cj. ⁇ alkyl optionally substituted with to six of -F, (c) -Ci-3alkyl substituted with one or two of -OCH3,
  • C]-3alkyl optionally substituted with one to three of -F.
  • R8 is selected from the group consisting of-H, ⁇ F, -OH, and -Ci-3alkyl optionally substituted with one to six of -F;
  • R9 is selected from the group consisting of (a) -H, (b) -F, (c) -OH,
  • RlO is selected from the group consisting of (a) -H, (b) -F, (c) -Cl -3alkyl optionally substituted with with substituents selected from (i) -OH and (ii) one to six of -F, and
  • Rll is selected from the group consisting of (a) -H, (b) -Ci -6alkyl optionally substituted with one to six of -F, (c) -C3-6cycloalkyl optionally substituted with -CH3, -CF3, -CN, -OH, or - NH2 or one to three of -F;
  • Rl2a is selected from the group consisting of (a) -H, (b) Ci-6alkyl optionally substituted with one to six of ⁇ F, (c) -C3-6cycloalkyl optionally substituted with -CFI3, -CF3, -CN, -OH, or one to three of -F; and
  • Rl2 j selected from the group consisting of (a) -Ci-galkyl optionally substituted with one to six of -F, and (b) -C3_6cycloalkyl optionally substituted with one to three of ⁇ F.
  • the sGC activator of Formula (I I) is selected from the group consisting of:
  • Example 6 1 -[6-(4-Chloro-3'-methyl-4 T - ⁇ [1 -(2,2,2-trifluoroe&yl)azetidiii-3- yljmethoxy ⁇ biphenyl-2-y])pyridin-2-yl]-5 -(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid;
  • Example 8 1 - ⁇ 6- [4-chloro-4'-(4-cyc3opropylpiperidin- 1 -yl)biphenyJ-2-yl]pyridin-2-yl ⁇ - 5 - (trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid ;
  • Example 44 1 - ⁇ 6-[4-chloro-4'-(4 5 4-difluorocyclohexyl)biphenyl-2-yl]pyridin-2-yl ⁇ -5- (trifluoromethyl)- lH-pyrazole-4-carboxylic acid;
  • Example 57 ! - ⁇ 6-[4'-(4-cycloprop>dpiperidin-l -yl)-4-methylbiphenyl-2-yl]pyridin-2-yI ⁇ -5- (trifluoromethyl)-l H-pyrazole-4-carboxylic acid;
  • Example 60 1 -(6- ⁇ 4-chloro-4'-[l -(2,2,2-triiluoroethyl)piperidin-4-yl]biphenyl-2-yl ⁇ pyridin-2- yl)-5-(trifluoromethyl)- lH-pyrazole-4-carboxylic acid;
  • Example 61 l-[2 , - ⁇ 4-[l-(2,2,2 rifluoroethyl)piperidin-4-yl]phenyl ⁇ -5'-(trifluoromethyl)-2 J 3'- bipyridin-6-yl] -5 -(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid;
  • Example 68 l-[6-(4-chloro-4'- ⁇ 4-[ ⁇ 2,2-difluorocyclopropyl)methyl]piperazin-l-yl ⁇ bipheny]-2- yl)pyridin-2-yl] - 5 -(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid;
  • Example 98 1 -(6- ⁇ 4-chloro-4'- [ 1 -(methoxycarbonyl)piperidin-4-yl]biphenyl-2-yl ⁇ pyridin-2-yl)-
  • Example 99 l-(6" ⁇ 4-chloro-4'-[l -(ethoxycarbonyl)piperidin-4-yl]biphenyl-2-yl ⁇ pyiidiii-2-yl)-5-
  • Example 101 1 -(6- (4-chloro-4'-[ 1 -(dimethylcarbamoyl)piperidin-4-yl]-3 '-methylbiphenyl-2- yl ⁇ pyridin-2-yl)-5 -(trifluoromethyl)- lH-pyrazole-4-carboxylic acid;
  • Example 1 1 l-(6- ⁇ 4-fluoro-4'-[l-(2,2,2-triflx]oroethyl)piperidin-4-yl]biphenyl-2-yl ⁇ pyridm-2- yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid;
  • Example 125 l-(6- ⁇ 3' J 4-difluoro-4'-[l -(2,2 : 2-trifliioroethyl)piperidin-4-yl]biphenyl-2-yl ⁇ -pyridiri-
  • Example 136 l-(6- ⁇ 4-fluoro-4'-[l-(33,3 rifluoropropyl)piperidin-4-yl]bipheny]-2-yl ⁇ pyridin-2- yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic cid;
  • Example 138 1 -(6- ⁇ 4-fluoro-3'-methyl-4'-[ 1 -(2,2,2-trifluoroethyl)piperidin-4-yl]biphenyl-2- yl ⁇ pyridin-2-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid;
  • Example 284 l 6- ⁇ 4-methyl-4'-[ l-(2,2,2 rifluoroethyl)piperidin-4-yl]biphenyl-2-yl ⁇ pyridin-2- yl)piperidine-4-carboxylic acid;
  • Example 285 l-(6 4-methyl-4'-[l -(2,2 5 2 rifluoroethyl)piperidin -yl]biphenyl-2-yl ⁇ pyridin-2- yl)aze ⁇ idine-3 -carboxylic acid;
  • Example 286 1 -(6- ⁇ 4-chloro-4'- [ 1 -(cyclopropylcarbonyl)piperidin-4-yl]biphenyl-2-yl ⁇ pyridin-2- yl)piperidme-4-carboxylic acid;
  • Example 291 (3R)- 1 -(6- ⁇ 4-chloro-4'-[ 1 -(2,2 s 2-trifluorocthyl)piperidiiv4-yl]biphenyl-2- yl ⁇ pyridin-2-yl)pyrrolidine-3-carboxylic acid;
  • Example 295 1 -(6- ⁇ 4-chloro-4'- [ 1 -(cyclopropylcarbonyl)piperidin-4-yl]-3'-methylbiphenyl-2- yl ⁇ pyridm-2-yl)pipendine-4-carboxylic acid;
  • Example 307 l -(6- ⁇ 4-chloro-4' 1-(2 J 2,2-trifluoroetliyl)piperidin-4-yl]biphenyl-2-yl ⁇ pyridin-2- yl)azetidine-3 -carboxylic acid.
  • Example 60 1 -(6-(4-chloro-4'-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-[1 , 1 '-biphenyl]-2- yl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;
  • Example 94 1 -(6-(4-chloro-4'-(1-(cyclopropanecarbonyl)piperidin-4-yl)-[1 , 1 '-biphenyl]-2- yl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid; and
  • Example 175 1 -(6-(4-chloro-4'-(4-(2,2,2-trifluoroethyl)piperazin-1 -yl)-[1 , 1 '-biphenyl]-2- yl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylic acid.
  • the invention provides methods of treating or preventing glaucoma or reducing intraocular pressure according to the first embodiment in which the method comprises administering to a subject in need of such therapy a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2010/099054 which is incorporated by reference for the compounds disclosed therein.
  • the fourth embodiment provides for the administration of a sGC activator of formula (III):
  • W is selected from the group consisting of CH and N;
  • Z is selected from the group consisting of:
  • Rl is selected from the group consisting of -OH, -OCj-e alkyl and -N(R5)2;
  • R2 is selected from the group consisting of -Ci -2 perfluoroalkyl and -NI3 ⁇ 4;
  • R3 is selected from the group consisting of:
  • R4 is selected from the group consisting of:
  • R5 is independently selected at each occurrence from -H and -C1-3 alkyl
  • R ⁇ is selected from the group consisting of -C]._3alkyl; -C3 relieve6cycIoalkyl optionally mono- or di- substituted with one or more substituents selected from the group consisting of -CH3 and ⁇ F; and -CH2-C3-6cycloalkyl optionally mono- or di-substituted with one or more
  • R? is selected from the group consisting of -H and -CH3;
  • Ra and Rb are independently selected at each occurrence from -F, -CI and -C1-3 alkyl
  • Rc and d are independently selected at each occurrence from -F, -CI and ⁇ Ci -3 alkyl
  • the sGC activator of Formula (III) is selected from the group consisting of:
  • a preferred sGC activator compound of Formula III which is suitable for use in the methods for the treatment or prevention of glaucoma or in the reduction of intraocular pressure provided in the fourth embodiment is 1 -(6-(2-((4-(1 -(methoxycarbonyl)piperidin-4-yl)benzyl)oxy)-3- (trifluoromethyl)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (example77 of WO2010/
  • the invention provides methods of treating or preventing glaucoma or reducing intraocular pressure according to the first embodiment in which the method comprises administering to a subject in need of such therapy a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2009/071504 which is incorporated by reference for the compounds disclosed therein.
  • a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2009/071504 which is incorporated by reference for the compounds disclosed therein.
  • the sGC activator of Formula (IV) is selected from the group consisting of:
  • a preferred sGC activator compound of Formula IV which is suitable for use in the methods for the treatment or prevention of glaucoma or in the reduction of intraocular pressure provided in the fifth embodiment is 1 -(6-(2-((3-methyl-4'-(trifluoromethoxy)-[1 , 1 '-biphenyl]-4- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-i/-/-pyrazole-4-carboxylic acid (example 9 of WO2009/071504) which has the structure:
  • the invention provides methods of treating or preventing glaucoma or reducing intraocular pressure according to the first embodiment in which the method comprises administering to a subject in need of such therapy a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2012/122340 which is incorporated by reference for the compounds disclosed therein.
  • a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2012/122340 which is incorporated by reference for the compounds disclosed therein.
  • the sixth embodiment provides for the administration of a sGC activator of formula (V):
  • A is a 5- or 6-membered aryl, heteroaryl or heterocyclyl group
  • B is a 5-7 membered heterocyclyl group containing one nitrogen, wherein one carbon of the heterocyclyl group is optionally substituted with an oxo group, or B is a 5-membered heteroaryl
  • R 1 and R 2 are independently selected from H, d-C 4 alkyl, C 3 -C 6 cycloalkyi,
  • R 3 is selected from H and methyl
  • R 4 is selected from H, C C 4 alkyl, C3-C7 cycloalkyi, -C(O) Ci-C 6 alkyl, CH 2 CF 3 , -S0 2 Ci- C 6 alkyl, S0 2 (CH 2 )i- 3 C0 2 H, C0 2 CrC 4 alkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 2 alkyl heterocyclyl C C 2 alkylaryl and C 1 -C 2 alkylheteroaryl, wherein said heterocyclyl, cycloalkyi, aryl and heteroaryl are optionally substituted with one to two groups independently selected from C-
  • R 4 is optionally not present when B is a heteroaryl group;
  • R is selected from H, Ci-C 3 alkyl, methoxy, trifluoromethyl, -CN and CI; and
  • R 6 is selected from H and methyl;
  • R 5 and R 6 are not both H
  • the sGC activator of Formula (V) is selected from the group consisting of:
  • Preferred sGC activator compounds of Formula V which are suitable for use in the methods for the treatment or prevention of glaucoma or in the reduction of intraocular pressure provided in the sixth embodiment are compounds 18 and 29 of WO2012/122340 which have the structures:
  • the invention provides methods of treating or preventing glaucoma or reducing intraocular pressure according to the first embodiment in which the method comprises administering to a subject in need of such therapy a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2013/025425 which is incorporated by reference for the compounds disclosed therein.
  • the seventh embodiment provides for the administration of a sGC activator of formula (VI):
  • E is selected from pyrrolidm- 1 ⁇ yl, piperidi.n-1 ⁇ yi azetidin-l-yi 5 ⁇ aza$piro[2.3Jhexan-5 ⁇ yi azep n- I -yh .Va3 ⁇ 4abicycto£3,
  • R" and R 5 ar iRde-pendeatly selected from H, ⁇ . ial geo, M and ⁇ £ provided tnat at least one of R " or R ⁇ Is H
  • R* selected fromTMC(0 ⁇ (R*)(R ? ), - €£0)R and -CH(R ⁇ ;
  • E is selected from H» C alkyi halogen, -CF* ⁇ -OC M alkyl, ⁇ 0 €J3 ⁇ 4 and ⁇ €N
  • the sGC activator of Formula (VI) is selected from the group consisting of:
  • Preferred sGC activator compounds of Formula VI which are suitable for use in the methods reatment or prevention of glaucoma or in the reduction of intraocular pressure provided in the seventh embodiment are compounds 151 and 234 of WO2013/025425 which have the structures:
  • the invention provides methods of treating or preventing glaucoma or reducing intraocular pressure according to the first embodiment in which the method comprises administering to a subject in need of such therapy a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2009/068652 which is incorporated by reference for the compounds disclosed therein.
  • a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2009/068652 which is incorporated by reference for the compounds disclosed therein.
  • n 1 or 2;
  • each R 1 independently represents haio or trifluoromeihyl; wherein halo represents fluoro, chloro or bromo;
  • R 2 represents hydrogen or Chalky!
  • X represents N or CH
  • -Z ⁇ represents a group selected from:
  • R 3 represents trtf!uoromethyi or Chalky!
  • R 4 represents hydrogen, trifluoromethyl or Ci. 3 alkyl
  • Z represents a thiophene group and X represents N
  • R 2 cannot represent C ⁇ alkyl
  • X represents CH
  • -Z- can additionally represent a group selected from:
  • the sGC activator of Formula (VII) is selected from the group consisting of:
  • Preferred sGC activator compounds of Formula VII which are suitable for use in the methods for the treatment or prevention of glaucoma or in the reduction of intraocular pressure provided in the eighth embodiment is 1- ⁇ 6-[3(trifluoromethyl)phenyl]-2-pyridinyl ⁇ -5-(trifluoromethyl)- 1 /-/-pyrazole-4-carboxylic acid, i.e., example 4, of WO2009/068652 which has the structure:
  • Preferred sGC activator compounds suitable for use in any one of embodiments 2 to 8 include those compounds which reduce lOP in monkey or human by at least 20% compared to baseline at 6 hours and/or 24 hours post topical ocular administration of the sGC activator. In certain compounds the lOP reduction is at least 25% or at least 30% at 6 and/or 24 hours post administration.
  • the invention provides methods of treating or preventing glaucoma or reducing lOP in a patient in need of such therapy, the method comprising administering an sGC activator selected from compounds according to Formula VIII or IX:
  • A is a bond or CH 2 0; R is C0 2 H or C(0)-C C 4 alkoxy;
  • R 1 is halogen, Ci-C 4 alkyl, or trifluoromethyl
  • R 2 is cyclohexyl substituted with R 4 , piperidinyl or piperazinyl each of which is substituted with R 5 or phenyl substituted with R 6 ;
  • R 3 is hydrogen
  • Ci-C 4 alkyl substituted with Ci-C 4 alkyl, halo Ci-C 4 alkyl, tetrahydropyranyl, tetrahydrofuranyl, benzyl, C(O) Ci-C 4 alkyl, C(O) C 3 -C 5 cycloalkyl, CH 2 -heteroaryl, which heteroaryl has 5 or 6 ring atoms, 1 or 2 ring heteroatoms independently selected from N, O and S and is optionally substituted by Ci-C 4 alkyl;
  • R 4 is C C 4 alkyl or haloC C 4 alkyl
  • R 5 is C C 4 alkyl, haloC C 4 alkyl, C(0)C C 4 alkyl, C(0)C 3 -C 6 cycloalkyl, C(0) 2 C C 4 alkyl, C(0) 2 C 3 -C 6 cycloalkyl;
  • R 6 is CrC 4 alkyl, haloCrC 4 alkyl, Ci-C 4 alkoxy or haloCrC 4 alkoxy;
  • R 7 is CrC 4 alkyl or haloCrC 4 alkyl
  • R 8 is hydrogen or Ci-C 4 alkyl.
  • the sGC activator suitable for use in the methods of the invention is selected from the group consisting of:
  • the sGC activator suitable for use in the methods of treating glaucoma is 1 - ⁇ 6-[5-chloro-2-( ⁇ 4-[frans-4-(trifluoromethyl)cyclohexyl]benzyl ⁇ oxy)phenyl]pyridine-2- yl ⁇ -5-(trifluoromethyl)- 7/-/-pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
  • the sGC activator suitable for use in the methods of treating glaucoma is 1 -(6-(2-((4-(1 -(methoxycarbonyl)piperidin-4-yl)benzyl)oxy)-3- (trifluoromethyl)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylic acid or a
  • the sGC activator suitable for use in the methods of treating glaucoma is 1-(6-(2-((3-methyl-4'-(trifluoromethoxy)-[1 ,1 '-biphenyl]-4-yl)methoxy)phenyl)pyridin-2- yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
  • the sGC activator suitable for use in the methods of treating glaucoma is 1 -(6-(5-methyl-2-((2-((4-methylthiazol-2-yl)methyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-i/-/-pyrazole-4-carboxylic acid or a
  • the sGC activator suitable for use in the methods of treating glaucoma is 1 -(6-(5-methyl-2-((2-(pyridin-2-ylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylic acid or a
  • Halogen denotes fluorine, chlorine, bromine or iodine.
  • a halogenated group or moiety such as halogenalkyl, can be mono-, poly- or per-halo- genated.
  • An aryl group, ring or moiety is a naphthyl or, preferably, phenyl group, ring or moiety.
  • a heteroaryl group, ring or moiety is a monocyclic aromatic 5- or 6-membered structure, in which structure 1 , 2, 3 or 4 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, such as furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl or pyridyl; or
  • bicyclic aromatic 9- or 10- or membered structure in which structure 1 , 2, 3, 4 or 5 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member.
  • the fused rings completing the bicyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated.
  • Heteroaryl groups which are bicyclic include at least one fully aromatic ring but the other fused ring may be aromatic or non-aromatic.
  • bicyclic heteroaryl groups include, benzofuranyl, benzothiophenyl, imidazopyridinyl, indazolyl, indolyl, isoquinolinyl, pyrazolopyridinyl and quinolinyl.
  • the heteroaryl radical may be bonded via a carbon atom or heteroatom.
  • the heteroaryl group is an aromatic 5- or 6-membered structure, in which structure 1 , 2, 3 or 4 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member.
  • a non-aromatic heterocyclyl group, ring or moiety is a non-aromatic 4-, 5-, 6- or 7-membered cyclic structure, in which cyclic structure 1 , 2 or 3 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, such as azetidinyl, oxetanyl, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl, morpholinyl or perhydroazepinyl. Any non-cyclic carbon containing group or moiety with more than 1 carbon atom is straight- chain or branched.
  • carbon containing groups, moieties or molecules contain 1 to 8, 1 to 6, 1 to 4 or 1 or 2 carbon atoms.
  • alkoxy alkenoxy and alkynoxy respectively denote alkyl, alkenyl and alkynyl groups when linked by oxygen.
  • a compound of the invention refers to a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or any embodiment thereof including the examples.
  • the sGC activator compound may be administered alone or in combination with a second therapeutic agent which is suitable for the treatment of glaucoma.
  • second therapeutic agents include beta-blockers, prostaglandin analogs, carbonic anhydrase inhibitors, a2 agonists, miotics, and neuroprotectants.
  • latanaprost is administered in combination with a sGC activator compound of any one of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX).
  • the concentration of the sGC activator in the compositions of the present invention can vary, but is preferably 0.01 to 3.0 w/v% and more preferably 0.05-1.0 w/v%.
  • the most preferred concentration range is from 0.05-0.5 w/v% and the most preferred concentration is about 0.1 w/v%.
  • the syk sGC activators of the present invention comprise the pharmaceutically useful hydrates and salts of such compounds and stereoisomers (where applicable), and may be formulated with a pharmaceutically acceptable vehicle.
  • compositions of the present invention may be utilized in various dosage regimens known to those of skill in the art. Such dosing frequency is maintained for a varying duration of time depending on the therapeutic regimen. The duration of a particular therapeutic regimen may vary from one-time dosing to a maintenance regimen that extends for a month, year or more. One of ordinary skill in the art would be familiar with determining a therapeutic regimen for a specific indication. Preferred dosage regimens of the present invention include, but are not limited to, once a day dosing and twice a day dosing.
  • administration to a subject of a composition of the present invention may be by various methods known to those of skill in the art, including, but not limited to, topical, subconjunctival, periocular, retrobulbar, subtenon, intraocular, subretinal, posterior juxtascleral, or suprachoroidal administration.
  • administration of a composition of the present invention is by topical administration to the ocular surface.
  • the methods of treating glaucoma may include administering the sGC activator compound by a technique selected from the group consisting of: periocular injection, sub-conjunctival injection, sub-tenon injection, intracameral injection, intravitreal injection, intracanalicular injection, implanting delivery device in the cul-de-sac, implanting delivery device adjacent to the sclera, implanting delivery device within the eye, oral administration, intravenous administration, subcutaneous administration, intramuscular administration, parenteral administration, dermal administration, and nasal administration.
  • formulations care which include both fixed and unfixed combinations of the two therapeutic agents effective in the treatment of glaucoma wherein one therapeutica agent is sGC activator disclosed supra and the second therapeutic agent is an active glaucoma drugs.
  • a pharmaceutical composition of the invention comprising a sGC activator can be administered to a patient alone or in combination with other IOP- lowering agents to increase the potency, efficacy and/or duration of the IOP reduction, including, but not limited to, carbonic anhydrase inhibitors, beta-blockers, prostaglandins, alpha-2 agonists, serotonin-2 agonists, alpha-1 antagonists, dopamine agonists, Rho kinase inhibitors, myosin-ll Ca2 +ATPase, inhibitors, matrix metalloproteinase activators, activator protein-1 (AP-1 ) activators, natriuretic peptide receptor-B agonists, phosphodiesterase inhibitors, K+
  • the combination therapy of the invention provides the benefit of lowering IOP by two mechanisms, including inducing uveoscleral outflow of aqueous humor and inhibiting aqueous humor inflow, which can allow for reduced dosages of the compounds thereby lowering the risk of side effects.
  • compositions of the invention can also be advantageously combined with suitable neuroprotective agents such as memantine, eliprodil, Ca2+ -channel blockers, betaxolol, and the like.
  • suitable neuroprotective agents such as memantine, eliprodil, Ca2+ -channel blockers, betaxolol, and the like.
  • a sGC activator and the second pharmaceutical agent are
  • a sGC activator and the second pharmaceutical agent are administered formulated together in a
  • compositions are administered sequentially in separate pharmaceutical compositions.
  • compositions of the present invention optionally comprise one or more excipients.
  • excipients commonly used in pharmaceutical compositions include, but are not limited to, tonicity agents, preservatives, chelating agents, buffering agents, surfactants and antioxidants.
  • Other excipients comprise solubilizing agents, stabilizing agents, comfort-enhancing agents, polymers, emollients, pH-adjusting agents and/or lubricants.
  • excipients may be used in compositions of the present invention including water, mixtures of water and water- miscible solvents, such as C1 -C7-alkanols, vegetable oils or mineral oils comprising from 0.5 to 5% non-toxic water-soluble polymers, natural products, such as alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia, starch derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably cross-linked polyacrylic acid and mixtures of those products.
  • concentration of the excipient is, typically, from 1 to 100,000 times the concentration of the sGC activator. In preferred embodiments, excipients are selected on the basis of their inertness towards the sGC activator.
  • suitable tonicity-adjusting agents include, but are not limited to, mannitol, sodium chloride, glycerin, sorbitol and the like.
  • Suitable buffering agents include, but are not limited to, phosphates, borates, acetates and the like.
  • Suitable surfactants include, but are not limited to, ionic and nonionic surfactants (though nonionic surfactants are preferred), RLM 100, POE 20 cetylstearyl ethers such as Procol ® CS20 and poloxamers such as Pluronic ® F68.
  • Suitable antioxidants include, but are not limited to, sulfites, ascorbates, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
  • compositions set forth herein may comprise one or more preservatives.
  • preservatives include p-hydroxybenzoic acid ester, sodium chlorite, benzalkonium chloride, parabens such as methylparaben or propylparaben, alcohols such as chlorobutanol, benzyl alcohol or phenyl ethanol, guanidine derivatives such as polyhexamethylene biguanide, sodium perborate, or sorbic acid.
  • the composition may be self-preserved that no preservation agent is required.
  • a sGC activator of the present invention will be formulated for topical application to the eye in aqueous solution in the form of drops.
  • aqueous typically denotes an aqueous composition wherein the composition is >50%, more preferably >75% and in particular >90% by weight water.
  • These drops may be delivered from a single dose ampoule which may preferably be sterile and thus render bacteriostatic components of the composition unnecessary.
  • the drops may be delivered from a multi-dose bottle which may preferably comprise a device which extracts any preservative from the composition as it is delivered, such devices being known in the art.
  • components of the invention may be delivered to the eye as a concentrated gel or a similar vehicle, or as dissolvable inserts that are placed beneath the eyelids.
  • components of the invention may be delivered to the eye as ointments, water-in-oil and oil-in- water emulsions, solutions, or suspensions.
  • compositions of the present invention are preferably isotonic or slightly hypotonic in order to combat any hypertonicity of tears caused by evaporation and/or disease. This may require a tonicity agent to bring the osmolality of the
  • compositions to a level at or near 210-320 milliosmoles per kilogram mOsm/kg.
  • the compositions of the present invention generally have an osmolality in the range of 220-320 mOsm/kg, and preferably have an osmolality in the range of 235-300 mOsm/kg.
  • the ophthalmic compositions will generally be formulated as sterile aqueous solutions.
  • a sGC activator of the present invention is formulated in a composition that comprises one or more tear substitutes.
  • tear substitutes include, but are not limited to: monomeric polyols, such as, glycerol, propylene glycol, and ethylene glycol; polymeric polyols such as polyethylene glycol; cellulose esters such hydroxypropylmethyl cellulose, carboxy methylcellulose sodium and hydroxy propylcellulose; dextrans such as dextran 70; vinyl polymers, such as polyvinyl alcohol; guars, such as HP-guar and other guar derivatives, and carbomers, such as carbomer 934P, carbomer 941 , carbomer 940 and carbomer 974P. Certain compositions of the present invention may be used with contact lenses or other ophthalmic products.
  • compositions set forth herein have a viscosity of 0.5-100 cps, preferably 0.5-50 cps, and most preferably 1-20 cps. These viscosities insure that the product is comfortable, does not cause blurring, and is easily processed during manufacturing, transfer and filling operations.
  • compositions are prepared using a buffering system that maintains the composition at a pH of about 3 to a pH of about 8.0, preferably 5.5-7.5, and most preferably 6.0-7.4.
  • Topical compositions are preferred which have a physiological pH matching the tissue to which the composition will be applied or dispensed.
  • Example 1 -A Ethyl 1 -(6-(5-chloro-2-((4-((1 r,4r)-4-
  • Example 1 1- ⁇ 6-[5-chloro-2-( ⁇ 4-[frans-4-(trifluoromethyl)cyclohexyl]benzyl ⁇ oxy)phenyl]pyridine-2- yl ⁇ -5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid
  • the reaction mixture was cooled to room temperature, and rendered acidic by addition of aqueous HCI.
  • the mixture was dilited with dioxane, and filtered.
  • the filtrate was purified by RP-HPLC (stationary phase; SunFireTM Ci 8 , OBDTM 5 ⁇ : mobile phase; gradient, 0.1 % TFA in H 2 0/CH 3 CN) to afford the title compound.
  • Example 2 1-(6-(2-((3-Methyl-4'-(trifluoromethoxy)-[1 , 1 '-biphenyl]-4-yl)methoxy)phenyl)pyridin-2- yl)-5-(trifluoromethyl)-1 H-pyrazole- -carboxylic acid
  • Example 3-A ferf-Butyl 4-(4-((2-(6-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1 /-/-pyrazol-1-yl)pyridin-2- yl)-6-(trifluoromethyl)phenoxy)methyl)phenyl)piperidine-1-carboxylate
  • Example 3-B Ethyl 1 -(6-(2-((4-(piperidin-4-yl)benzyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)-5- (trifluoromethyl)-1 H-pyrazole-4-carboxylate
  • Example 3-C Methyl 4-(4-((2-(6-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-2- yl)-6-(trifluoromethyl)phenoxy)methyl)phenyl)piperidine-1 -carboxylate
  • Example 4-A Ethyl 1-(6-(5-methyl-2-((2-(pyridin-2-ylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylate
  • Example 4 1 -(6-(5-methyl-2-((2-(pyridin-2-ylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid
  • Example 5-A Ethyl 1 -(6-(5-methyl-2-((2-((4-methylthiazol-2-yl)methyl)-1 ,2,3,4- tetrahydroisoquinolin-6-yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4- carboxylate
  • Example 5 1 -(6-(5-Methyl-2-((2-((4-methylthiazol-2-yl)methyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylic acid
  • Example 6 1 -(6-(5-Methyl-2-((2-(4-(trifluoromethyl)cyclohexyl)-1 ,2,3,4-tetrahydroisoquinolin- 6-yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (single diastereomer, peak-1 ) and 1 -(6-(5-methyl-2-((2-(4-(trifluoromethyl)cyclohexyl)-1 ,2,3,4- tetrahydroisoquinolin-6-yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4- carboxylic acid (single diastereomer, peak-2).
  • sGC compounds which are suitable for use in the formulations and methods for the treatment of glaucoma and/or ocular hypertension are tabulated infra.
  • the compounds may be prepared in accordance with the reference synthethesis which is incorporated herein by reference.
  • CHO cells overexpressing soluble guanylate cyclase were generated to test the effect of sGC activators in a cellular context.
  • Human cDNAs for GUCYA3 (RefSeq: NM_000856.3) and GUCYB3 (RefSeq: NM_000857.1 ) were amplified by PCR from a HUVEC (Human Umbilical Vein Endothelial Cells) cDNA library and cloned into mammalian expression vectors.
  • HUVEC Human Umbilical Vein Endothelial Cells
  • CHO K1 cells ATCC CCL-61
  • CHO GUCY clone 8E10 was used for subsequent experiments.
  • sGC activators were serially diluted in DMSO, then diluted in assay buffer prior to adding to cells (10ul/well, final DMSO concentration 0.5%). Cells were incubated with compounds for 1 h room temperature, then assayed for cGMP production using Cisbio cGMP HTRF kit (62GM2PEC) according to manufacturer's instructions. The EC50s are calculated based on the amount of cGMP interpolated from the standard curve, using a 4-parameter sigmoidal dose-response.
  • GTM-3 cells SV40-transformed human glaucomatous trabecular meshwork cells, Alcon Laboratories
  • sGC activators serially diluted in DMSO were added (final DMSO concentration 0.1 %). Cells were incubated 30 min at 37°C, then cGMP was quantitated using CatchPoint Cyclic-GMP
  • the EC50s are calculated based on the amount of cGMP interpolated from the standard curve, using a 4-parameter sigmoidal dose-response.
  • the listed compounds were tested in the CHO and/or GTM-3 cell-based assays.
  • the average EC50 calculated from 2-4 independent experiments is shown, along with the maximal concentration of cGMP generated by each compound.
  • Conscious intraocular pressure was determined with an Alcon Pneumatonometer (Alcon Laboratories, Inc., Fort Worth, TX.) after light corneal anesthesia with 0.25% proparacaine. Right eyes were hypertensive as a result of laser trabeculoplasty. Left eyes were intact and with normal lOP. After a baseline lOP measurement, the animals were randomly divided into two groups with similar group mean of lOP. Compounds in Formula 1 vehicle were administered topical ocular of both eyes in 8-9 conscious ocular hypertensive Cynomolgus monkeys.
  • the Formula 1 vehicle used in the current studies include hydroxypropyl methylcellulose (0.5%), anhydrous dibasic sodium phosphate (0.2-0.5%), sodium chloride (0.5-0.75%), disodium EDTA (Edetate disodium) (0.01 %), polysorbate 80, (0.05%), benzalkonium chloride (0.01 %), sodium hydroxide/hydrochloric acid (for adjusting pH to 7.3-7.4), and purified water (q.s. to 100%), Vehicle was instilled in both eyes of 8-9 additional animals as control. Subsequent lOP measurements were typically taken at 1 , 3, 6, and 24 hours post-dose. The percent change in lOP from baseline was determined for each animal for every IOP measurement. Group mean and standard error of the mean (SEM) were calculated. Statistical significance of IOP change from baseline and also versus treatment groups were determined by repeated measures ANOVA and Bonferroni t-test at p ⁇ 0.05.
  • QD once-daily
  • BID twice daily administration

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Abstract

An ophthalmic pharmaceutical composition useful in the treatment of glaucoma and control of intraocular pressure comprising an effective amount of a soluble guanylate cyclase (sGC) activator is disclosed. Also disclosed is a method of treating glaucoma and controlling intraocular pressure comprising applying a therapeutically effective amount of a pharmaceutical composition comprising a soluble guanylate cyclase (sGC) activator to an affected eye of a patient.

Description

sGC ACTIVATORS FOR THE TREATMENT OF GLAUCOMA
FIELD OF THE INVENTION
The present invention is related generally to treatments for glaucoma and more specifically to agents which activate soluble guanylate cyclase (sGC) thereby lowering intraocular pressure such as that associated with glaucoma and ocular hypertension.
BACKGROUND OF THE INVENTION
The eye disease glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve. The several morphologically or functionally distinct types of glaucoma are typically characterized by an undesirable elevation of intraocular pressure (IOP), which is considered to be causally related to the pathological course of the disease. Continuously elevated IOP has been associated with the progressive loss of retinal ganglion cells, optic nerve damage ultimately resulting in the loss of visual function. In some cases, ocular hypertension, a condition in which IOP is elevated, can present without apparent loss of visual function. However, patients with ocular hypertension are considered to be at a high risk for eventually developing the visual loss associated with glaucoma. Therefore, lowering IOP is the current treatment objective for the of glaucoma patients and for patients with ocular hypertension in order to decrease the potential for, or severity of, glaucomatous retinopathy. Unfortunately, many individuals do not respond well when treated with existing glaucoma therapies.
Patients known as normotensive or low-tension glaucoma patients have relatively low IOP, yet present with glaucomatous visual field loss. These patients may benefit from agents that lower and control IOP, because glaucoma that is detected early and treated promptly may have reduced or delayed loss of visual function. Conventional therapeutic agents that have proven to be effective for the reduction of IOP include both agents that decrease aqueous humor production and agents that increase the uveoscleral outflow. There are currently no approved agents that directly increase conventional outflow facility via trabecular meshwork and Schlemm's canal. Such agents are in general administered by one of two routes; topically by direct application to the eye, or orally.
However, many of these agents have associated side effects which may render them undesirable as ocular therapeutic agents.
Soluble guanylate cyclase (sGC) is a receptor enzyme for the second messenger, nitric oxide (NO) in several cell types including muscle, epithelia, neuronal, and endothelial cells. In humans, functional sGC is a heterodimer composed of either an alpha 1 or alpha 2 subunit combined with the beta 1 subunit which has a heme prosthetic group. Under physiological conditions, NO binds to the prosthetic heme of sGC which activates the enzyme to catalyze the conversion of guanosine-5'-triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP is a second messanger which in turn exerts its effects by activating cGMP dependent protein kinase (PKG) isoforms, phosphodiesterases, and cGMP gated ion channels. In doing so, sGC can thus modulate numerous pathways associated with diseases including hypertension (arterial and pulmonary), heart failure, atherosclerosis, erectile dysfunction, liver cirrhosis, and renal fibrosis. Under aforementioned pathologic conditions prolonged oxidative stress can cause the oxidation of the heme group of sGC (from ferrous to ferric state) which is incapable of being activated by NO and can contribute to exacerbation of disease processes. As a consequence of sGC oxidation and unresponsiveness to NO, endothelial dysfunction, atherosclerosis, hypertension, stable or unstable angina pectoris, thromboses, myocardial infarction, strokes or erectile dysfunction are worsened. Therefore, pharmacological stimulation or activation of sGC offers a possibility to normalize cGMP production and therefore makes possible the treatment and/or prevention of such disorders.
To this effort, there are two classes of compounds have been identified, including NO- independent/reduced heme-dependent sGC stimulators and NO-independent/heme-independent sGC activators. sGC stimulators are dependent on heme, but they are not active once sGC become oxidized. sGC activators on the other hand can still activate the enzyme to generate cGMP even in the absence of nitric oxide (NO) synthesis, NO availability and oxidative stress induced heme iron oxidation of sGC in disease pathology. Thus the activity of sGC in these situations will be corrected by sGC activators, but not by sGC stimulators, and will have the potential to provide benefit in many diseases caused by defective signaling in the NO pathway especially following oxidative stress.
SUMMARY OF THE INVENTION
The present invention in part relates to methods of treating glaucoma in human patients or other mammals. The present invention also relates to methods of lowering or controlling normal or elevated IOP in a human patient or other mammals. In particular, the invention provides methods of treating and/or preventing glaucoma by administration of an sGC activator compound described infra.
In the eye, the trabecular outflow pathway by which 70-80% of aqueous humor would normally leave the anterior chamber of the eye and lower intraocular pressure (IOP), is
pathologically compromised in primary open angle glaucoma (POAG). Oxidative stress is thought to be an underlying factor that can adversely affect trabecular meshwork function, resulting from/in IOP elevation in POAG. Reactive oxygen species (ROS) not only decrease the bioavailability of nitric oxide (NO) but also shift the sGC redox equilibrium to its oxidized form, which as mentioned before is unresponsive to NO. Selective activation of the oxidized form of sGC should target only the diseased state of the target enzyme in the putative target tissue, trabecular
meshwork/Schlemm's canal tissue, thus offering a highly innovative therapy for glaucoma that should work adjunctively with current therapies. Certain embodiments of the present invention comprise compositions or methods which include or use compounds capable of activating sGC thereby modulating intraocular pressure in the eye. By activating sGC receptor activity, subject compounds according to certain embodiments of the present invention are accordingly useful for lowering and/or controlling IOP associated with normal-tension glaucoma, ocular hypertension, and glaucoma, including primary open-angle glaucoma in humans and other warm-blooded animals. When used in such applications, the compounds may be formulated in pharmaceutical compositions suitable for topical delivery to the eye.
Certain sGC activators which are contemplated for use in the methods of the instant invention include those compounds prepared and disclosed by WO2009/032249, WO2012/058132, WO2010/099054, WO2009/071504, WO2012/122340, WO2013/025425 and WO2009/068652, each of which is incorporated by reference.
The foregoing brief summary broadly describes the features and technical advantages of certain embodiments of the present invention. Additional features and technical advantages will be described in the detailed description of the invention that follows. Novel features which are believed to be characteristic of the invention will be better understood from the detailed description of the invention when considered in connection with any accompanying figures. However, figures provided herein are intended to help illustrate the invention or assist with developing an understanding of the invention, and are not intended to be definitions of the invention's scope
DESCRIPTION OF THE INVENTION
In a first embodiment, the present invention relates to a method of treating or preventing glaucoma or reducing intraocular pressure comprising administering to a subject in need thereof a sGC activator. The invention has surprisingly shown, in a clinically relevant animal model, that administration of certain classese of sGC activators provides desirable sustained efficacy in reducing intraocular pressure (IOP) that is superior to reduction observed by administration of sGC stimulators. Thus, sGC activators are useful in the treatment of glaucoma and ocular hypertension.
As the term are used herein, a "sGC activator" is a compound capable of modulating sGC activity in pathologically changed heme-free sGC (i.e., following heme oxidation) to generate cGMP signaling which would otherwise be unresponsive to nitric oxide. In contrast, "sGC stimulators" refers to compounds that are capable of synergizing with nitric oxide and can directly stimulate cGMP production so long as the heme domain is present in the enzyme.
In a second embodiment, the invention provides methods of treating or preventing glaucoma or reducing intraocular pressure according to the first embodiment in which the method comprises administering to a subject in need of such therapy a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2009/032249 which is incorporated by reference for the compounds disclosed therein. In particular, the second embodiment provides for the administration of a sGC activator of formula (I):
Figure imgf000005_0001
And pharmaceutically acceptable salts thereof, wherein Z1 is selected from the group consisting of CH and N;
ring selected from the grup consisting of
Figure imgf000005_0002
Dl is CH, CR4 or N;
R7 is selected from the group consisting of
1) hydrogen,
2) Ci-6 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms and unsubstituted or monosubstituted with OC 1-3 alkyl,
3) C3-6 cycloalkyl wherein the cycloalkyl group may be unsubstituted or substituted with
1-3 fluorine atoms and unsubstituted or monosubstituted with OCi-3 alkyl, and
4) phenyl, wherein the phenyl group is unsubstituted or substituted with C1.4 alkyl, -OCi-
4 alkyl, halogen, CN, NO2, and S(O)0-2Cl-4 alkyl, wherein Ci-4 alkyl and -OC1-4 alkyl are unsubstituted or substituted with 1-3 flourine atoms;
Li is selected from the group consisting of O, S, C(Rl )2; and CF2;
L2 is selected from the group consisting of (CH2>2-4, -C(Rl2)2, -CF2- O, and S, provided that when Ll is 0 or S, L2 is not O or S;
Rl2 is independently selected from the group consisting of hydrogen and C 1.3 alkyl, wherein C
1-3 alkyl is unsubstituted or substituted with 1-3 flourine atoms;
E is a ring selected from the group consisting of
1) a 6-10 membered aryl ring,
2) a 5-10 membered heteroaryl ring having 1, 2 or 3 heteroatoms independently selected from the group consisting of 0, 1, 2, and 3 N atoms, 0 or 1 O atoms, and 0 or 1 S atoms,
3) a C3-8 cycloalkyl ring; wherein aryl, heteroaryl, and C -j_g cycloalkyl are unsubstituted or monosubstituted with R-*, and unsubstituted, monosubstituted or independently disubstituted with R^; in each instance in which it occurs, is independently selected from the group consisting of halogen,
Cj-6 alkyl, wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms,
-O-Ci-6 alkyl, wherein the alkyl group may be unsubstituted or substituted with 1-3
fluorine atoms,
C3-8 cycloalkyl, unsubstituted or substituted with 1-3 fluorine atoms,
-O-C3-8 cycloalkyl, unsubstituted or substituted with 1-3 fluorine atoms,
CN, and
N02;
in each instance in which it occurs, is independently selected from the group consisting of
1) R6
2) -OR6,
3) Ci-6 alkyl which may be unsubstituted or substituted with 1-3 fluorine atoms, and unsubstituted or monosubstituted with a group independently selected from C3.6 cycloalkyl, -O-C1.4 alkyl, OH, =0, S(O)0-2Cl-4 alkyl, -OR6 and R ,
4) Ci-6 alkenyl which may be unsubstituted or substituted with 1-3 fluorine atoms and unsubstituted or monosubstituted with a group independently selected from -O-Ci-4 alkyl, OH, =0, S(O)0-2Ci-4 alkyl, -OR6 and R6,
5) O-Ci-6 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, and unsubstituted or monosubstituted with a group independently selected from C3.6 cycloalkyl and R6,
6) -S-C 1-6 alkyl,
7) a C3-8 cycloalkyl ring which is unsubstituted or mono, di- or tri-substituted with groups independently selected from fluoro and CI -4 alkyl, and unsubstituted or
monosubstituted with a group independently selected from Ci-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, -O-Cl-4 alkyl, OH, =0, S(O)0-2Cl-4 alkyl, -OR6, R and NR9R10, 8) a C5-8 cycloalkenyl ring which is unsubstituted or mono, di- or tri-substituted with a group independently selected from fluoro and Cl-4 alkyl, and unsubstituted or monosubstituted with a group independently selected from Cl-4 alkyl, wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, -O-Ci-4 alkyl, OH, =0, S(O)0-2Cl-4 alkyl, and R6,
9) a 5- to 6 membered heterocyclyl ring having 1 or 2 heteroatoms selected from the group consisting of N, O and S, and which is unsubstituted or monosubstituted with a group independently selected from C 1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, -OCi-4 alkyl, and =0, and
10) halogen;
KG is selected from the group consisting of
1) a phenyl ring which is unsubstituted, monosubstituted or disubstituted with a group independently selected from the group consisting of halogen, OH, CN, C1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, OC]-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, NO2, S(O)0-2Q-4 alkyl, C2-4 alkenyl, O-C2-4 alkenyl, NR9R10, and COOH, and
2) a 5-6 membered heteroaryl ring containing 1-2 heteroatoms which are independently selected from N, O and S, wherein the heteroaryl ring is unsubstituted, monosubstituted or disubstituted with a group independently selected from: halogen, OH, CN, C1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, OC1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms, NO2, S(O)0-2Cl-6 alkyl, S(O)0-2 aryl, C2-6 alkenyl, OC2-6 alkenyl, NR9R10, and COOH;
R8 is selected from the group consisting of
C1-4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms,
C2-4 alkenyl,
halogen,
¾-6 cycloalkyl, wherein the cycloalkyl group may be unsubstituted or substituted with 1- 3 fluorine atoms OCj_4 alkyl wherein the alkyl group may be unsubstituted or substituted with 1-3 fluorine atoms*
O-C2-4 alkenyl,
N02)
S(O)0-2C 1 -4 alkyl, and
CN;
R9 and RlO are independently selected from the group consisting of hydrogen and Ci-6 alkyl; and
R1 1 is selected from the group consisting of hydrogen and Ci-6 alkyl.
In certain aspects of the second embodiment, the sGC activator of Formula (I) is selected from
l-[6-(2-{ [4-(2-Phenylemyl)benzyl]oxy}phenyl)pyridm-2-yl]-5-(trifluoromethyl)-lH-pyrazole-4- carboxylic acid,
5-(Trifluorometiiyl)-l-[6-(2-{[4'-(trifluoromeA^
lH-pyrazole-4-carboxylic acid,
5-(Trifluoromethyl)-l-(6-{2-[(4-{2 4-(trifluoromethyl)phenyl]ethyl}benzyl)- oxy]phenyl}pyridin-2-yl)-lH-pyrazole-4-carboxylic acid, l-{6-[2-({4-[(l S,2S)-2-Phenylcyclopropyl]benzyl } oxy)phenyl]pyridtn-2-yl } -5-(trifluoromethyl)- lH-pyrazole-4-carboxylic acid, l-{6-[2-({4-[(lR,2R)-2-Phenylcyclopropyl]benzyl}oxy)phenyl]pyridin-2-yl}-5- (trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid, l-[6-(2-{[4-(4-CUorophenoxy)benzyl]oxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl)-lH- pyrazole-4-carboxylic acid,
5-(Trifluoromethyl)- 1 - { 6- [2-( {4-[4-(trifluoromethyl)phenoxy]benzyl} oxy) phenyl]pyridin-2-yl } - lH-pyrazole-4-carboxylic acid,
5-(Trifluoromethyl)- 1 -(6- {2-[(4- { [4-(trifluoromethyl)phenoxy]methyl }benzyl)- oxy]phenyl}pyridin-2-yl)-l /-pyrazole-4-carboxylic acid, l-{6-[5-Methyl-2-({4-[irani-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5- (trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid, l-{6-[5-Methyl-2-({4-[c/j-4-(trifluorometbyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5- (trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid, l-{6-[5-C oro-2-({4-[/rans^-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridin-2-yl}-5- (trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid,
1 - { 6- [5-Chloro-2-( {4- [ci j-4-(trifluoromethyl)cyclohexyl]benzyl } oxy)phenyl]pyridin-2-yl } -5- (trifluoromethyl)-lH -pyrazole-4-carboxylic acid, l-[6-(2-{[4-(4-Oxocyclohexyl)benzyl]oxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl)-lH- pyrazole-4-carboxylic acid,
1 -[6-(2-{ [4-(4,4-Difluorocyclohexyl)benzyl]oxy}phenyl)pyridin-2-yl]-5-(trifluoromethyl)- 1H- pyrazole-4-carboxylic acid, l-[6-(2-{[4-( row-4-Methoxycyclohexyl)benzyl]oxy}phenyl)pyridin-2-yl]- 5-(trifluoromethyl)- lH-pyrazole-4-carboxylic acid, l-[6-(2-{ [4-(c s^-Methoxycyclohexyl)benzyl]oxy}phenyl)pyridin-2-yl]- 5-(trifluoromethyl)- lH-pyrazole-4-carboxylic acid, l -[6-(2-{[4-(/ram)^-Methoxycyclohexyl)-2-methylbeiizyl]oxy}phenyl)pyridin-2-yl]-5- (trifluoromethyl)-lH -pyrazole-4-carboxylic acid,
5-(Trifluoromethyl)-l-{6-[2-({4-[6-(trifluoromethyl)pyridui-3-yl]benzyl}-oxy)phenyl]pyri yl}-lH-pyrazole-4-carboxylic acid, l-(6-{2-[(2,4-Dimethylbenzyl)oxy]-3-methylphenyl}pyridin-2-yl)-5-(trifluoromethyl)-lH- pyrazole-4-carboxylic acid,
Ethyl l-{6-[5-cUoro-2-({4-[/rani^-(trifluoromethyl)cyclohexyl]beiizyl}-oxy)phenyl]pyrazin-2- yl } -5-(trifluoromethyl)- 1 H-pyrazole-4-carboxylate,
Ethyl 1 - { 6- [5-chloro-2-( {4- [c/s-4-(trifluoromethy l)cyclohexyl]benzyl } -oxy)phenyl]pyrazin-2- yl}-5-(trifluoromethyl)-lH-pyrazole-4-carboxylate,
Figure imgf000011_0001
yl]-lH-pyrazole-4-carboxylic acid,
1 -[2 -(2- { [4-(2-Phenylethyl)benzyl]oxy}phenyl)pyrimidin-4-yl]-5-(trifluoromethyl)-l H-pyrazole- 4-carboxylic acid, 1 - {4-Methyl-6-[5-methyl-2-({4-[/ra/w-4-(trifluoroinethyl)cyclohexyl]benzyl } - oxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid,
5-(Trifluoromethyl)-l-[6-(2-{2-[4'-(trifluoromethyl)biphenyl-4-yl]ethyl}phenyl)pyridin-2-y lH-pyrazole-4-carboxylic acid,
5- (Trifluoromethyl)- 1 -(2'- { [4'-(trifluoromethyl)biphenyl-4-yl]methoxy} -2,3 '-bipyridin-6-yl)- 1 H- pyrazole-4-carboxylic acid, l-(5'-Methyl-2'-{[3-methyl-4'-(trifluoromethyl)biphenyl-4-yl]methoxy}-2,3'-bipyri^
(trifluoromethyl)- lH-pyrazole-4-carboxylic acid,
1 -(5'-CWoro-2'- { [3-metoyl-4'-(Mfluoromethy
(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid,
1 -[2'- { [3-Methyl-4'-(trifluoromethyl)biphenyl-4-yl]methoxy} -5'-(trifluoromethyl)-2,3 '-bipyridin-
6- yl]-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid,
5-(Trifluoromethyl)-l-{6-[2-({[4'-(trifluoro
yl}-lH-pyrazole-4-carboxylic acid,
5-(Trifluoromethyl)- 1 -(6- { 2- [( { 5- [4-(trifluoromethyl)phenyl]pyridin-2- yl}oxy)methyl]phenyl}pyridin-2-yl)-lH-pyrazole-4-carboxylic acid,
1 -{6-[5- ethyl-2-({ [4'-(trifluoromethyl)biphenyl-4-yl]methyl }thio)phenyl]pyridin-2-yl} -5- (trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid, l-[6-(2-{Difluoro[4'-(trifluoromethyl)biphenyl-4-yl]me1hoxy}phenyl)pyridin-2-yl]-5- (trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid, l-{6-[2-^ifluoro{4-[rra/J5'-4-(trifluoromethyl)cyclohexyl]phenyl}methoxy)phenyl]pyridin- yl } -5-(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid,
1 - { 6- [2-(difluoro {A-[ci j-4-(trifluoromethyl)cyclohexyl]phenyl } methoxy)phenyl]pyridin-2-yl }-5- (trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid,
1- (6-{2-[{2-Ethyl-4-[4 (trifluoromethyl)cyclohexyl]phenyl}(difluoro)methoxy]phenyl}pyridin-
2- yl)-5-(trifluoromethyl)- lH-pyrazole-4-carboxylic acid,
1 - { 6- [2-(Difluoro { [4'-(trifluoromethyl)biphenyl-4-yl] oxy } methyl)phenyl] pyridin-2-yl } -5 - (trifluoromethyl)-lH-pyrazole-4-carboxylic acid, and
5-(Trifluoromethyl)- 1 -[6-(2- { [4'-(trifluoromethyl)biphenyl^-yl]methoxy}phenyl)pyridin-2-yl]- lH-l,2,3-triazole-4-carboxylic acid and pharmaceutically acceptable salts thereof.
A preferred sGC activator compound of Formula I which is suitable for use in the methods for the treatment or prevention of glaucoma or in the reduction of intraocular pressure provided in the second embodiment is 1-{6-[5-chloro-2-({4-[frans-4-
(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridine-2-yl}-5-(trifluoromethyl)-1 H-pyrazole-4- carboxylic acid (trans isomer of example 9 of WO2009/032249) which has the structure:
Figure imgf000013_0001
In a third embodiment, the invention provides methods of treating or preventing glaucoma or reducing intraocular pressure according to the first embodiment in which the method comprises administering to a subject in need of such therapy a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2012/058132 which is incorporated by reference for the compounds disclosed therein. In particular, the third embodiment provides for the administration of a sGC activator of formula (II):
Figure imgf000014_0001
II
And pharmaceutically acceptable salts thereof, wherein
X is selected from the group consisting of CH, CR.2 and N;
la and Rib are independently selected from the group consisting of -H, -F, -Cl, -Br, -CN? cyclopropyl, -Ci^alkyl optionally substituted with one to six of-F, and -0-C]-3alkyl optionally substituted with one to six of -F;
R2 is selected from the group consisting of -F, -CI, -Br, -CN, cyclopropyl, -Chalky! optionally substituted with one to six of -F, and -0-Ci_3alkyl optionally substituted with one to six of-F;
-Ci-3alkyl optionally substituted with one to six of -F, and -0-Ci_3alkyl optionally substituted with one to six of— F;
Figure imgf000014_0002
wheiein R6a and R&h are independently selected from the group consisting of -H, -CI, -F, =0 (oxo), -O-Ci-^alkyl, and -Ci -3alkyl optionally substituted with one to six of-F, and provided that only one of Roa and R6b can be (but is not required to be) oxo; and Rl3 is selected from the group consisting of -H and -C1 -6 alkyl;
R4 is selected from the group consisting of:
a) -C\ .galkyl optionally substituted with one to three substituents independently selected from the group consisting of -F, -OH, , and -OCi-3alkyl; and optionally substituted with one of oxo; b) ~Cl-6alkenyl optionally substituted with one to three substituents independently selected from the group consisting of -F, -OH, , and -OCi_3alkyl; and optionally substituted with one of oxo; c) -OCi-4alkyl optionally substituted with:
(i) one to three substituents independently selected from the group consisting of - F, -OH, and -OC1 _3alkyl; and optionally substituted with one of oxo, (ii) -C3..6cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of -OH, -CN, -CI, -F, -Cj-3alkyl optionally substituted with one to six of -F, and -0-Ci_3alkyl; and optionally substituted with one of oxo,
(iii) phenyl optionally substituted with one to three substituents independently- selected from the group consisting of -OH, -CN, -CI, -F, -Ci-.3a.kyi optionally substituted with one to six of-F, and -0-C] -3alkyl optionally substituted with one to six of-F; and optionally substituted with one of oxo,
(iv) a 4 to 6 membered heterocycle containing one to two heteroatoms selected from one to two of N, zero or one of O, and zero or one of S, wherein the ring is optionally substituted with one to three substituents independently selected from the group consisting of - OH, -CN, -CI, -F, -Ci _3alkyl optionally substituted with one to six of-F, and -0-Ci-3alkyl; and is optionally substituted with one of oxo, or
(v) a 5 to 6 membered heteroaryl containing one to three heteroatoms selected from zero to three of N, zero or one of O, and zero or one of S, wherein the ring is optionally substituted with one to three substituents independently selected from the group consisting of - OH, -CN, -CI, -F, oxo, -Ci -3alkyl optionally substituted with one to six of -F, and -0-Ci_3alkyl optionally substituted with one to six of -F; and is optionally substituted with one of oxo;
d) -S(O)0.2C1-3alkyl;
e) -C3-6cycloalkyl optionally substituted with one to three substituents independently selected from the group consisting of -F, -OH, -CF3, and -OC1 -3alkyl; and optionally substituted with one of oxo ;
f) -C3_6cycIoalkenyl optionally substituted with one or more substituents independently selected from the group consisting of -F, -OH, -CF3, and -OCl_3alkyl; and optionally substituted with one of oxo;
g) a 5-6 membered heteroaryl containing one to three heteroatoms selected from zero to three of N, zero or one of 0, and zero or one of S, wherein the ring is optionally substituted with one to three substituents independently selected from the group of -OH, -CN, CI, -F, -Cl-3alkyl optionally substituted with one to six of -F, and -0-C ]-3alkyl optionally substituted with one to six of-F; and is optionally substituted with one of oxo; and
h) a heterocycle selected from the group consisting of:
Figure imgf000016_0001
R5 is selected from the group consisting of ~~H, -F, -OH, -CF3, -OCj -3alkyi and -OCF3;
j is an integer selected from 0 and 1 ;
k is an integer selected from 0 and 1 ;
W is selected from the group consisting of CR& and N;
R7 is selected from the group consisting of (a) -H, (b) -Cj.^alkyl optionally substituted with to six of -F, (c) -Ci-3alkyl substituted with one or two of -OCH3,
(d) -(CH2)Q. J -C3-6cycloalkyI optionally substituted with (i) one to three of -F or (ii)
C]-3alkyl optionally substituted with one to three of -F.
Figure imgf000016_0002
R8 is selected from the group consisting of-H, ~F, -OH, and -Ci-3alkyl optionally substituted with one to six of -F;
R9 is selected from the group consisting of (a) -H, (b) -F, (c) -OH,
(d) -C 1 -3alkyl optionally substituted with substituents selected from the group consisting of (i) -OH and (ii) one to six of -F,
(e) -C3-6cycloalkyl optionally substituted with one to three of™F, and
(f) -0-C i-3alkyl optionally substituted with -OH;
RlO is selected from the group consisting of (a) -H, (b) -F, (c) -Cl -3alkyl optionally substituted with with substituents selected from (i) -OH and (ii) one to six of -F, and
(d) -0-Ci-3alkyl;
Rll is selected from the group consisting of (a) -H, (b) -Ci -6alkyl optionally substituted with one to six of -F, (c) -C3-6cycloalkyl optionally substituted with -CH3, -CF3, -CN, -OH, or - NH2 or one to three of -F;
Rl2a is selected from the group consisting of (a) -H, (b) Ci-6alkyl optionally substituted with one to six of ~F, (c) -C3-6cycloalkyl optionally substituted with -CFI3, -CF3, -CN, -OH, or one to three of -F; and
Rl2 js selected from the group consisting of (a) -Ci-galkyl optionally substituted with one to six of -F, and (b) -C3_6cycloalkyl optionally substituted with one to three of ~F.
Certain preferred compounds of the third embodiment include compounds of Formula Ha:
Figure imgf000017_0001
In certain aspects of the third embodiment, the sGC activator of Formula (I I) is selected from the group consisting of:
Example 6: 1 -[6-(4-Chloro-3'-methyl-4T- { [1 -(2,2,2-trifluoroe&yl)azetidiii-3- yljmethoxy} biphenyl-2-y])pyridin-2-yl]-5 -(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid;
Example 8 : 1 - { 6- [4-chloro-4'-(4-cyc3opropylpiperidin- 1 -yl)biphenyJ-2-yl]pyridin-2-yl } - 5 - (trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid ;
Example 44: 1 - {6-[4-chloro-4'-(454-difluorocyclohexyl)biphenyl-2-yl]pyridin-2-yl}-5- (trifluoromethyl)- lH-pyrazole-4-carboxylic acid;
Example 57 : ! - { 6-[4'-(4-cycloprop>dpiperidin-l -yl)-4-methylbiphenyl-2-yl]pyridin-2-yI } -5- (trifluoromethyl)-l H-pyrazole-4-carboxylic acid;
Example 60: 1 -(6- {4-chloro-4'-[l -(2,2,2-triiluoroethyl)piperidin-4-yl]biphenyl-2-yl}pyridin-2- yl)-5-(trifluoromethyl)- lH-pyrazole-4-carboxylic acid;
Example 61 : l-[2,-{4-[l-(2,2,2 rifluoroethyl)piperidin-4-yl]phenyl}-5'-(trifluoromethyl)-2J3'- bipyridin-6-yl] -5 -(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid;
Example 68: l-[6-(4-chloro-4'-{4-[{2,2-difluorocyclopropyl)methyl]piperazin-l-yl}bipheny]-2- yl)pyridin-2-yl] - 5 -(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid;
Example 98: 1 -(6- { 4-chloro-4'- [ 1 -(methoxycarbonyl)piperidin-4-yl]biphenyl-2-yl }pyridin-2-yl)-
5-(trifluoromethyl)- 1 //-pyrazole-4-carboxylic acid;
Example 99: l-(6"{4-chloro-4'-[l -(ethoxycarbonyl)piperidin-4-yl]biphenyl-2-yl}pyiidiii-2-yl)-5-
(trifluoromethyl)-lH-pyrazole-4-carboxylic acid;
Example 101 : 1 -(6- (4-chloro-4'-[ 1 -(dimethylcarbamoyl)piperidin-4-yl]-3 '-methylbiphenyl-2- yl } pyridin-2-yl)-5 -(trifluoromethyl)- lH-pyrazole-4-carboxylic acid;
Example 1 1 1 : l-(6-{4-fluoro-4'-[l-(2,2,2-triflx]oroethyl)piperidin-4-yl]biphenyl-2-yl}pyridm-2- yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid;
Example 125: l-(6-{3'J4-difluoro-4'-[l -(2,2:2-trifliioroethyl)piperidin-4-yl]biphenyl-2-yl}-pyridiri-
2-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid;
Example 136: l-(6-{4-fluoro-4'-[l-(33,3 rifluoropropyl)piperidin-4-yl]bipheny]-2-yl}pyridin-2- yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic cid; Example 138: 1 -(6- {4-fluoro-3'-methyl-4'-[ 1 -(2,2,2-trifluoroethyl)piperidin-4-yl]biphenyl-2- yl}pyridin-2-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid;
Example 139: l -(5'-chloro-2'-{3-methyl-4-[l ^
bipyridin-6-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid;
Example 284: l 6-{4-methyl-4'-[ l-(2,2,2 rifluoroethyl)piperidin-4-yl]biphenyl-2-yl}pyridin-2- yl)piperidine-4-carboxylic acid;
Example 285: l-(6 4-methyl-4'-[l -(2,252 rifluoroethyl)piperidin -yl]biphenyl-2-yl}pyridin-2- yl)aze†idine-3 -carboxylic acid;
Example 286: 1 -(6- {4-chloro-4'- [ 1 -(cyclopropylcarbonyl)piperidin-4-yl]biphenyl-2-yl } pyridin-2- yl)piperidme-4-carboxylic acid;
Example 287: l -(6-{4-methyl-4'-[l -(2,2J2-trifluoroeihyl)piperidm-4-yl]biphenyl-2-yl}pyri
yl)- 5 -oxopyrrolidine-3 -carboxylic acid ;
Example 291 : (3R)- 1 -(6-{4-chloro-4'-[ 1 -(2,2s2-trifluorocthyl)piperidiiv4-yl]biphenyl-2- yl}pyridin-2-yl)pyrrolidine-3-carboxylic acid;
Example 295 : 1 -(6- {4-chloro-4'- [ 1 -(cyclopropylcarbonyl)piperidin-4-yl]-3'-methylbiphenyl-2- yl}pyridm-2-yl)pipendine-4-carboxylic acid; and
Example 307: l -(6-{4-chloro-4' 1-(2J2,2-trifluoroetliyl)piperidin-4-yl]biphenyl-2-yl}pyridin-2- yl)azetidine-3 -carboxylic acid.
Certain preferred sGC activator compounds of Formula II which are suitable for use in the methods for the treatment or prevention of glaucoma or in the reduction of intraocular pressure provided in the third embodiment include
Example 60: 1 -(6-(4-chloro-4'-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-[1 , 1 '-biphenyl]-2- yl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;
Example 94: 1 -(6-(4-chloro-4'-(1-(cyclopropanecarbonyl)piperidin-4-yl)-[1 , 1 '-biphenyl]-2- yl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid; and
Example 175: 1 -(6-(4-chloro-4'-(4-(2,2,2-trifluoroethyl)piperazin-1 -yl)-[1 , 1 '-biphenyl]-2- yl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylic acid.
In a fourth embodiment, the invention provides methods of treating or preventing glaucoma or reducing intraocular pressure according to the first embodiment in which the method comprises administering to a subject in need of such therapy a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2010/099054 which is incorporated by reference for the compounds disclosed therein. In particular, the fourth embodiment provides for the administration of a sGC activator of formula (III):
Figure imgf000019_0001
And pharmaceutically acceptable salts thereof, wherein
W is selected from the group consisting of CH and N;
Z is selected from the group consisting of:
Figure imgf000019_0002
Rl is selected from the group consisting of -OH, -OCj-e alkyl and -N(R5)2;
R2 is selected from the group consisting of -Ci -2 perfluoroalkyl and -NI¾;
R3 is selected from the group consisting of:
1) -Cl-6 al yl substituted with 1-3 of -F,
2) -COR4 and
3) -SO2R6;
R3a is selected from the group consisting of -H; -C1-3 alkyl; C3-6 cycloalkyl optionally mono- or di-substituted with one or more substituents selected from the group consisting of -CH3 and -F; and -CH2-C3-6cycloalkyI optionally mono- or di-substituted with one or more substituents selected from the group consisting of -CH3 and -F
R4 is selected from the group consisting of:
1) -H,
2) -C 1.3 alkyl,
3) -OCl-3 alkyl
4) -C3-6 cycloalkyl optionally mono- or di-substituted with one or more substituents
selected from the group consisting of -CH3 and -F,
5) -CH2-C3-6cyeloalkyl optionally mono- or di-substituted with one or more substituents selected from the group consisting of -CH3 and -F,
6) -OC3-6 cycloalkyl optionally mono- or di-substituted with one or more substituents selected from the group consisting of -CH3 and -F, and
7) -N(R5)2;
R5 is independently selected at each occurrence from -H and -C1-3 alkyl;
R< is selected from the group consisting of -C]._3alkyl; -C3„6cycIoalkyl optionally mono- or di- substituted with one or more substituents selected from the group consisting of -CH3 and ~F; and -CH2-C3-6cycloalkyl optionally mono- or di-substituted with one or more
substituents selected from the group consisting o -CH3 and -F;
R? is selected from the group consisting of -H and -CH3;
Ra and Rb are independently selected at each occurrence from -F, -CI and -C1-3 alkyl
optionally substituted with 1-3 of -F; and
Rc and d are independently selected at each occurrence from -F, -CI and ~Ci -3 alkyl
optionally substituted with 1 -3 of -F.
In certain aspects of the fourth embodiment, the sGC activator of Formula (III) is selected from the group consisting of:
l-[6-[2-[[4-[l-(2,2,2-Trifluoroe&yl)-4^iperi 5-
(trifluoromet yl)-l H-pyrazole-4-carboxyiic acid;
1 -(6-(3-Chloro-5-fluoro-2-((4-(l -(2,2,2-trifluoroethyl)piperidiri-4- yl)benzyl)oxy)- phenyl)pyridin-2-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid;
1 -(6-(2-((2-Methyl-4-( 1 -(2:2,2~trifluoroethyl)piperidin-4-yl)benzyl)oxy )phenyl)pyridin-2-yl)-
5 -(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid ;
l-{6-[3-fluoro-2-({4-[!-(methoxycarbony])piperidin-4 yl] benzyl }oxy)phenyl3pyridin-2- yl}-5-
(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid;
1 -(6-(2-((4-( 1 -(methoxycarbonyl)piperidin-4-yl)bet^
2-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid;
I-(6-(2-((4-(l-(cycIopropylcarbonyl)piperidin-4-yl)benzyl)oxy)-3-(trifluoromethyi)- phenyl)pyridin-2-yl)-5-(trifluoromethyl)-IH-pyrazole-4-carboxylic acid;
1 -(6-(2-((4-( 1 ^ropionylpiperidin-4-yl)benzyl)oxy)-3-(trifl oromethyl)phenyI)pyridin-2-yl)-5-
(trifluoromethyl)-lH-pyrazole-4-carboxylic acid;
l-(6-(3-chloro-2-((4-(l-(cyc3opropylcarbonyl)piperidin-4-yl)benzyl)oxy)phenyl)pyridin-2-yl)-
5-(trifluoromethyl)-lH-pyrazole-4~carboxylic acid;
1 - { 6 - [2-( { 4- [ 1 -(Cy cl opropylcarbonyl)piperidin-4-yl] benzyl } oxy)-3 -
(difluororaethyl)phenyl]pyridin-2-yl}-5-(trifluoromethyl)- lH-pyrazole-4-carboxylic acid; l-(6-(3-methyl-2-((4-(l-(2,252 rifluoroethyl)piperidin-4-yI)benzyl)oxy)phenyl)pyridin-2- yl)-5-
(trifluorornethyl)- ί H-pyrazole-4-carboxylic acid; l-(6-(3,5-difluoro-2 (4-(l-(252,2 rifluoroethyl)piperidin-4-yl)benzyl)oxy)phenyl)pyridi
yl)- 5 -(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid;
5 -(Trifluoromethyl)- 1 - { 6- [ 3 -(tri fluoromethyl)-2-( { 4- 1 -(3 ,3 ,3 -tri fluoropropyl )pyrrolidin- 3 - yl]benzyl}oxy)phenyl]pyridin-2-yl}-lH-pyrazoIe-4-carboxylic acid (enantiomer A);
1 -(6-(5-fluoro-2-((2-methyl-4-(l -(2,2,2-trifluoroethyl)piperidin-4- yl)benzyl)oxy)- phenyl)pyridin-2-yl)-5-(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid;
1 ~(6-(4-fluoro-2-((2-methyl-4-( 1 -(2i2s2-trifluoroethyl)piperidin-4- yl)benzyl)- oxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)- 1 H-pyrazole-4-carboxylic acid;
l-(6-(2-((4-(l-(methoxycarbonyl)pipcridin-4-yl)benzyl)oxy)-3-raethylphenyl)pyridin-2-yl)-5-
(trifluoromethyl)- lH-pyrazole-4-caxboxylic acid;
l -(6-(3-(difluoromethyl)-2-((4-(l-(methoxycarbonyl)piperidin-4-y])benzyl)oxy)- phenyl)pyridin-2-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid; l-(6-(2-((4-(l-(Methoxycarbonyl)azetidin-3-yl)benzyl)oxy)-3-(trifluoromethyl)- phenyl)pyridin-2-yl)-5-(trifluoromethyl)-lH-pyrazole-4-carboxylic acid; and the pharmaceutically acceptable salts thereof.
A preferred sGC activator compound of Formula III which is suitable for use in the methods for the treatment or prevention of glaucoma or in the reduction of intraocular pressure provided in the fourth embodiment is 1 -(6-(2-((4-(1 -(methoxycarbonyl)piperidin-4-yl)benzyl)oxy)-3- (trifluoromethyl)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (example77 of WO2010/
Figure imgf000022_0001
In a fifth embodiment, the invention provides methods of treating or preventing glaucoma or reducing intraocular pressure according to the first embodiment in which the method comprises administering to a subject in need of such therapy a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2009/071504 which is incorporated by reference for the compounds disclosed therein. In particular, the fourth
embodiment provides for the administration of a sGC activator of formula (IV):
Figure imgf000022_0002
In certain aspects of the fifth embodiment, the sGC activator of Formula (IV) is selected from the group consisting of:
1 -[6-(2-(4-(phenethyl)phenylmethyloxy)-phenyl)p^
carboxylic acid;
1-[6-(2-(4-(phenethyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-methyl-pyrazole-4- carboxylic acid;
Figure imgf000022_0003
acid;
1-[6-(2-(4-(phenethyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid;
1 -[6-(2-(4-(4-(t-butyl)phenylmethyloxy)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(5-fluoro-2-(4-(4-methoxyphenyloxy)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-fluoro-2-(4-(4-cyanophenyloxy)phenylmethyloxy)-phenyl)pyridine-2-yl]-piperidine- 4-carboxylic acid;
1-[6-(5-fluoro-2-(4-(4-fluorophenyloxy)phenylmethyloxy)-phenyl)pyridine-2-yl]-piperidine- 4-carboxylic acid;
1-[6-(5-fluoro-2-(4-(4 rifluoromethylphenyloxy)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(4-(4 rifluoromethylphenoxy)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(4-(4-cyanophenoxy)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-chloro-2-(4-(4-trifluoromethylphenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]- piperidine-4-carboxylic acid;
1 -[6-(5-chloro-2-(4-(4-cyanophenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-piperidine-4- carboxylic acid;
1-[6-(3,5-difluoro-2-(4-(5 rifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2- yl]-piperidine-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(4-(5-cyanopyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-chloro-2-(4-(54rifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)- phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid;
1-[6-(2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]- piperidine-4-carboxylic acid;
1 -[6-(2-(4-(phenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4- carboxylic acid;
1 -[6-(2-(4-(4-cyanophenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(4-(4-cyanophenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-chloro-2-(4-(4-cyanophenyloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-iodo-phenyloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid; 1-[6-(5-chloro-2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyri 5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- methyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(5-chloropyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]- 5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methoxy-4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-chloro-2-(2-methyl-4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]- 5-trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(2-((6-(3,4-dichlorophenoxy)pyridine-3-yl)methyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(2-((6-(4-chlorophenoxy)pyridine-3-yl)methyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(2-((6-(4-chlorophenoxy)pyridine-3-yl)methyloxy)-phenyl)pyridine-2-yl]-5-methyl- pyrazole-4-carboxylic acid;
1 -[6-(2-((6-(4-methoxyphenoxy)pyridine-3-yl)methyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(2-((6-(4-methoxyphenoxy)pyridine-3-yl)methyloxy)-phenyl)pyridine-2-yl]-5-methyl- pyrazole-4-carboxylic acid;
1 -[6-(5-fluoro-2-((6-(3,4-dichlorophenoxy)pyridine-3-yl)methyloxy)-phenyl)pyridine-2-yl]-5- trif luoromethyl-pyrazole-4-carboxylic acid ;
1 -[6-(2-(4-(44rifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl-pyrazole-4- carboxylic acid;
1-[6-(2-(4-(4-azidophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-methyl-pyrazole-4- carboxylic acid;
1-[6-(2-(4-(4 -butylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-chlorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoroiTiethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-iTiethyl-pyrazole-4- carboxylic acid; pyrazole-4-carboxylic acid;
1-[6-(2-(4-(3,4-dichlorophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-fluoro-2-methylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-methoxy-2-methyl-phenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-iodophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid; 1- [6-(2-(2-methyl-4-(4-methoxy-34rifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridi
2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(3-chloro-4-methoxy-phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(3,4-dichloro-phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(3-chloro-4-isopropyloxylphenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1- [6-(2-(2-methyl-4-(4-ethyloxy-3-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-
2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-ethyloxy-3-methylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methy 4-(3,4-dimethoxy-phenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-chloro-2 rifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(2,4-dimethoxy-phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1- [6-(2-(2-methyl-4-(4-methoxy-2-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-
2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4 luoro-2-methylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-methoxy-2-methylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-isopropyloxyl-2-methylphenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-chloro-2-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-chloro-2-ethyloxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(2-chloro-4-ethyloxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(2-chloro-4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methoxy-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methoxy-4-(4-trifluoromethylphenyl)^
trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methoxy-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methoxy-4-(4-methoxy-3-trifluoromethylphenyl)phenylmet yloxy)- phenyl)pyridine-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methoxy-4-(2-chloro-4-methoxy-p enyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- 5-trif I uorom et y l-pyrazol e-4-carboxyl ic acid ;
1-[6-(2-(2-methoxy-4-(4-methoxy-2-methylphenyl)phenylmethyloxy)-p enyl)pyridine-2-yl]- 5-trifluoromet yl-pyrazole-4-carboxylic acid;
1 -[6-(2-(2-(2-methyl-propyloxy)-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- 5-trif I uorom ethy l-pyrazol e-4-carboxyl ic acid ;
1-[6-(2-(2-(2-methyl-propyloxy)-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-(2-methyl-propyloxy)-4-(4-cyanophenyl)phenylmeth^^
5-trif I uorom ethy l-pyrazol e-4-carboxyl ic acid ;
1-[6-(2-(2-propyloxy-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-propyloxy-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-(methoxyethyloxy)-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-(methoxyethyloxy)-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- 5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-(methoxyethyloxy)-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(5-chloro-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(5-fluoro-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(3,5-difluoro-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(3,5-difluoro-2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(3,5-difluoro-2-(1 -(4-(4-methoxyphenyl)phenyl)ethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(3,5-difluoro-2-(1 -(4-(4-cyanophenyl)phenyl)ethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(3,5-difluoro-2-(1 -(4-(4-trifluoromethylphenyl)phenyl)ethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(5-chloro-2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(5-chloro-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(5-chloro-2-(2-methyl-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(5 luoro-2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(5-fluoro-2-(2-methyl-4-(4-methoxy-2-methyl-phenyl)phenylmethyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(2-(4-(54rifluoromethylpyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(54rifluoromethylpyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-methy^ pyrazole-4-carboxylic acid;
1-[6-(2-(4-(5-cyanopyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5 rifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(5-methoxypyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(5-methoxypyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-methyl- pyrazole-4-carboxylic acid;
1-[6-(2-((6-(4-methoxyphenyl)pyridine-3-yl)methyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-methylthiazol-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-methyl-pyrazole- 4-carboxylic acid; 1-[6-(2-(2-methyl-4-(6-methoxypyridin-3-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(5-trifluoromethylpyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(5-chloropyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(5-methoxypyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2-yl)phenylmethyloxy)- phenyl)pyridine-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2-yl)phenylmethyloxy)- phenyl)pyridine-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-chlorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid;
1-[6-(2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(2-(2-propyloxy-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-chloro-2-(2-methyl-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-chloro-2-(2-methyl-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(5-fluoro-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1- [6-(4-chloro-2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridine-
2- yl]-5-trif luoromethyl-pyrazole-4-carboxylic acid ;
1- [6-(6-chloro-2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridine-
2- yl]-5-trif luoromethyl-pyrazole-4-carboxylic acid ;
1- [6-(4-fluoro-2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridine-
2- yl]-5-trif luoromethyl-pyrazole-4-carboxylic acid ;
1- [6-(6-fluoro-2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridine-
2- yl]-5-trif luoromethyl-pyrazole-4-carboxylic acid ;
1-[6-(5-iodo-2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]- 5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-chloro-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid;
1-[6-(5-chloro-2-(2-methyl-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-fluoro-2-(4-(4-trifluoromethylphenyl)phenylmethoxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(4-(4-methoxy-2-methylphenyl)phenylmethoxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(4-(4-fluoro-2-methylphenyl)phenylmethoxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(5-fluoro-2-(2-fluoro-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-fluoro-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-fluoro-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-piperidine-4-carboxylic acid;
1- [6-(5-methyl-2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridine-
2- yl]-piperidine-4-carboxylic acid;
Figure imgf000031_0001
2- yl]-piperidine-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(4-methoxy-2-trifluoromethylphenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(4-chloro-2-trifluoromethylphenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid;
1-[6-(5-methyl-2-(2-propyloxy-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-1- piperidine-4-carboxylic acid;
1-[6-(5-methyl-2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1- [6-(5-methyl-2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridin-
2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1 -[6-(5-methyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2-yl)phenylmethyloxy)- phenyl)pyridine-2-yl]-1 -piperidine-4-carboxylic acid;
1 -[6-(5-methyl-2-(2-methyl-4-(5-cyanopyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2- piperidine-4-carboxylic acid;
1-[6-(5-trifluoromethyl-2-(2-methyl-4-(4-cya
yl]-piperidine-4-carboxylic acid;
1-[6-(5-trifluoromethyl-2-(2-propyloxy-4-(4-chloro-2-trifluoromethyl- phenyl)phenylmethyloxy)-p enyl)pyridine-2-yl]-1 -piperidine-4-carboxylic acid;
1-[6-(5-trifluoromethyl-2-(2-propyloxy-4-(2-methyl-4-trifluoromethyl- phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-1 -piperidine-4-carboxylic acid;
1-[6-(5-trifluoromethyl-2-(2-propyloxy-4-(4-cyano-2-methyl-phenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-1 -piperidine-4-carboxylic acid;
1-[6-(5-trifluoromethyl-2-(2-propyloxy-4-(2-chloro-4-methoxy-phenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-1 -piperidine-4-carboxylic acid;
1-[6-(5-trifluoromethyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2- yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid;
1-[6-(5-trifluoromethyl-2-(2-mGthyl-4-(5-cyanopyridin-2-yl)phenylmethyloxy)- phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid;
1-[6-(2-(4-(4-aminocarbonylphenyloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-(aminocarbonyl)phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-methyl- pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(5-(aminocarbonyl)pyridine-2-yl)phenylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-carboxyphenyloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-(6-{2-[({6-[(4-carboxyphenyl)oxy]-3-pyridinyl}methyl)oxy]phenyl}-pyridin-2-yl)-5- (trifluoromethyl)-l /- -pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-carboxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromet yl- pyrazole-4-carboxylic acid;
1-[6-(2-(2-mGthyl-4-(4-carboxyphenyl)phenylmGthyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methoxy-4-(4-carboxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(4-(4-carboxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-chloro-2-(2-methyl-4-(4-carboxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromGthyl-pyrazolG-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-fluoro-4-(4-carboxyp enyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-methoxy-4-(4-carboxyphenyl)phenylmethyloxy)-p enyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-fluoro-4-(4-carboxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(4-(4-methoxyphenyl)phenylmethyloxy)-ph
carboxylic acid;
1-[6-(2-(2-methyl-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-m
pyrrole- 3-carboxylic acid;
1-[6-(5-fluoro-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-methy^
pyrrole- 3-carboxylic acid;
1-[6-(2-(4-(4-methoxyphenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-methyl-pyrrole-3- carboxylic acid;
1-[6-(2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-methyl-pyrrole-3- carboxylic acid;
1-[6-(2-(2-methyl-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-meth^
pyrrole-3-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2- methyl-pyrrole-3-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2- methyl-pyrrole-3-carboxylic acid;
1-[6-(2-(4-(4-cyanophenyloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-methyl-pyrrole-3- carboxylic acid;
4-[6-(2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-benzoic acid;
4- [6-(2-(4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-benzoi acid;
1-[6-(3-(propen-2-yl)-2-(4-(4-t fluoromethylphenyl)pheny^
5- trif I uorom ethy l-pyrazole-4-carboxyl ic acid ;
1-[6-(3-propyl-2-(4-(4-trifluoromethylphenyl)ph^
trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(3-(propen-2-yl)-2-(2-methyl-4-(4-trifluoromethylphenyl)phenylrnethyloxy)- phenyl)pyridine-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(3-propyl-2-(2-methyl-4-(4-trifluoromethylph
yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(3-(propen-2-yl)-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(3-propyl-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
A preferred sGC activator compound of Formula IV which is suitable for use in the methods for the treatment or prevention of glaucoma or in the reduction of intraocular pressure provided in the fifth embodiment is 1 -(6-(2-((3-methyl-4'-(trifluoromethoxy)-[1 , 1 '-biphenyl]-4- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-i/-/-pyrazole-4-carboxylic acid (example 9 of WO2009/071504) which has the structure:
Figure imgf000034_0001
In a sixth embodiment, the invention provides methods of treating or preventing glaucoma or reducing intraocular pressure according to the first embodiment in which the method comprises administering to a subject in need of such therapy a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2012/122340 which is incorporated by reference for the compounds disclosed therein. In particular, the sixth embodiment provides for the administration of a sGC activator of formula (V):
Wherein
A is a 5- or 6-membered aryl, heteroaryl or heterocyclyl group;
B is a 5-7 membered heterocyclyl group containing one nitrogen, wherein one carbon of the heterocyclyl group is optionally substituted with an oxo group, or B is a 5-membered heteroaryl
group containing at least 2 nitrogens;
R1 and R2 are independently selected from H, d-C4alkyl, C3-C6 cycloalkyi,
tetrahydropyranyl, trifluoromethyl, CH2CF3, and CH2CH2CO2H;
R3 is selected from H and methyl;
R4 is selected from H, C C4alkyl, C3-C7 cycloalkyi, -C(O) Ci-C6alkyl, CH2CF3, -S02Ci- C6alkyl, S02(CH2)i-3C02H, C02 CrC4alkyl, heterocyclyl, aryl, heteroaryl, C1-C2alkyl heterocyclyl C C2alkylaryl and C1-C2alkylheteroaryl, wherein said heterocyclyl, cycloalkyi, aryl and heteroaryl are optionally substituted with one to two groups independently selected from C-|-C3alkyl,
trifluoromethyl, and halogen;
or R4 is optionally not present when B is a heteroaryl group; R is selected from H, Ci-C3alkyl, methoxy, trifluoromethyl, -CN and CI; and R6 is selected from H and methyl;
provided that R5 and R6 are not both H;
or a salt thereof.
In certain aspects of the sixth embodiment, the sGC activator of Formula (V) is selected from the group consisting of:
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0002
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Preferred sGC activator compounds of Formula V which are suitable for use in the methods for the treatment or prevention of glaucoma or in the reduction of intraocular pressure provided in the sixth embodiment are compounds 18 and 29 of WO2012/122340 which have the structures:
Figure imgf000040_0001
18 29
In a seventh embodiment, the invention provides methods of treating or preventing glaucoma or reducing intraocular pressure according to the first embodiment in which the method comprises administering to a subject in need of such therapy a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2013/025425 which is incorporated by reference for the compounds disclosed therein. In particular, the seventh embodiment provides for the administration of a sGC activator of formula (VI):
Figure imgf000040_0002
wherein
E is selected from pyrrolidm- 1 ~yl, piperidi.n-1~yi azetidin-l-yi 5~aza$piro[2.3Jhexan-5~yi azep n- I -yh .Va¾abicycto£3, | ,0,Jhexan-3*y cyclohexyl cyclohc.xe.n- yl, cyeiohexylantiito and cydopentylamino, wherein each Rl k substituted with »0¾H or ~€fiC XH and optionally further su sttuted by a grotsp selected fr m Ch lky!, OIL -C sO e, -CI3 .? and Hp, and wherein two different carbons in said pyrrolidine 1 -yi pip ridin- l-yis azetidin-l-yl or a&e au-l-yl may optionall be joined by a C5.3alkyk.ue bridge; or R{ is ~ CR6} B2)i.; 02K;
R" and R 5 ar iRde-pendeatly selected from H, Ο . ial geo, M and ~ £ provided tnat at least one of R" or R■ Is H
R* selected from™C(0} (R*)(R?), -€£0)R and -CH(R¥;
E" is selected from H» C alkyi halogen, -CF*< -OCMalkyl, ~0€J¾ and ~€N
In certain aspects of the seventh embodiment, the sGC activator of Formula (VI) is selected from the group consisting of:
Figure imgf000042_0001
Figure imgf000043_0001
42
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
53
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001

Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
63
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001

Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
Figure imgf000074_0001
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
76
Figure imgf000078_0001
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0001
Figure imgf000083_0001
Figure imgf000084_0001
Figure imgf000085_0001
Figure imgf000086_0001
Figure imgf000087_0001
Figure imgf000088_0001
Preferred sGC activator compounds of Formula VI which are suitable for use in the methods reatment or prevention of glaucoma or in the reduction of intraocular pressure provided in the seventh embodiment are compounds 151 and 234 of WO2013/025425 which have the structures:
Figure imgf000089_0001
151 234
In an eighth embodiment, the invention provides methods of treating or preventing glaucoma or reducing intraocular pressure according to the first embodiment in which the method comprises administering to a subject in need of such therapy a sGC activator selected from compounds specifically or generically disclosed in international patent application WO 2009/068652 which is incorporated by reference for the compounds disclosed therein. In particular, the eighth
embodiment provides for the administration of a sGC activator of formula (VII):
Figure imgf000089_0002
(VII) or salt thereof, wherein
n represents 1 or 2;
each R1 independently represents haio or trifluoromeihyl; wherein halo represents fluoro, chloro or bromo;
R2 represents hydrogen or Chalky!;
X represents N or CH;
wherein -Z~ represents a group selected from:
Figure imgf000090_0001
wherein R3 represents trtf!uoromethyi or Chalky!; and R4 represents hydrogen, trifluoromethyl or Ci.3alkyl; with the proviso that where Z represents a thiophene group and X represents N, R2 cannot represent C^alkyl; and when X represents CH, -Z- can additionally represent a group selected from:
Figure imgf000090_0002
In certain aspects of the sixth embodiment, the sGC activator of Formula (VII) is selected from the group consisting of:
H6-(3,4-Dichlorophenyl)~2~pyridinyl]^ acid;
1 -{6-[4-{Trifluoromethyl)phenyl}-2-pyridinyi}-5-(trifiuoiOmethyi)-1 H-pyrazo!e-4-carboxyiic acid; 1-[6-(2,3-Dichlorophenyi)-2-pyr!dinyl]-5-{trif!uoromethyl)-1 W-pyrazole-4-carboxyiic acid;
1 -{6-[3-{Trifiuoromethyl)phenyl]-2-pyridiny!}-5-(trifiuorornethyi)-1 H-pyrazole-4-carboxyiic acid; 1 -[6-(3,4-Difluoropheny!)-2-pyrtdinyl]-5-(trifluoromethyl)-1 W-pyrazole-4-carboxylic acid;
1 -{6-[3,5-bfS(Trifluoromethy1)phenyl]-2-py
acid;
1 -[6-(3-Chiorc>-4-fluorophenyi)-2-pyridinyl3-5-(trifiuorornethyl)-1 H-pyrazoie-4-carboxylic acid; 1 - 6-(4-Bromo-3-fiuorophenyi)-2-pyridinyf]-5-(trifluoromethyl)-1 H-pyrazoie-4-carboxylic acid; l-je-iSjS-DichlorophenyiJ^-pyridinyiJ-S- rtfluorornethy -I W-pyrazole^-carboxyiic acid;
1 -[6-{3.4-Dichiorc heny!)-4-methyl-2^yridtnyl]-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;
1-(6~(3!4~dichiorophenyi)-pyridin~2-y1)-pyrro!e~3-carboxylic acid;
1-(6-(3,4-dich!orophenyf)-pyridin-2-y!)-2-methyl-pyrro!e-3-carboxyiic acid;
1-(6-(3,4-dichlorophenyl)-pyricl!n-2-yl)-piperidine--4-carboxylic acid; 4- {6-(3-trifluoromeihyiphenyl)-pyridin-2-y!oxy)-benzoic acid;
5- (6-(3-trifiuoromethylphenyl)-pyridin-2-yl)-thiophene-2-carboxy!ic acid;
5-(2-(3-trifluoromethyiphenyi)-pyrimidin-4-yl)-thiop ene-2-carboxyiic acid;
1-[2-(3,4-dichlorop envi)-4-pyrimidinyl^^ acid;
5-(tnfluoromethyl)-1 2-[3-(trifluoromethyl)phenylj-4^yrimi
add;
or a salt thereof, in an embodiment a pharmaceutically acceptable sait thereof,
Preferred sGC activator compounds of Formula VII which are suitable for use in the methods for the treatment or prevention of glaucoma or in the reduction of intraocular pressure provided in the eighth embodiment is 1-{6-[3(trifluoromethyl)phenyl]-2-pyridinyl}-5-(trifluoromethyl)- 1 /-/-pyrazole-4-carboxylic acid, i.e., example 4, of WO2009/068652 which has the structure:
Figure imgf000091_0001
Preferred sGC activator compounds suitable for use in any one of embodiments 2 to 8 include those compounds which reduce lOP in monkey or human by at least 20% compared to baseline at 6 hours and/or 24 hours post topical ocular administration of the sGC activator. In certain compounds the lOP reduction is at least 25% or at least 30% at 6 and/or 24 hours post administration.
In a further aspect, the invention provides methods of treating or preventing glaucoma or reducing lOP in a patient in need of such therapy, the method comprising administering an sGC activator selected from compounds according to Formula VIII or IX:
Figure imgf000091_0002
VIII IX
Or a pharmaceutically acceptable salt thereof, wherein
A is a bond or CH20; R is C02H or C(0)-C C4alkoxy;
R1 is halogen, Ci-C4alkyl, or trifluoromethyl;
R2 is cyclohexyl substituted with R4, piperidinyl or piperazinyl each of which is substituted with R5 or phenyl substituted with R6;
R3 is hydrogen; or
R2 and R3, taken in combination, form a saturated 6 member azacycle
substituted with Ci-C4alkyl, halo Ci-C4alkyl, tetrahydropyranyl, tetrahydrofuranyl, benzyl, C(O) Ci-C4alkyl, C(O) C3-C5cycloalkyl, CH2-heteroaryl, which heteroaryl has 5 or 6 ring atoms, 1 or 2 ring heteroatoms independently selected from N, O and S and is optionally substituted by Ci-C4alkyl;
R4 is C C4alkyl or haloC C4alkyl;
R5 is C C4alkyl, haloC C4alkyl, C(0)C C4alkyl, C(0)C3-C6cycloalkyl, C(0)2C C4alkyl, C(0)2C3-C6cycloalkyl;
R6 is CrC4alkyl, haloCrC4alkyl, Ci-C4alkoxy or haloCrC4alkoxy;
R7 is CrC4alkyl or haloCrC4alkyl; and
R8 is hydrogen or Ci-C4alkyl.
In certain aspects, the sGC activator suitable for use in the methods of the invention is selected from the group consisting of:
1 -{6-[5-chloro-2-({4-[frans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridine-2-yl}-5- (trifluoromethyl)-7/-/-pyrazole-4-carboxylic acid;
1 -(6-(2-((4-(1 -(methoxycarbonyl)piperidin-4-yl)benzyl)oxy)-3-(trifluoromethyl)phenyl)pyridin- 2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;
1 -(6-(2-((3-methyl-4'-(trifluoromethoxy)-[1 , 1 '-biphenyl]-4-yl)methoxy)phenyl)pyridin-2-yl)-5- (trifluoromethyl)-l H-pyrazole-4-carboxylic acid;
1 -(6-(5-methyl-2-((2-((4-methylthiazol-2-yl)methyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-i/-/-pyrazole-4-carboxylic acid; and
1 -(6-(5-methyl-2-((2-(pyridin-2-ylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylic acid.
In a preferred embodiment, the sGC activator suitable for use in the methods of treating glaucoma is 1 -{6-[5-chloro-2-({4-[frans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridine-2- yl}-5-(trifluoromethyl)- 7/-/-pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, the sGC activator suitable for use in the methods of treating glaucoma is 1 -(6-(2-((4-(1 -(methoxycarbonyl)piperidin-4-yl)benzyl)oxy)-3- (trifluoromethyl)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylic acid or a
pharmaceutically acceptable salt thereof. In a preferred embodiment, the sGC activator suitable for use in the methods of treating glaucoma is 1-(6-(2-((3-methyl-4'-(trifluoromethoxy)-[1 ,1 '-biphenyl]-4-yl)methoxy)phenyl)pyridin-2- yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof.
In a preferred embodiment, the sGC activator suitable for use in the methods of treating glaucoma is 1 -(6-(5-methyl-2-((2-((4-methylthiazol-2-yl)methyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-i/-/-pyrazole-4-carboxylic acid or a
pharmaceutically acceptable salt thereof.
In a preferred embodiment, the sGC activator suitable for use in the methods of treating glaucoma is 1 -(6-(5-methyl-2-((2-(pyridin-2-ylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylic acid or a
pharmaceutically acceptable salt thereof.
Halogen denotes fluorine, chlorine, bromine or iodine.
A halogenated group or moiety, such as halogenalkyl, can be mono-, poly- or per-halo- genated.
An aryl group, ring or moiety is a naphthyl or, preferably, phenyl group, ring or moiety.
A heteroaryl group, ring or moiety is a monocyclic aromatic 5- or 6-membered structure, in which structure 1 , 2, 3 or 4 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, such as furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl or pyridyl; or
a bicyclic aromatic 9- or 10- or membered structure, in which structure 1 , 2, 3, 4 or 5 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member. The fused rings completing the bicyclic groups may contain only carbon atoms and may be saturated, partially saturated, or unsaturated. Heteroaryl groups which are bicyclic include at least one fully aromatic ring but the other fused ring may be aromatic or non-aromatic. Examples of bicyclic heteroaryl groups include, benzofuranyl, benzothiophenyl, imidazopyridinyl, indazolyl, indolyl, isoquinolinyl, pyrazolopyridinyl and quinolinyl. The heteroaryl radical may be bonded via a carbon atom or heteroatom.
In one embodiment, the heteroaryl group is an aromatic 5- or 6-membered structure, in which structure 1 , 2, 3 or 4 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member.
A non-aromatic heterocyclyl group, ring or moiety is a non-aromatic 4-, 5-, 6- or 7-membered cyclic structure, in which cyclic structure 1 , 2 or 3 ring members are hetero ring members independently selected from the group, consisting of a nitrogen ring member, an oxygen ring member and a sulfur ring member, such as azetidinyl, oxetanyl, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl, morpholinyl or perhydroazepinyl. Any non-cyclic carbon containing group or moiety with more than 1 carbon atom is straight- chain or branched.
Unless defined otherwise, carbon containing groups, moieties or molecules contain 1 to 8, 1 to 6, 1 to 4 or 1 or 2 carbon atoms.
The terms "alkoxy", "alkenoxy" and "alkynoxy" respectively denote alkyl, alkenyl and alkynyl groups when linked by oxygen.
The phrase "a compound of the invention" refers to a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or any embodiment thereof including the examples.
In a further aspect of the invention, the sGC activator compound may be administered alone or in combination with a second therapeutic agent which is suitable for the treatment of glaucoma. Certain preferred second therapeutic agents include beta-blockers, prostaglandin analogs, carbonic anhydrase inhibitors, a2 agonists, miotics, and neuroprotectants. In one preferred combination, latanaprost is administered in combination with a sGC activator compound of any one of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX).
It is contemplated that the concentration of the sGC activator in the compositions of the present invention can vary, but is preferably 0.01 to 3.0 w/v% and more preferably 0.05-1.0 w/v%. The most preferred concentration range is from 0.05-0.5 w/v% and the most preferred concentration is about 0.1 w/v%. The syk sGC activators of the present invention comprise the pharmaceutically useful hydrates and salts of such compounds and stereoisomers (where applicable), and may be formulated with a pharmaceutically acceptable vehicle.
Compositions of the present invention may be utilized in various dosage regimens known to those of skill in the art. Such dosing frequency is maintained for a varying duration of time depending on the therapeutic regimen. The duration of a particular therapeutic regimen may vary from one-time dosing to a maintenance regimen that extends for a month, year or more. One of ordinary skill in the art would be familiar with determining a therapeutic regimen for a specific indication. Preferred dosage regimens of the present invention include, but are not limited to, once a day dosing and twice a day dosing.
In the methods set forth herein, administration to a subject of a composition of the present invention may be by various methods known to those of skill in the art, including, but not limited to, topical, subconjunctival, periocular, retrobulbar, subtenon, intraocular, subretinal, posterior juxtascleral, or suprachoroidal administration. In preferred embodiments, administration of a composition of the present invention is by topical administration to the ocular surface.
The methods of treating glaucoma may include administering the sGC activator compound by a technique selected from the group consisting of: periocular injection, sub-conjunctival injection, sub-tenon injection, intracameral injection, intravitreal injection, intracanalicular injection, implanting delivery device in the cul-de-sac, implanting delivery device adjacent to the sclera, implanting delivery device within the eye, oral administration, intravenous administration, subcutaneous administration, intramuscular administration, parenteral administration, dermal administration, and nasal administration.
In certain aspects of the invention, formulations care provided which include both fixed and unfixed combinations of the two therapeutic agents effective in the treatment of glaucoma wherein one therapeutica agent is sGC activator disclosed supra and the second therapeutic agent is an active glaucoma drugs. In other embodiments, a pharmaceutical composition of the invention comprising a sGC activator can be administered to a patient alone or in combination with other IOP- lowering agents to increase the potency, efficacy and/or duration of the IOP reduction, including, but not limited to, carbonic anhydrase inhibitors, beta-blockers, prostaglandins, alpha-2 agonists, serotonin-2 agonists, alpha-1 antagonists, dopamine agonists, Rho kinase inhibitors, myosin-ll Ca2 +ATPase, inhibitors, matrix metalloproteinase activators, activator protein-1 (AP-1 ) activators, natriuretic peptide receptor-B agonists, phosphodiesterase inhibitors, K+-channel blockers and maxi-K-channel activators. The combination therapy of the invention provides the benefit of lowering IOP by two mechanisms, including inducing uveoscleral outflow of aqueous humor and inhibiting aqueous humor inflow, which can allow for reduced dosages of the compounds thereby lowering the risk of side effects.
Pharmaceutical compositions of the invention can also be advantageously combined with suitable neuroprotective agents such as memantine, eliprodil, Ca2+ -channel blockers, betaxolol, and the like.
In certain embodiments, a sGC activator and the second pharmaceutical agent are
administered concurrently in separate pharmaceutical compositions. In other embodiments, a sGC activator and the second pharmaceutical agent are administered formulated together in a
pharmaceutical composition. In yet other embodiments, the sGC activator and the second
pharmaceutical agent are administered sequentially in separate pharmaceutical compositions.
In addition to a sGC activator, the compositions of the present invention optionally comprise one or more excipients. Excipients commonly used in pharmaceutical compositions include, but are not limited to, tonicity agents, preservatives, chelating agents, buffering agents, surfactants and antioxidants. Other excipients comprise solubilizing agents, stabilizing agents, comfort-enhancing agents, polymers, emollients, pH-adjusting agents and/or lubricants. Any of a variety of excipients may be used in compositions of the present invention including water, mixtures of water and water- miscible solvents, such as C1 -C7-alkanols, vegetable oils or mineral oils comprising from 0.5 to 5% non-toxic water-soluble polymers, natural products, such as alginates, pectins, tragacanth, karaya gum, xanthan gum, carrageenin, agar and acacia, starch derivatives, such as starch acetate and hydroxypropyl starch, and also other synthetic products such as polyvinyl alcohol, polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide, preferably cross-linked polyacrylic acid and mixtures of those products. The concentration of the excipient is, typically, from 1 to 100,000 times the concentration of the sGC activator. In preferred embodiments, excipients are selected on the basis of their inertness towards the sGC activator.
Relative to ophthalmic formulations, suitable tonicity-adjusting agents include, but are not limited to, mannitol, sodium chloride, glycerin, sorbitol and the like. Suitable buffering agents include, but are not limited to, phosphates, borates, acetates and the like. Suitable surfactants include, but are not limited to, ionic and nonionic surfactants (though nonionic surfactants are preferred), RLM 100, POE 20 cetylstearyl ethers such as Procol® CS20 and poloxamers such as Pluronic® F68. Suitable antioxidants include, but are not limited to, sulfites, ascorbates, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
The compositions set forth herein may comprise one or more preservatives. Examples of such preservatives include p-hydroxybenzoic acid ester, sodium chlorite, benzalkonium chloride, parabens such as methylparaben or propylparaben, alcohols such as chlorobutanol, benzyl alcohol or phenyl ethanol, guanidine derivatives such as polyhexamethylene biguanide, sodium perborate, or sorbic acid. In certain embodiments, the composition may be self-preserved that no preservation agent is required.
In preferred compositions a sGC activator of the present invention will be formulated for topical application to the eye in aqueous solution in the form of drops. The term "aqueous" typically denotes an aqueous composition wherein the composition is >50%, more preferably >75% and in particular >90% by weight water. These drops may be delivered from a single dose ampoule which may preferably be sterile and thus render bacteriostatic components of the composition unnecessary. Alternatively, the drops may be delivered from a multi-dose bottle which may preferably comprise a device which extracts any preservative from the composition as it is delivered, such devices being known in the art.
In other aspects, components of the invention may be delivered to the eye as a concentrated gel or a similar vehicle, or as dissolvable inserts that are placed beneath the eyelids. In yet other aspects, components of the invention may be delivered to the eye as ointments, water-in-oil and oil-in- water emulsions, solutions, or suspensions.
The compositions of the present invention, and particularly the topical compositions, are preferably isotonic or slightly hypotonic in order to combat any hypertonicity of tears caused by evaporation and/or disease. This may require a tonicity agent to bring the osmolality of the
composition to a level at or near 210-320 milliosmoles per kilogram (mOsm/kg). The compositions of the present invention generally have an osmolality in the range of 220-320 mOsm/kg, and preferably have an osmolality in the range of 235-300 mOsm/kg. The ophthalmic compositions will generally be formulated as sterile aqueous solutions. In certain embodiments, a sGC activator of the present invention is formulated in a composition that comprises one or more tear substitutes. A variety of tear substitutes are known in the art and include, but are not limited to: monomeric polyols, such as, glycerol, propylene glycol, and ethylene glycol; polymeric polyols such as polyethylene glycol; cellulose esters such hydroxypropylmethyl cellulose, carboxy methylcellulose sodium and hydroxy propylcellulose; dextrans such as dextran 70; vinyl polymers, such as polyvinyl alcohol; guars, such as HP-guar and other guar derivatives, and carbomers, such as carbomer 934P, carbomer 941 , carbomer 940 and carbomer 974P. Certain compositions of the present invention may be used with contact lenses or other ophthalmic products.
In certain embodiments, the compositions set forth herein have a viscosity of 0.5-100 cps, preferably 0.5-50 cps, and most preferably 1-20 cps. These viscosities insure that the product is comfortable, does not cause blurring, and is easily processed during manufacturing, transfer and filling operations.
Preferred compositions are prepared using a buffering system that maintains the composition at a pH of about 3 to a pH of about 8.0, preferably 5.5-7.5, and most preferably 6.0-7.4. Topical compositions (particularly topical ophthalmic compositions) are preferred which have a physiological pH matching the tissue to which the composition will be applied or dispensed.
The following examples are presented to further illustrate selected embodiments of the present invention.
TOPICAL FORMULATION EXAMPLE
The following Examples illustrate the invention, but do not limit it. EXAMPLES
Abbreviations
Ac acetyl
AcOH acetic acid
aq. aqueous
atm atmosphere
Boc tertiary butyloxy carboxy
br. Broad
BSA bovine serum albumin
Bu butyl
BuOH butanol
calcd. Calculated
d doublet
dd doublet of doublets
DCE 1 ,2-dichloroethane
DEAD diethyl azodicarboxylate
DIAD diisopropyl azodicarboxylate
DIPEA /V,/V-diisopropylethylamine
DME 1 ,2-dimethoxyethane
DMEM Duibecco's Modified Eagle Medium
DMF A/,/V-dimethylformamide
DMSO dimethylsulfoxide
dppf 1 , 1 '-bis(diphenylphosphino)ferrocene
ESI electrospray ionization
EtOAc ethyl acetate
Et ethyl
EtOH ethanol
g grams
h, hr hour(s)
HBSS Hank's Balanced Salt Solution
HPLC high performance liquid chromatography
IBMX 1-meihyi-3-(2-methy!propyl)-7H-purine-2,6-d
IR infrared spectroscopy
L liter(s) M molar
MHz mega Hertz
m multiplet
Me methyl
MeOH methanol
mg milligram(s)
min minutes
ml. milliliter(s)
mmol millimoles
MS mass spectrometry
Ms methyanesulfonyl
m/z mass to charge ratio
N normal
NMR nuclear magnetic resonance
ODQ 1 H-jl 12,4]oxadiazoioi4!3-a]quinoxaiin-1 -one
PBS phosphate buffered saline
Pd/C palladium on carbon
Ph phenyl
ppm parts per million
rac racemic
RP- reverse phase
s singlet
satd. saturated
SFC supercritical fluid chromatography t triplet
tert- tertiary
TFA trifluoroacetic acid
THF tetrahydrofuran
TMS trimethylsilyl
tr retention time
Tris tris(hydroxymethyl)aminomethane
Ts p-toluenesulfonyl
TsOH p-toluenesulfonic acid
v/v volume per volume
w/v weight per volume Example 1.
Example 1 -A: Ethyl 1 -(6-(5-chloro-2-((4-((1 r,4r)-4-
(trifluoromethyl)cyclohexyl)benzyl)oxy)phenyl)pyridin-2-yl)-5-(trifluorometh
carboxylate
Figure imgf000100_0001
To a solution of ethyl 1-(6-(5-chloro-2-hydroxyphenyl)pyridin-2-yl)-3-(trifluoromethyl)-1 /-/- pyrazole-4-carboxylate (described in WO2009/032249 Example 9 Step A, 1.3 g, 3.1 mmol), (4- ((1 r,4r)-4-(trifluoromethyl)cyclohexyl)phenyl)methanol (described in WO2009/032249 Example 8 Step E, 800 mg, 3.1 mmol) and PPh3 (1 .2 g, 4.7 mmol ) in CH2CI2 (5.0 mL) at 0 °C was added DIAD (950 mg, 4.7 mmol) dropwise within 0.5 h. The mixture was stirred at room temperature for 18 h, and then concentrated. The resulting resdue was purified by silica gel flash column
chromatography (pentane/EtOAc = 10:1 to 1 :1 ), followed by SFC (stationary phase; Chiralpak® AD- 3: mobile phase; gradient from 5% to 40% (0.05% diethylamine in MeOH) in C02, column temp. 38 °C, flow rate 2.5 mL/min) to afford the title compound.
1H NMR (400 MHz, CDCI3) δ 8.15 (dd, J=0.61 , 7.95 Hz, 1 H), 8.13 (s, 1 H), 7.98 (d, J=2.69 Hz, 1 H), 7.88 (dt, J=7.80, 8.00 Hz, 1 H), 7.57 (dd, J=0.61 , 7.82 Hz, 1 H), 7.24-7.33 (m, 3H), 7.16-7.22 (m, 2H), 6.99 (d, J=8.80 Hz, 1 H), 5.12 (s, 2H), 4.39 (q, J=l M Hz, 2H), 2.47-2.58 (m, 1 H), 1.95-2.15 (m, 5H), 1 .44-1.52 (m, 4H), 1.40 (t, J=l A 5 Hz, 3H). MS (ESI+) m/z 652.5 (M).
Example 1 : 1-{6-[5-chloro-2-({4-[frans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridine-2- yl}-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid
Figure imgf000100_0002
To a suspension of ethyl 1 -(6-(5-chloro-2-((4-((1 r,4r)-4- (trifluoromethyl)cyclohexyl)benzyl)oxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4- carboxylate (described in WO2009/032249 Example 9 Step B) (285 mg, 0.437 mmol) in 1 ,4- dioxane (4 mL) was added aq. LiOH (2M, 0.87 mL, 1 .74 mmol). The reaction mixture was then warmed to 50 °C for 0.5 h. The reaction mixture was cooled to room temperature, and rendered acidic by addition of aqueous HCI. The mixture was dilited with dioxane, and filtered. The filtrate was purified by RP-HPLC (stationary phase; SunFire™ Ci8, OBD™ 5μηη: mobile phase; gradient, 0.1 % TFA in H20/CH3CN) to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1 H), 8.21 (dd, J=1.0, 8.0 Hz, 1 H), 8.13-8.18 (m, 1 H), 7.75-7.80 (m, 2H), 7.50 (dd, J=2.8, 8.8 Hz, 1 H), 7.31-7.37 (m, 3H), 7.23 (d, J=8.1 Hz, 2H), 5.23 (s, 2H), 2.52-2.58 (m, 1 H), 2.26-2.40 (m, 1 H), 1.92-2.00 (m, 2H), 1.83-1 .91 (m, 2H), 1 .46-1.57 (m, 2H), 1.34-1.46 (m, 2H). HRMS calcd. for CsoHzsCIFeNsOs (M+H) 624.1483, found 624.1465.
Example 2: 1-(6-(2-((3-Methyl-4'-(trifluoromethoxy)-[1 , 1 '-biphenyl]-4-yl)methoxy)phenyl)pyridin-2- yl)-5-(trifluoromethyl)-1 H-pyrazole- -carboxylic acid
Figure imgf000101_0001
To a solution of ethyl 1-(6-(2-((3-methyl-4'-(trifluoromethoxy)-[1 ,1 '-biphenyl]-4- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylate (described in WO 2009/071504 Description 77) (300 mg, 0.468 mmol) and aq. LiOH (2 ml_, 2 mmol) in THF/MeOH (2/1 ml.) was stirred at room temperature for 1.5h. The reaction was quenched with half satd.
KHS04. The mixture was then extracted with CH2CI2. The organic phase was then washed successively with H20 and brine, dried over Na2S04, filtered, and concentrated. The resulting residue was purified by RP-HPLC (Gemini® 5μηι C18 1 10A: mobile phase; gradient, 0.1 mM NH4OH in H20/CH3CN) to afford the title compound. 1 H NMR (400 MHz, CD3OD) δ 8.62-8.68 (m, 1 H), 8.00-8.08 (m, 2H), 7.71 -7.80 (m, 3H), 7.64 (d, J=7.83 Hz, 1 H), 7.43 (d, J=7.83 Hz, 1 H), 7.27-7.31 (m, 1 H), 7.06-7.15 (m, 3H), 6.95-7.00 (m, 1 H), 6.92 (d, J=8.30 Hz, 1 H), 5.03 (s, 2H), 4.08 (s, 2H), 3.93 (s, 2H), 3.00-3.07 (m, 2H), 2.98 (d, J=5.05 Hz, 2H), 2.31 (s, 3H). HRMS: calcd. for
C3i H22F6N304 (M+H) 614.1509, found 614.1569.
Example 3.
Example 3-A: ferf-Butyl 4-(4-((2-(6-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1 /-/-pyrazol-1-yl)pyridin-2- yl)-6-(trifluoromethyl)phenoxy)methyl)phenyl)piperidine-1-carboxylate
Figure imgf000101_0002
To a solution of ethyl 1 -(6-(2-hydroxy-3-(trifluoromethyl)phenyl)pyridin-2-yl)-5- (trifluoromethyl)-1 H-pyrazole-4-carboxylate (described in US 2010/0216764 Example 136 Step D) (815 mg, 1 .829 mmol), ferf-butyl 4-(4-(hydroxymethyl)phenyl)piperidine-1-carboxylate (CAS# 864359-18-2, 693 mg, 2.378 mmol) and PPh3 (624 mg, 2.378 mmol) in CH2CI2 (10 mL) was added DIAD (0.462 mL, 2.378 mmol). The mixture was then stirred at room temperature for 13.5 h, and then concentrated. The resulting residue was purified by flash column chromatography (RediSep® Rf Normal-phase silica, heptane/EtOAc = 100:0 to 0:100) to afford the title compound. MS (ESI+) m/z 719.0 (M+H).
Example 3-B: Ethyl 1 -(6-(2-((4-(piperidin-4-yl)benzyl)oxy)-3-(trifluoromethyl)phenyl)pyridin-2-yl)-5- (trifluoromethyl)-1 H-pyrazole-4-carboxylate
Figure imgf000102_0001
A mixture of ferf-butyl 4-(4-((2-(6-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1 H-pyrazol-1 - yl)pyridin-2-yl)-6-(trifluoromethyl)phenoxy)methyl)phenyl)piperidine-1 -carboxylate (750 mg, 1.044 mmol) and 4M HCI in dioxane (5.2 mL, 20.8 mmol) was stirred at room temperature for 20 min. The reaction mixture was concentrated to furnish the title compound. MS (ESI+) m/z 618.9 (M+H).
Example 3-C: Methyl 4-(4-((2-(6-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1 H-pyrazol-1 -yl)pyridin-2- yl)-6-(trifluoromethyl)phenoxy)methyl)phenyl)piperidine-1 -carboxylate
Figure imgf000102_0002
To a solution of ethyl 1-(6-(2-((4-(piperidin-4-yl)benzyl)oxy)-3-(trifluoromethyl)phenyl)pyridin- 2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate (235 mg, 0.301 mmol) and DIPEA (0.21 1 mL, 1.205 mmol) in CH2CI2 (3 mL) at room temperature was added methyl chloroformate (0.030 mL, 0.392 mmol). The mixture was then stirred at room temperature for 2 h. The reaction mixture was then diluted with H20 and then with brine. The organic layer was then separated, and
concentrated. The resulting residue was purified by flash column chromatography (RediSep® Rf Normal-phase silica, heptane/EtOAc = 100:0 to 20:80) to afford the title compound. MS (ESI+) m/z 677.0 (M+H). Example 3: 1 -(6-(2-((4-(1 -(Methoxycarbonyl)piperidin-4-yl)benzyl)oxy)-3- (trifluoromethyl)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylic acid
Figure imgf000103_0001
To a solution of methyl 4-(4-((2-(6-(4-(ethoxycarbonyl)-5-(trifluoromethyl)-1 H-pyrazol-1 - yl)pyridin-2-yl)-6-(trifluoromethyl)phenoxy)methyl)phenyl)piperidine-1 -carboxylate (174 mg, 0.257 mmol) in THF (2.5 mL) and MeOH (0.25 mL) was added aq. NaOH (1 M, 0.514 mL). The mixture was then stirred at 60 °C for 2 h. The reaction mixture was renderd acidic by 1 M aq. HCI by pH around 1 . The mixture was then diluted with EtOAc and brine. The organic layer was separated and dried over Na2S04, filtered and concentrated. The resulting residue was purified by flash column chromatography (Silicycle SilaSep™ Cyano, heptane/EtOAc = 80:20 to 0:100) to afford the title compound. 1 H NMR (400 MHz, CDCI3) δ 8.24 (s, 1 H), 8.12 (dd, J=0.73, 7.82 Hz, 1 H), 8.04 (dd, J=1.41 , 7.76 Hz, 1 H), 7.92 (dd, J=7.80, 8.00 Hz, 1 H), 7.74 (dd, J=1 .34, 7.82 Hz, 1 H), 7.68 (dd, J=0.73, 7.82 Hz, 1 H), 7.39 (t, J=7.70 Hz, 1 H), 7.10-7.19 (m, 4H), 4.58 (s, 2H), 4.30 (br. s., 2H), 3.73 (s, 3H), 2.80-2.94 (m, 2H), 2.61 -2.72 (m, 1 H), 1 .78-1.88 (m, 2H), 1 .55-1.71 (m, 2H). HRMS calcd. for C3i H27F6N405 (M+H) 649.1886, found 649.1878.
Example 4.
Example 4-A: Ethyl 1-(6-(5-methyl-2-((2-(pyridin-2-ylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylate
Figure imgf000103_0002
To a solution of ethyl 1-(6-(5-methyl-2-((1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate (described in
WO2012/122340 Example 26: 26-97) (21 1 mg, 0.393 mmol), 2-pyridinecarboxaldehyde (0.075 mL, 0.786 mmol) and AcOH (0.045 mL, 0.786 mmol) in DCE (4 mL) was added NaBH(OAc)3 (250 mg, 1.179 mmol). The mixture was then stirred at room temperautre for 0.5 h. The reaction mixture was then diluted with sat.NaHC03aq and CH2CI2. The organic layer was separated, and then concentrated. The resulting residue was purified by flash column chromatography (Interchim; puriFlash® NH2 50μηι heptane/EtOAc = 100:0 to 50:50) to afford the title compound. MS m/z 536.9 (M).
Example 4: 1 -(6-(5-methyl-2-((2-(pyridin-2-ylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid
Figure imgf000104_0001
To a solution of Ethyl 1 -(6-(5-methyl-2-((2-(pyridin-2-ylmethyl)-1 ,2,3,4-tetrahydroisoquinolin- 6-yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylate (169 mg, 0.269 mmol) in THF/MeOH (2.5 ml./ 0.25 mL) at room temperature was added 1 M NaOHaq (0.539 ml_, 0.539 mmol). The mixture was then stirred at 60 °C for 2.5 h. The mixture was then cooled to room temperature and diluted with 1 M HCIaq (0.6 ml) to reach pH of ~5 and then diluted with EtOAc and brine. The organic layer was separated and dried over Na2S04, filtered and concentrated. The resulting residue was purified by flash column chromatography (Interchim; puriFlash® DIOL 50μηι, CH2CI2/MeOH = 100:0 to 90:10) to afford the title compound. 1 H N MR (400 MHz, CDCI3) δ 8.62- 8.68 (m, 1 H), 8.00-8.08 (m, 2H), 7.71-7.80 (m, 3H), 7.64 (d, J=7.83 Hz, 1 H), 7.43 (d, J=7.83 Hz, 1 H), 7.27-7.31 (m, 1 H), 7.06-7.15 (m, 3H), 6.95-7.00 (m, 1 H), 6.92 (d, J=8.30 Hz, 1 H), 5.03 (s, 2H), 4.08 (s, 2H), 3.93 (s, 2H), 3.00-3.07 (m, 2H), 2.98 (d, J=5.05 Hz, 2H), 2.31 (s, 3H). HRMS: calcd. for C33H29F3N503 (M+H) 600.2217, found 600.2156.
Example 5:
Example 5-A: Ethyl 1 -(6-(5-methyl-2-((2-((4-methylthiazol-2-yl)methyl)-1 ,2,3,4- tetrahydroisoquinolin-6-yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4- carboxylate
Figure imgf000104_0002
To a solution of ethyl 1-(6-(5-methyl-2-((1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate (described in
WO2012/122340 Example 26: 26-97) (21 1 mg, 0.393 mmol), 4-methyl-2-thiazolecarboxaldehyde (124 uL, 1.151 mmol) AcOH (66 uL, 1 .151 mmol) in DCE (8 mL) at room temperature was added NaBH(OAc)3 (325 mg, 1.534 mmol). The mixture was then stirred at room temperautre for 0.5 h. The reaction mixture was then diluted with sat.NaHC03aq and CH2CI2. The organic layer was separated, and then concentrated. The resulting residue was purified by flash column
chromatography (heptane/EtOAc = 100:0 to 0:100) to afford the title compound. MS (ESI+) 648.0 m/z (M+H).
Example 5: 1 -(6-(5-Methyl-2-((2-((4-methylthiazol-2-yl)methyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylic acid
Figure imgf000105_0001
To a solution of ethyl 1-(6-(5-methyl-2-((2-((4-methylthiazol-2-yl)methyl)-1 ,2,3,4- tetrahydroisoquinolin-6-yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4- carboxylate (156 mg, 0.226 mmol) in THF/MeOH (2 ml./ 0.2 ml.) at room temperature was added 1 M NaOHaq (0.453 ml_, 0.453 mmol). The mixture was then stirred at 60 °C for 2 h. The mixture was then cooled to room temperature and diluted with 1 M HCIaq (0.5 ml) to reach pH of ~3 and then diluted with EtOAc, THF and brine. The products were extracted three times with EtOAc/THF. The combined organic layers were washed brine, dried over Na2S04, filtered, and then
concentrated. The residue was triturated with EtOH//'-PrOH. The precipitated solid was collected. The collected solid was washed with /'-PrOH, dried under reduced pressure. The solid was then triturated with EtOH, and filtered, and then dried up to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ 13.46 (br. s., 1 H), 8.27 (s, 1 H), 8.07-8.18 (m, 2H), 7.69 (dd, J=1.20, 7.52 Hz, 1 H), 7.59 (d, J=1.77 Hz, 1 H), 7.20-7.26 (m, 1 H), 7.12-7.19 (m, 4H), 7.03 (d, J=8.21 Hz, 1 H), 5.14 (s, 2H), 3.94 (s, 2H), 3.69 (s, 2H), 2.74-2.84 (m, 4H), 2.34 (d, J=0.88 Hz, 3H), 2.28 (s, 3H). HRMS: calcd. for C32H29F3N503S (M+H) 620.1938, found 620.1893.
Example 6; 1 -(6-(5-Methyl-2-((2-(4-(trifluoromethyl)cyclohexyl)-1 ,2,3,4-tetrahydroisoquinolin- 6-yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (single diastereomer, peak-1 ) and 1 -(6-(5-methyl-2-((2-(4-(trifluoromethyl)cyclohexyl)-1 ,2,3,4- tetrahydroisoquinolin-6-yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4- carboxylic acid (single diastereomer, peak-2).
Figure imgf000106_0001
A diastereomeric mixture of 1 -(6-(5-methyl-2-((2-(4-(trifluoromethyl)cyclohexyl)-1 , 2,3,4- tetrahydroisoquinolin-6-yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4
acid prepared as described in WO2012/122340 Compound 33, was separated into distinct isomers via SFC (stationary phase; Chiralpak® AD-H, 21 x250mm, 5μηι: mobile phase; 35% (10mM NH4OH in MeOH) in C02, column temp. 40 °C, flow rate 80g/min) to afford 1-(6-(5-methyl-2-((2-(4- (trifluoromethyl)cyclohexyl)-1 ,2,3,4-tetrahydroisoquinolin-6-yl)methoxy)phenyl)pyridin-2-yl)-5- (trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (single diastereomer, peak-1 ) (peak-1 , tr = 2.9 min) and 1 -(6-(5-methyl-2-((2-(4-(trifluoromethyl)cyclohexyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (single
diastereomer peak-2) (peak-2, tr = 4.6 min).
1-(6-(5-Methyl-2-((2-(4-(trifluoromethyl)cyclohexyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (single
diastereomer, peak-1 ). 1H NMR (400 MHz, CD3OD) δ 8.01 (d, J=7.80 Hz, 1 H), 7.90-7.97 (m, 2H), 7.64 (s, 1 H), 7.57 (d, J=7.46 Hz, 1 H), 7.15-7.20 (m, 2H), 7.13 (s, 1 H), 7.03-7.1 1 (m, 2H), 5.1 1 (s, 2H), 4.18 (br. s., 2H), 3.21-3.45 (m, 2H, obscured by MeOH peak), 3.05-3.17 (m, 1 H), 2.99 (t, J=5.50 Hz, 2H), 2.36-2.50 (m, 1 H), 2.31 (s, 3H), 2.06 (dd, J=4.52, 13.69 Hz, 2H), 1 .93 (d, J=5.26 Hz, 4H), 1.71 -1 .84 (m, 2H). HRMS calcd. for C34H3i F6N403 (M-H) 657.2300, found 657.2292.
1-(6-(5-Methyl-2-((2-(4-(trifluoromethyl)cyclohexyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid (single
diastereomer peak-2). 1H NMR (400 MHz, CD3OD) δ 7.91 -8.01 (m, 3H), 7.60 (d, J=1.96 Hz, 1 H), 7.58 (dd, J=1 .10, 7.58 Hz, 1 H), 7.14-7.20 (m, 2H), 7.12 (br. s, 1 H), 7.04-7.10 (m, 2H), 5.12 (s, 2H), 4.25 (s, 2H), 3.34-3.43 (m, 2H), 3.20 (t, J=1 1 .80 Hz, 1 H), 3.01 (t, J=6.1 1 Hz, 2H), 2.31 (s, 3H), 2.18- 2.27 (m, 3H), 2.09-2.17 (m, 2H), 1.58-1 .70 (m, 2H), 1.43-1.55 (m, 2H). HRMS calcd. for
C34H33F6N403 (M+H) 659.2457, found 659.2482.
Additional sGC compounds which are suitable for use in the formulations and methods for the treatment of glaucoma and/or ocular hypertension are tabulated infra. The compounds may be prepared in accordance with the reference synthethesis which is incorporated herein by reference.
Figure imgf000106_0002
Figure imgf000107_0001
(M+H) 605.1987, found 605.1943.
Figure imgf000108_0001
595.1724, found 595.1729.
Figure imgf000109_0001
Figure imgf000110_0001
Hz, 1 H), 7.13-7.21 (m, 3H), 7.07 (d, J=8.44
Hz, 1 H), 7.03 (d, J=8.07 Hz, 1 H), 5.1 1 (s,
2H), 4.14 (s, 2H), 3.94 (s, 2H), 3.04-3.09
(m, 2H), 2.92-2.98 (m, 2H), 2.32 (s, 3H).
HRMS calcd. for C32H28F3N603 (M+H)
601 .2175, found 601 .2190.
Comparative Example 1 : methyl (4,6-diamino-2-(1-(2-fluorobenzyl)-1 H-pyrazolo[3,4-i)]pyridin-3- yl)pyrimidin-5-yl)(methyl)carbamate
Figure imgf000111_0001
A methyl (4,6-diamino-2-(1-(2-fluorobenzyl)-1 /-/-pyrazolo[3,4-b]pyridin-3-yl)pyrimidin-5- yl)(methyl)carbamate was synthesized by the procedure described in WO 03/095451 Beispiel 8. 1H NMR (400 MHz, CD3OD) δ 7.99 (d, J=8.31 Hz, 2H), 7.43 (d, J=8.31 Hz, 2H), 7.31 (d, J=8.07 Hz, 2H), 7.10-7.26 (m, 9H), 7.05 (d, J=7.70 Hz, 1 H), 6.91 (dt, J=0.92, 7.43 Hz, 1 H), 5.02 (s, 2H), 4.15 (s, 2H), 3.05-3.12 (m, 2H), 2.91 -3.02 (m, 4H), 2.81 -2.91 (m, 4H), 2.20 (t, J=6.97 Hz, 2H), 1.57-1 .67 (m, 2H), 1 .44-1.55 (m, 2H). HRMS; calcd. for C36H4oN05 566.2906, found 566.2910.
CHO cell-based assay
Chinese hamster ovary (CHO) cells overexpressing soluble guanylate cyclase were generated to test the effect of sGC activators in a cellular context. Human cDNAs for GUCYA3 (RefSeq: NM_000856.3) and GUCYB3 (RefSeq: NM_000857.1 ) were amplified by PCR from a HUVEC (Human Umbilical Vein Endothelial Cells) cDNA library and cloned into mammalian expression vectors. CHO K1 cells (ATCC CCL-61 ) were transfected using Lipofectamine 2000 following manufacturer's instructions and stably expressing clones were identified by antibiotic selection. CHO GUCY clone 8E10 was used for subsequent experiments.
Cells were seeded at a density of 3000 cells/well in white 384-well proxyplates (Perkin Elmer) and incubated overnight, then the medium was removed and cells were washed with assay buffer (HBSS, 0.1 % BSA, 1 mM IBMX, 20uM ODQ). sGC activators were serially diluted in DMSO, then diluted in assay buffer prior to adding to cells (10ul/well, final DMSO concentration 0.5%). Cells were incubated with compounds for 1 h room temperature, then assayed for cGMP production using Cisbio cGMP HTRF kit (62GM2PEC) according to manufacturer's instructions. The EC50s are calculated based on the amount of cGMP interpolated from the standard curve, using a 4-parameter sigmoidal dose-response.
GTM-3 cell-based assay
GTM-3 cells (SV40-transformed human glaucomatous trabecular meshwork cells, Alcon Laboratories), were used for additional profiling of selected sGC activators. Cells were plated in 96- well plates at a density of 50,000 cells/well and incubated overnight. Medium was removed and cells were incubated with assay buffer (DMEM, 1 mM IBMX, 0.1 % BSA, 20uM ODQ) for 15 min, then sGC activators serially diluted in DMSO were added (final DMSO concentration 0.1 %). Cells were incubated 30 min at 37°C, then cGMP was quantitated using CatchPoint Cyclic-GMP
Fluorescent Assay Kit (Molecular Devices) following manufacturer's instructions.
The EC50s are calculated based on the amount of cGMP interpolated from the standard curve, using a 4-parameter sigmoidal dose-response.
CHO cell-based assay results
Figure imgf000112_0001
Figure imgf000112_0002
GTM-3 cell-based assay results
Figure imgf000113_0001
The listed compounds were tested in the CHO and/or GTM-3 cell-based assays. The average EC50 calculated from 2-4 independent experiments is shown, along with the maximal concentration of cGMP generated by each compound.
Determination of Intraocular Pressure (lOP) in Lasered (Hypertensive) Eyes of Cynomolgus Monkeys
Conscious intraocular pressure (lOP) was determined with an Alcon Pneumatonometer (Alcon Laboratories, Inc., Fort Worth, TX.) after light corneal anesthesia with 0.25% proparacaine. Right eyes were hypertensive as a result of laser trabeculoplasty. Left eyes were intact and with normal lOP. After a baseline lOP measurement, the animals were randomly divided into two groups with similar group mean of lOP. Compounds in Formula 1 vehicle were administered topical ocular of both eyes in 8-9 conscious ocular hypertensive Cynomolgus monkeys. The Formula 1 vehicle used in the current studies include hydroxypropyl methylcellulose (0.5%), anhydrous dibasic sodium phosphate (0.2-0.5%), sodium chloride (0.5-0.75%), disodium EDTA (Edetate disodium) (0.01 %), polysorbate 80, (0.05%), benzalkonium chloride (0.01 %), sodium hydroxide/hydrochloric acid (for adjusting pH to 7.3-7.4), and purified water (q.s. to 100%), Vehicle was instilled in both eyes of 8-9 additional animals as control. Subsequent lOP measurements were typically taken at 1 , 3, 6, and 24 hours post-dose. The percent change in lOP from baseline was determined for each animal for every IOP measurement. Group mean and standard error of the mean (SEM) were calculated. Statistical significance of IOP change from baseline and also versus treatment groups were determined by repeated measures ANOVA and Bonferroni t-test at p<0.05.
The compounds listed below were formulated and dosed either as a once-daily (QD) topical ocular administration or twice daily administration (BID) in laser-induced ocular hypertensive cynomolgus monkeys along with a separate group of monkeys treated with vehicle formulation (n = 8-9 monkeys per group). * Denotes statistical significance of average percent IOP reduction from baseline (pre-dose) IOP and versus vehicle dosed group. All IOP data herein are for ocular hypertensive eyes. The percent change in IOP from baseline was determined for each animal for every IOP measurement.
MIOP reduction (300ug QD)
Figure imgf000114_0001
* indicates p < 0.05 for the measurement at the indicated timepoint. Stimulator
Figure imgf000115_0001
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Claims

An ophthalmic pharmaceutical composition useful in the treatment of glaucoma and control of intraocular pressure comprising: an effective amount of a soluble guanylate cyclase activator.
The composition of claim 1 , wherein the sGC activator is selected from compounds of Formula VIII or IX:
Figure imgf000116_0001
VIII IX
Or a pharmaceutically acceptable salt thereof, wherein
A is a bond or CH20;
R is C02H or C(0)-C C4alkoxy;
R1 is halogen, C1-C4alkyl, or trifluoromethyl;
R2 is cyclohexyl substituted with R4, piperidinyl or piperazinyl each of which is substituted with R5 or phenyl substituted with R6;
R3 is hydrogen; or
R2 and R3, taken in combination, form a saturated 6 member azacycle substituted with CrC4alkyl, halo CrC4alkyl, tetrahydropyranyl, tetrahydrofuranyl, benzyl, C(O) d- C4alkyl, C(O) C3-C5cycloalkyl, CH2-heteroaryl, which heteroaryl has 5 or 6 ring atoms, 1 or 2 ring heteroatoms independently selected from N, O and S and is optionally substituted by CrC4alkyl;
R4 is C C4alkyl or haloC C4alkyl;
R5 is C C4alkyl, haloC C4alkyl, C(0)C C4alkyl, C(0)C3-C6cycloalkyl, C(0)2CrC4alkyl, C(0)2C3-C6cycloalkyl;
R6 is CrC4alkyl, haloCrC4alkyl, CrC4alkoxy or haloCrC4alkoxy;
R7 is CrC4alkyl or haloCrC4alkyl; and
R8 is hydrogen or C1-C4alkyl.
3. The composition of claim 1 , wherein the sGC activator is selected from the group consisting of:
1 -{6-[5-chloro-2-({4-[frans-4-(trifluoromethyl)cyclohexyl]benzyl}oxy)phenyl]pyridine-2-yl}- 5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;
1 -(6-(2-((4-(1 -(methoxycarbonyl)piperidin-4-yl)benzyl)oxy)-3- (trifluoromethyl)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 /-/-pyrazole-4-carboxylic acid;
1 -(6-(2-((3-methyl-4'-(trifluoromethoxy)-[1 , 1 '-biphenyl]-4-yl)methoxy)phenyl)pyridin-2-yl)- 5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;
1 -(6-(5-methyl-2-((2-((4-methylthiazol-2-yl)methyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid; and
1 -(6-(5-methyl-2-((2-(pyridin-2-ylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid and pharmaceutically acceptable salts thereof.
4. The composition of any one of claims 1 to 3 comprising a pharmaceutically acceptable salt of said selective modulator.
5. The composition of any one of claims 1 to 4 further comprising a compound selected from the group consisting of: ophthalmologically acceptable preservatives, surfactants, viscosity enhancers, penetration enhancers, gelling agents, hydrophobic bases, vehicles, buffers, sodium chloride, and water.
6. The composition of any one of claims 1 to 5 further comprising a glaucoma treatment agent.
7. The composition of claim 5 wherein said glaucoma treatment agent is selected from the group consisting of: .beta. -blockers, prostaglandin analogs, carbonic anhydrase inhibitors, a2 agonists, miotics, and neuroprotectants.
8. The composition of any one of claims 1 to 7 wherein said composition comprises from about 0.01 percent weight/volume to about 5 percent weight/volume of said compound.
9. The composition of any one of claims 1 to 8 wherein said composition comprises from about 0.25 percent weight/volume to about 2 percent weight/volume of said compound.
10. The composition of any one of claims 1 to 9, wherein said composition further comprises a preservative, tonicity agent, antioxidant, stabilizer, wetting agent, clarifying agent or a viscosity-increasing agent.
1 1 . A method of treating glaucoma and controlling intraocular pressure comprising: applying a therapeutically effective amount of a pharmaceutical composition comprising a soluble guanylate cyclase activator to an affected eye of a patient.
12. The method of claim 1 1 , wherein the pharmaceutical composition comprises asoluble guanylate cyclase activator selected from compounds of Formula (VI) or (VI I):
Figure imgf000118_0001
VI VII
Wherein
A is a bond or CH20;
R is C02H or C(0)-C C4alkoxy;
R1 is halogen, Ci-C4alkyl, or trifluoromethyl;
R2 is cyclohexyl substituted with R4, piperidinyl or piperazinyl each of which is substituted with R5 or phenyl substituted with R6;
R3 is hydrogen; or
R2 and R3, taken in combination, form a saturated 6 member azacycle substituted with Ci-C4alkyl, halo Ci-C4alkyl, tetrahydropyranyl, tetrahydrofuranyl, benzyl, C(O) d- C4alkyl, C(O) C3-C5cycloalkyl, CH2-heteroaryl, which heteroaryl has 5 or 6 ring atoms, 1 or 2 ring heteroatoms independently selected from N, O and S and is optionally substituted by Ci-C4alkyl;
R4 is Ci-C4alkyl or haloC C4alkyl;
R5 is Ci-C4alkyl, haloC C4alkyl, C(0)C C4alkyl, C(0)C3-C6cycloalkyl, C(0)2C C4alkyl, C(0)2C3-C6cycloalkyl;
R6 is CrC4alkyl, haloCrC4alkyl, Ci-C4alkoxy or haloCrC4alkoxy;
R7 is CrC4alkyl or haloCrC4alkyl; and
R8 is hydrogen or Ci-C4alkyl.
13. The method of claim 1 1 or claim 12, wherein the pharmaceutical composition comprises a soluble guanylate cyclase activator selected from the group consisting of 1 -{6-[5-chloro-2-({4-[frans-4-(triflu^
5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;
1 -(6-(2-((4-(1 -(methoxycarbonyl)piperidin-4-yl)benzyl)oxy)-3- (trifluoromethyl)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;
1 -(6-(2-((3-methyl-4'-(trifluoromethoxy)-[1 , 1 '-biphenyl]-4-yl)methoxy)phenyl)pyridin-2-yl)- 5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;
1 -(6-(5-methyl-2-((2-((4-methylthiazol-2-yl)methyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid; and
1 -(6-(5-methyl-2-((2-(pyridin-2-ylmethyl)-1 ,2,3,4-tetrahydroisoquinolin-6- yl)methoxy)phenyl)pyridin-2-yl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid and pharmaceutically acceptable salts thereof.
14. The method of claim 12 wherein said applying comprises: applying a composition of claim 1.
15. The method of claim 14 wherein said applying comprises applying using a technique selected from the group consisting of: periocular injection, sub-conjunctival injection, sub-tenon injection, intracameral injection, intravitreal injection, intracanalicular injection, implanting delivery device in the cul-de-sac, implanting delivery device adjacent to the sclera, implanting delivery device within the eye, oral administration, intravenous administration, subcutaneous administration, intramuscular administration, parenteral administration, dermal administration, and nasal administration.
16. The method of any one of claims 12 to 15, wherein method further comprises
administering to the affected eye of the patient a glaucoma treatment agent selected from the group consisting of: .beta. -blockers, prostaglandin analogs, carbonic anhydrase inhibitors, a2 agonists, miotics, and neuroprotectants.
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WO2016014463A1 (en) 2014-07-22 2016-01-28 Boehringer Ingelheim International Gmbh Heterocyclic carboxylic acids as activators of soluble guanylate cyclase
WO2017103888A1 (en) * 2015-12-18 2017-06-22 Novartis Ag Indane derivatives and the use thereof as soluble guanylate cyclase activators
WO2018016611A1 (en) 2016-07-22 2018-01-25 トーアエイヨー株式会社 Therapeutic agent for glaucoma
US10208018B2 (en) 2014-07-02 2019-02-19 Novartis Ag Indane and indoline derivatives and the use thereof as soluble guanylate cyclase activators
WO2020245342A1 (en) * 2019-06-07 2020-12-10 Bayer Aktiengesellschaft The use of sgc activators for the treatment of ophthalmologic diseases
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WO2022122917A1 (en) * 2020-12-10 2022-06-16 Bayer Aktiengesellschaft The use of sgc activators for the treatment of ophthalmologic diseases
WO2022122914A1 (en) * 2020-12-10 2022-06-16 Bayer Aktiengesellschaft Substituted pyrazolo piperidine carboxylic acids
CN114981257A (en) * 2020-12-10 2022-08-30 拜耳公司 Substituted pyrazolopiperidinecarboxylic acids
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JP2023543646A (en) * 2020-12-10 2023-10-18 バイエル・アクチエンゲゼルシヤフト Substituted pyrazolopiperidine carboxylic acids
JP7451700B2 (en) 2020-12-10 2024-03-18 バイエル・アクチエンゲゼルシヤフト Substituted pyrazolopiperidine carboxylic acids
JP7458683B2 (en) 2020-12-10 2024-04-01 バイエル・アクチエンゲゼルシヤフト Use of sGC activators for the treatment of ophthalmological diseases

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